Leg length, sitting height, and body proportions references for achondroplasia: New tools for monitoring growth

Achondroplasia is the most common form of inherited disproportionate short stature. We report leg length, sitting height, and body proportion curves for achondroplasia. Seven centile format of sitting height, leg length, sitting height/leg length ratio, sitting height/height ratio, and head circumference/height ratio were estimated by the LMS method. The Q-test was applied to assess the goodness of fit. For comparison, centiles of sitting height and leg length were graphed using Argentine national growth references for achondroplasia and non-achondroplasia populations. The sample consisted of 342 children with achondroplasia (171 males, 171 females) aged 0–18 years. The median (interquartile range) number of measurements per child was 6 (3, 12) for sitting height and 8 (3, 13) for head circumference. Median leg length increased from 14 cm at age 1 week to 44 and 40 cm (males and females, respectively) in achondroplasia adolescents which is 3.5 cm shorter than non-achondroplasia children at age 1 week and, 38 cm shorter at adolescence. Median sitting height increased from 34 cm at birth to 86 and 81 in adolescents' boys and girls respectively, only 5 cm shorter than non-achondroplasia children. Sitting height/leg length decreased from 2.61 at birth to approximately 1.90 at adolescent. Median head circumference/height ratio decreased from 0.79 at birth to 0.46 at 18 years in both sexes. Growth of lower limbs is affected early in life and becomes more noticeable throughout childhood. The disharmonic growth between the less affected trunk and the severely affected limbs determine body disproportion in achondroplasia.

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The art and science of choosing efficacy endpoints for rare disease clinical trials

An important challenge in rare disease clinical trials is to demonstrate a clinically meaningful and statistically significant response to treatment. Selecting the most appropriate and sensitive efficacy endpoints for a treatment trial is part art and part science. The types of endpoints should align with the stage of development (e.g., proof of concept vs. confirmation of clinical efficacy). The patient characteristics and disease stage should reflect the treatment goal of improving disease manifestations or preventing disease progression. For rare diseases, regulatory approval requires demonstration of clinical benefit, defined as how a patient, feels, functions, or survives, in at least one adequate and well-controlled pivotal study conducted according to Good Clinical Practice. In some cases, full regulatory approval can occur using a validated surrogate biomarker, while accelerated, or provisional, approval can occur using a biomarker that is likely to predict clinical benefit. Rare disease studies are small by necessity and require the use of endpoints with large effect sizes to demonstrate statistical significance. Understanding the quantitative factors that determine effect size and its impact on powering the study with an adequate sample size is key to the successful choice of endpoints. Interpreting the clinical meaningfulness of an observed change in an efficacy endpoint can be justified by statistical methods, regulatory precedence, and clinical context. Heterogeneous diseases that affect multiple organ systems may be better accommodated by endpoints that assess mean change across multiple endpoints within the same patient rather than mean change in an individual endpoint across all patients.

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Two de novo novel mutations in one SHANK3 allele in a patient with autism and moderate intellectual disability

SHANK3 encodes for a scaffolding protein that links neurotransmitter receptors to the cytoskeleton and is enriched in postsynaptic densities of excitatory synapses. Deletions or mutations in one copy of the SHANK3 gene cause Phelan-McDermid syndrome, also called 22q13.3 deletion syndrome, a neurodevelopmental disorder with common features including global developmental delay, absent to severely impaired language, autistic behavior, and minor dysmorphic features. By whole exome sequencing, we identified two de novo novel variants including one frameshift pathogenic variant and one missense variant of unknown significance in a 14-year-old boy with delayed motor milestones, delayed language acquisition, autism, intellectual disability, ataxia, progressively worsening spasticity of the lower extremities, dysmorphic features, short stature, microcephaly, failure to thrive, chronic constipation, intrauterine growth restriction, and bilateral inguinal hernias. Both changes are within the CpG island in exon 21, separated by a 375 bp sequence. Next generation sequencing of PCR products revealed that the two variants are most frequently associated with each other. Sanger sequencing of the cloned PCR products further confirmed that both changes were on a single allele. The clinical presentation in this individual is consistent with other patients with a truncating mutation in exon 21, suggesting that the missense change contributes none or minimally to the phenotypes. This is the first report of two de novo mutations in one SHANK3 allele.

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International investigation of neurocognitive and behavioral phenotype in 47,XXY (Klinefelter syndrome): Predicting individual differences

47,XXY (KS) occurs in 1:650 male births, though less than 25% are ever identified. We assessed stability of neurocognitive features across diverse populations and quantified factors mediating outcome. Forty-four boys from the Netherlands (NL) and 54 boys from the United States (US) participated. The Wechsler Intelligence Scales assessed intellectual functioning; the ANT program evaluated cognitive function; and the CBCL assessed behavioral functioning. ANOVA was used for group comparisons. Hierarchical regressions assessed variance explained by each independent variable: parental education, timing of diagnosis, testosterone, age, and nationality. Parental education, timing of diagnosis, and hormonal treatment all played an important role in neurocognitive performance. The observed higher IQ and better attention regulation in the US group as compared to the NL group was observed with decreased levels of behavioral problems in the US group. Cognitive measures that were different between the NL and US groups, i.e., attention regulation and IQ scores, were also significantly influenced by external factors including timing of diagnosis, testosterone treatment, and parental education. On the ANT, a cognitive phenotype of 47,XXY was observed, with similar scores on 9 out of the 10 ANT subtests for the NL and US groups. This study lays additional features to the foundation for an algorithm linking external variables to outcome on various neurodevelopmental measures.

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Electrophysiological evidence of low salience distractor interference during visual search

Abstract

Visual search displays often include distractors of lesser salience in addition to a target and one or more salient distractors. We investigated low salience distractor effects on the N2pc, an ERP component indexing the deployment of attention, and the Ptc, a component purported to reflect attentional disengagement. We hypothesized that salient distractors pull the attentional focus away from the target, which could lead to increased attentional processing of low salience distractors close to the target and salient distractor. Participants looked for a colored inverted T during a visual search task while ignoring an L of the same color at a fixed distance on an imaginary circle around fixation. There were four conditions: no additional gray (low salience) distractors, two additional gray distractors between color items, two additional gray distractors just outside the area delimited by the colored items, and four additional gray distractors inside and outside the attended region. The gray distractors impacted N2pc and Ptc amplitude and latency, indicating an effect of gray distractors on attentional processing. Also, additional gray distractors led to increasingly more deviation of the N2pc and Ptc waveforms from the baseline offered by the condition with no additional gray distractors. When we increased the difficulty to individuate the target, we observed more displacement of lateralized activity from the N2pc to the Ptc time window. We argue that distractor-related modulations likely result from increased variance in the latency of attentional engagement activity to the target instead of distractor inhibition or attentional disengagement.

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Combined assessment of attentional reserve and cognitive-motor effort under various levels of challenge with a dry EEG system

Abstract

A novel ERP approach was proposed to index variations in mental workload, particularly in attentional reserve, which is complementary to EEG spectral content thought to reflect mental effort. To our knowledge, no study has assessed mental effort and attentional reserve simultaneously in EEG gel-based and, importantly, dry systems, which are particularly well suited for real-world settings. Therefore, by systematically considering ERP, EEG spectral, and importantly the combination of both, this study examined if a small set of dry EEG electrodes could detect changes in both spectral and ERP metrics to assess the mental workload under various challenges with a similar fidelity to their gel-based counterparts in a laboratory setting. By employing both EEG gel-based and dry systems, the ERP and spectral markers were computed while participants executed a visuomotor task under three levels of challenge. For both EEG systems, more challenging levels of difficulty were associated with concomitant changes in ERP amplitude, and spectral power reflected a reduction of the attentional reserve and an increase in cognitive-motor effort, respectively. Those variations in attentional reserve and cognitive-motor effort collectively indexed mental workload with nearly identical fidelity for both gel-based and dry EEG systems. These findings promise to assess the mental workload in situations where the use of dry EEG systems could be advantageously employed to examine human cognitive-motor performance.

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Positive Interictal Epileptiform Discharges in Adults: a Case Series of a Rare Phenomenon

The polarity of interictal epileptiform discharges (IEDs) recorded from scalp EEG is predominantly negative relative to a suitable reference electrode and is generally interpreted as indicative of dipoles oriented perpendicularly to the cortical surface with their negative poles near the surface (Gloor, 1985). The deeper positive poles usually fail to produce a detectable surface potential but can be recorded with invasive electrodes. In some instances, horizontal dipoles such as benign epileptiform discharges of childhood can be recorded from the scalp surface showing both, the positive and the negative potential particularly with generators in the central or Sylvian fissure (Lüders et al., 1987).

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Disruption of cortical synaptic homeostasis in individuals with chronic low back pain

Chronic low back pain (cLBP) is a prevalent and disabling musculoskeletal condition with few effective treatments (Balague et al., 2012). Although precise mechanisms remain unclear, structural and functional reorganization of the sensorimotor cortex has been identified in cLBP, and is associated with pain severity, pain duration and movement dysfunction (Kregel et al., 2015; Masse-Alarie et al., 2016). Cortical reorganisation in cLBP is hypothesised to be a marker of maladaptive synaptic plasticity, and this concept provides the foundation for contemporary theories of pain persistence (Moseley and Flor, 2012).

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Ultrasound-guided Percutaneous Needle Tenotomy for Chronic Proximal Tensor Fascia Lata Tendinopathy: A Report of 2 Cases

Proximal tensor fascia lata (TFL) tendinopathy at its origin on the anterior superior iliac crest is one potential cause of lateral hip pain. However, there is limited literature regarding the mechanism, disease course or management of this condition. There is growing evidence supporting the effective treatment of percutaneous needle tenotomy (PNT) for chronic tendinopathy. Only a single case series has examined the efficacy of PNT for tendinopathy about the hip and pelvis. Presented here are examples of two cases of chronic recalcitrant proximal ultrasound confirmed TFL tendinopathy effectively treated with ultrasound-guided PNT.

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Imaging of Spondylolysis: The Evolving Role of Magnetic Resonance Imaging

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Deep sequencing of the mitochondrial genome reveals common heteroplasmic sites in NADH dehydrogenase genes

Abstract

Increasing evidence implicates mitochondrial dysfunction in aging and age-related conditions. But little is known about the molecular basis for this connection. A possible cause may be mutations in the mitochondrial DNA (mtDNA), which are often heteroplasmic—the joint presence of different alleles at a single locus in the same individual. However, the involvement of mtDNA heteroplasmy in aging and age-related conditions has not been investigated thoroughly. We deep-sequenced the complete mtDNA genomes of 356 Framingham Heart Study participants (52% women, mean age 43, mean coverage 4570-fold), identified 2880 unique mutations and comprehensively annotated them by MITOMAP and PolyPhen-2. We discovered 11 heteroplasmic "hot" spots [NADH dehydrogenase (ND) subunit 1, 4, 5 and 6 genes, n = 7; cytochrome c oxidase I (COI), n = 2; 16S rRNA, n = 1; D-loop, n = 1] for which the alternative-to-reference allele ratios significantly increased with advancing age (Bonferroni correction p < 0.001). Four of these heteroplasmic mutations in ND and COI genes were predicted to be deleterious nonsynonymous mutations which may have direct impact on ATP production. We confirmed previous findings that healthy individuals carry many low-frequency heteroplasmy mutations with potentially deleterious effects. We hypothesize that the effect of a single deleterious heteroplasmy may be minimal due to a low mutant-to-wildtype allele ratio, whereas the aggregate effects of many deleterious mutations may cause changes in mitochondrial function and contribute to age-related diseases. The identification of age-related mtDNA mutations is an important step to understand the genetic architecture of age-related diseases and may uncover novel therapeutic targets for such diseases.

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Pathway-induced allelic spectra of diseases in the presence of strong genetic effects

Abstract

Complex diseases are frequently modeled as following an additive model that excludes both intra- and inter-locus interaction, while at the same time reports on non-additive biological structures are ample, prominently featuring numerous metabolic and signaling pathways. Using extensive forward population simulations, we explored the impact of three basic pathway motifs on the relationship between epidemiological parameters, including disease prevalence, relative risk, sibling recurrence risk as well as causal variant number and allele frequency. We found that some but not all pathway motifs can shift the relationships between these parameters in comparison to the classical additive liability threshold model. The strongest deviations were observed with linear, cascade-like motifs that form an integral part of many reported pathways. We also modeled maturity-onset diabetes of the young (MODY) as a combination of different basic pathway motifs and observed a good concordance in epidemiological parameter values between our simulated data under this model and those reported in the literature. Given the widespread nature of pathways, including those in the etiology of human diseases, our results re-emphasize the need for non-additive interaction modeling of genetic variants to become an additional standard approach in analyzing human genetic data.

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Validity of self-reported tooth counts and masticatory status study of a Japanese adult population

Abstract

Self-reported measures of oral health are often used to assess oral health in populations or groups, but their validity or reliability needs repeated confirmation. The objective of this cross-sectional study was to evaluate the validity of self-reported tooth counts and masticatory status, using data obtained from a sample of Japanese adults. A total of 2,356 adults aged 40 to 75 years participated in a questionnaire survey and a clinical oral examination from 2013 through 2016. Self-reported measures were compared with clinically measured values. For tooth counts, mean clinical and self-reported tooth counts in all participansts were 23.68 and 23.78 teeth, and no significant difference was detected. Spearman's, Pearson's and intra-class correlation coefficients between clinical and self-reported tooth counts were 0.771, 0.845 and 0.843, respectively. According to the Bland-Altman analysis, the mean difference between clinical and self-reported tooth counts was -0.098 (95% CI: -0.242, 0.047). The upper limit of agreement was 6.919 (95% CI: 6.669, 7.169) and lower limit of agreement was -7.115 (95% CI: -7.365, -6.865). No significant fixed or proportional bias was observed. For masticatory status, the crude or age and gender adjusted mean numbers of total teeth, posterior teeth and three kinds of functional tooth units significantly decreased with the deterioration of masticatory status. The current study indicated that self-reports were within an acceptable range of clinical measures. Therefore, self-reports were considered valid alternatives to clinical measures to estimate tooth counts and masticatory status in a current Japanese adult population.

This article is protected by copyright. All rights reserved.

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Analysis of the reliability of the Italian Version of the Oral Behaviors Checklist and the relationship between oral behaviors and trait anxiety in healthy individuals

Abstract

Background

The Oral Behaviors checklist (OBC) is a valid 21-item instrument quantifying the self-reported frequency of oral behaviors. An Italian version (OBC-It) has been released recently.

Anxiety and oral behaviors are known to be associated in individuals with orofacial pain due to temporomandibular disorders (TMD). However, information about this relationship in pain-free individuals is still limited.

Objectives

The aim of this study was to test the reliability of the OBC-It and its reduced version (OBC-It 6), focusing on tooth clenching related wake time oral behaviors, and the effect of patient instructions on reliability. A second aim was to test the association between trait anxiety and oral behaviors in pain-free individuals.

Methods

282 TMD-free students, divided in two groups (Group A, n=139, mean age±SD = 22.6±5.4 years; group B, n=143, 23.7±4.2 years), filled in the State-Trait-Anxiety Inventory and the OBC-It. Group B received instructions about the OBC-It, while Group A did not. After two weeks (T1), both groups filled in the OBC-It again. However, group B was further divided in two subgroups, B₁ and B_2. The first received the same instructions again, while B₂ did not.

Results

The test-retest reliability of the OBC-It (A: ICC=.87, B1: ICC=.94; B2: ICC=.95) and OBC-It 6 (A: ICC=.85, B₁: ICC=.89, B₂: ICC=.93) was excellent in all groups. Trait anxiety was weakly associated with OBC-It only in females (R²=.043, P=.021).

Conclusions

The OBC-It is a reliable tool but further subjects' instructions may be needed. Trait anxiety has a limited effect on oral behaviors in TMD-free subjects.

This article is protected by copyright. All rights reserved.

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Energy expenditure of rugby players during a 14-day in-season period, measured using doubly labelled water

Abstract

Criterion data for total energy expenditure (TEE) in elite rugby are lacking, which prediction equations may not reflect accurately. This study quantified TEE of 27 elite male rugby league (RL) and rugby union (RU) players (U16, U20, U24 age groups) during a 14-day in-season period using doubly labelled water (DLW). Measured TEE was also compared to estimated, using prediction equations. Resting metabolic rate (RMR) was measured using indirect calorimetry, and physical activity level (PAL) estimated (TEE:RMR). Differences in measured TEE were unclear by code and age (RL 4369 ± 979; RU 4365 ± 1122; U16, 4010 ± 744; U20, 4414 ± 688; U24, 4761 ± 1523 Kcal day^− 1). Differences in PAL (overall mean 2.0 ± 0.4) were unclear. Very likely differences were observed in RMR by code (RL 2366 ± 296; RU 2123 ± 269 Kcal day^− 1). Differences in relative RMR between U20 and U24 were very likely (U16, 27 ± 4; U20, 23 ± 3; U24, 26 ± 5 Kcal kg^− 1 day^− 1). Differences were observed between measured and estimated TEE, using Schofield, Cunningham and Harris–Benedict equations for U16 (187 ± 614, unclear; − 489 ± 564, likely and − 90 ± 579, unclear Kcal day^− 1), U20 (− 449 ± 698, likely; − 785 ± 650, very likely and − 452 ± 684, likely Kcal day^− 1) and U24 players (− 428 ± 1292; − 605 ± 1493 and − 461 ± 1314 Kcal day^− 1, all unclear). Rugby players have high TEE, which should be acknowledged. Large inter-player variability in TEE was observed demonstrating heterogeneity within groups, thus published equations may not appropriately estimate TEE.

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Relationship between power–duration parameters and mechanical and anthropometric properties of the thigh in elite cyclists

Abstract

Purpose

The curvature constant (W′) and asymptote (critical power; CP) of the power–duration relationship are important parameters for explaining cycling performance. Short-duration endurance cycling events rely more heavily on the W′; however, the full mechanistic underpinning of this parameter is yet to be determined. Evidence suggests both muscle volume and muscle strength may contribute to the magnitude of W′. Therefore, the present study investigated the relationship between power–duration parameters (CP and W′) and (1) anthropometric and (2) mechanical properties of thigh muscles in a sample of elite cyclists.

Methods

Eleven elite male cyclists had gross thigh volume (T_VOL), quadriceps muscle volume (Q_VOL), vastus lateralis (VL) muscle pennation angle (PA) and VL muscle thickness (MT) measured. Additionally, maximum torque production of the knee extensors (F_MAX) was assessed. The relationship between these anthropometric and mechanical measures and both the CP and W′ were determined.

Results

W′ showed a very strong positive and significant relationship with F_MAX (r = 0.87, p < 0.001) and a large positive and significant relationship with T_VOL (r = 0.60, p =  0.05). No other anthropometric characteristics were related to the W′. The CP was not associated with any mechanical or anthropometric parameter.

Conclusion

In addition to muscle size, the maximal evocable force of a muscle (group) appears to be linked to the magnitude of the W′ in elite cyclists.

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Validity of the Polar V800 monitor for measuring heart rate variability in mountain running route conditions

Abstract

Purpose

This study was conducted to test, in mountain running route conditions, the accuracy of the Polar V800™ monitor as a suitable device for monitoring the heart rate variability (HRV) of runners.

Method

Eighteen healthy subjects ran a route that included a range of running slopes such as those encountered in trail and ultra-trail races. The comparative study of a V800 and a Holter SEER 12 ECG Recorder™ included the analysis of RR time series and short-term HRV analysis. A correction algorithm was designed to obtain the corrected Polar RR intervals. Six 5-min segments related to different running slopes were considered for each subject.

Results

The correlation between corrected V800 RR intervals and Holter RR intervals was very high (r = 0.99, p < 0.001), and the bias was less than 1 ms. The limits of agreement (LoA) obtained for SDNN and RMSSD were (− 0.25 to 0.32 ms) and (− 0.90 to 1.08 ms), respectively. The effect size (ES) obtained in the time domain HRV parameters was considered small (ES < 0.2). Frequency domain HRV parameters did not differ (p > 0.05) and were well correlated (r ≥ 0.96, p < 0.001).

Conclusion

Narrow limits of agreement, high correlations and small effect size suggest that the Polar V800 is a valid tool for the analysis of heart rate variability in athletes while running high endurance events such as marathon, trail, and ultra-trail races.

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Evaluation of the convergent validity of an estimated cardiorespiratory fitness algorithm

Abstract

Purpose

Examine the convergent validity of a cardiorespiratory fitness (CRF) algorithm when compared to treadmill-assessed CRF.

Methods

Data from the 1999–2004 NHANES were used (N = 3259 adults 20–49 years). Cardiorespiratory fitness was estimated from an algorithm. Participants completed a submaximal treadmill-based protocol. We (1) evaluated the pairwise association (and ICC) between estimated and measured cardiorespiratory fitness, (2) employed a paired samples t test to examine potential mean differences between estimated and measured cardiorespiratory fitness, (3) constructed a Bland–Altman plot and 95% limits of agreement (LoA) to explore systematic differences and random error between estimated and measured cardiorespiratory fitness, and (4) examined the association (via linear regression) of estimated and measured cardiorespiratory fitness with chronic disease prevalence and C-reactive protein (CRP).

Results

Mean estimated CRF (10.68 METs) was lower than the mean measured CRF of 11.37 METs (p < 0.0001). The calculated pairwise correlation was of a moderate strength, r = 0.43 (p < 0.0001), with an ICC of 0.40 (p < 0.001). Calculated LoA indicated that estimated CRF may differ from measured CRF by 40% below to 48% above. Regression analyses yielded statistically significant inverse associations of estimated (unstandardized coefficient = − 0.026; p < 0.001) and measured (unstandardized coefficient = − 0.007; p = 0.002) CRF with chronic disease and estimated (unstandardized coefficient = − 0.08; p < 0.001) and measured (unstandardized coefficient = − 0.03; p < 0.001) CRF with CRP.

Conclusion

Measured and estimated CRF were moderately correlated. However, estimated and measured CRF were statistically significant different from one another with noteworthy scatter around the average difference. As such, when feasible, objective measurements of CRF should be taken.

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Sodium bicarbonate supplementation improves severe-intensity intermittent exercise under moderate acute hypoxic conditions

Abstract

Acute moderate hypoxic exposure can substantially impair exercise performance, which occurs with a concurrent exacerbated rise in hydrogen cation (H⁺) production. The purpose of this study was therefore, to alleviate this acidic stress through sodium bicarbonate (NaHCO₃) supplementation and determine the corresponding effects on severe-intensity intermittent exercise performance. Eleven recreationally active individuals participated in this randomised, double-blind, crossover study performed under acute normobaric hypoxic conditions (FiO₂% = 14.5%). Pre-experimental trials involved the determination of time to attain peak bicarbonate anion concentrations ([HCO₃⁻]) following NaHCO₃ ingestion. The intermittent exercise tests involved repeated 60-s work in their severe-intensity domain and 30-s recovery at 20 W to exhaustion. Participants ingested either 0.3 g kg bm⁻¹ of NaHCO₃ or a matched placebo of 0.21 g kg bm⁻¹ of sodium chloride prior to exercise. Exercise tolerance (+ 110.9 ± 100.6 s; 95% CI 43.3–178 s; g = 1.0) and work performed in the severe-intensity domain (+ 5.8 ± 6.6 kJ; 95% CI 1.3–9.9 kJ; g = 0.8) were enhanced with NaHCO₃ supplementation. Furthermore, a larger post-exercise blood lactate concentration was reported in the experimental group (+ 4 ± 2.4 mmol l⁻¹; 95% CI 2.2–5.9; g = 1.8), while blood [HCO₃⁻] and pH remained elevated in the NaHCO₃ condition throughout experimentation. In conclusion, this study reported a positive effect of NaHCO₃ under acute moderate hypoxic conditions during intermittent exercise and therefore, may offer an ergogenic strategy to mitigate hypoxic induced declines in exercise performance.

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Effect of dietary nitrate supplementation on thermoregulatory and cardiovascular responses to submaximal cycling in the heat

Abstract

Purpose

This study investigated whether reported improvements in blood flow distribution, and the possible related effects on thermoregulation during exercise following supplementation with beetroot juice (BR), a rich source of dietary nitrate (NO₃⁻), are mitigated in the heat.

Methods

12 male endurance-trained cyclists (age 27 ± 6 years, VO_2peak 68.6 ± 8.1 ml kg⁻¹ min⁻¹) completed two 60 min submaximal cycling trials at 60% of VO_2peak power output. Trials were performed in hot environmental conditions (33.3 ± 0.4 °C, 48.8 ± 3.0% RH) following 3 days of supplementation with either NO₃⁻-rich BR (6.5 mmol NO₃⁻ for 2 days and 13 mmol NO₃⁻ on the final day) or NO₃⁻-depleted placebo (PLA). Salivary NO₃⁻ and nitrite (NO₂⁻) were measured before and after the supplementation period. During exercise, cutaneous blood flow, blood pressure (MAP), core temperature (T_c), mean skin temperature (T_sk), indices of muscle oxygenation and oxygen (O₂) consumption were measured.

Results

Salivary NO₃⁻ and NO₂⁻ increased significantly following BR by 680 and 890%, respectively. There were no significant differences observed for cutaneous blood flow, MAP, T_c, T_sk, muscle oxygenation, or O₂ consumption between BR and PLA.

Conclusion

This investigation shows that the ergogenic effects and health benefits of BR supplementation, such as augmented cutaneous blood flow, reduced MAP, increased muscle oxygenation, and improved aerobic efficiency may be attenuated when exercise is performed in hot conditions.

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Lower body blood flow restriction training may induce remote muscle strength adaptations in an active unrestricted arm

Abstract

Purpose

We examined the concurrent characteristics of the remote development of strength and cross-sectional area (CSA) of upper body skeletal muscle in response to lower body resistance training performed with an applied blood flow restriction (BFR).

Methods

Males allocated to an experimental BFR group (EXP; n = 12) or a non-BFR control group (CON; n = 12) completed 7-weeks of resistance training comprising three sets of unilateral bicep curls [50% 1-repetition maximum (1-RM)], then four sets of bilateral knee extension and flexion exercises (30% 1-RM). EXP performed leg exercises with an applied BFR (60% limb occlusion pressure). 1-RM strength was measured using bilateral leg exercises and unilateral bicep curls in both trained and untrained arms. Muscle CSA was measured via peripheral quantitative computed tomography in the dominant leg and both arms.

Results

1-RM in the trained arm increased more in EXP (2.5 ± 0.4 kg; mean ± SEM) than the contralateral untrained arm (0.8 ± 0.4 kg), and the trained arm of CON (0.6 ± 0.3 kg, P < 0.05). The increase in knee extension 1-RM was twofold that of CON (P < 0.01). Knee flexion 1-RM, leg CSA, and trained arm CSA increased similarly between groups (P > 0.05), while untrained arm CSA did not change (P > 0.05).

Conclusion

Lower limb BFR training increased trained arm strength more than the contralateral untrained arm, and the trained arm of controls. However, there was no additional effect on muscle CSA. These findings support evidence for a BFR training-derived remote strength transfer that may be relevant to populations with localised movement disorders.

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Oviposition-like central pattern generators in pregenital segments of male and female grasshoppers

Abstract

Grasshoppers produce an extraordinary oviposition behavior that is associated with multiple specializations of the skeletal and neuromuscular systems in the posterior abdomen, including a central pattern generator (CPG) in the female's terminal abdominal ganglion. Two pairs of shovel-shaped appendages, the ovipositor valves on the abdomen tip, excavate the soil for deposition of eggs. By contrast, the sexually monomorphic pregenital region of the abdomen is without appendages. Morphological homologues of ovipositor muscles and efferent neurons in the eighth abdominal segment are nevertheless present in pregenital segments of males and females. In both sexes, a robust rhythmic motor program was induced in pregenital segments by the same experimental methods used to elicit oviposition digging. The activity, recorded extracellularly, was oviposition-like in burst period (5–6 s) and homologous muscle phase relationships, and it persisted after sensory inputs were removed, indicating the presence of pregenital CPGs. The abdomen exhibited posterior-going waves of activity with an intersegmental phase delay of approximately 1 s. These results indicate that serially homologous motor systems, including functional CPGs, provided the foundation for the evolution of oviposition behavior.

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Distribution of Antimicrobial Resistance Genes and Class 1 Integron Gene Cassette Arrays in Motile Aeromonas spp. Isolated from Goldfish (Carassius auratus)

Microbial Drug Resistance , Vol. 0, No. 0.


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Selection on Expected Maximum Haploid Breeding Values Can Increase Genetic Gain in Recurrent Genomic Selection

Genomic selection (GS) offers the possibility to estimate the effects of genome-wide molecular markers, which can be used to calculate genomic estimated breeding values (GEBVs) for individuals without phenotypes. GEBVs can serve as a selection criterion in recurrent GS, maximizing single-cycle but not necessarily long-term genetic gain. As simple genome-wide sums, GEBVs do not take into account other genomic information, such as the map positions of loci and linkage phases of alleles. Therefore, we herein propose a novel selection criterion called expected maximum haploid breeding value (EMBV). EMBV predicts the expected performance of the best among a limited number of gametes that a candidate contributes to the next generation, if selected. We used simulations to examine the performance of EMBV in comparison with GEBV as well as the recently proposed criterion optimal haploid value (OHV) and weighted GS. We considered different population sizes, numbers of selected candidates, chromosome numbers and levels of dominant gene action. Criterion EMBV outperformed GEBV after about 5 selection cycles, achieved higher long-term genetic gain and maintained higher diversity in the population. The other selection criteria showed the potential to surpass both GEBV and EMBV in advanced cycles of the breeding program, but yielded substantially lower genetic gain in early to intermediate cycles, which makes them unattractive for practical breeding. Moreover, they were largely inferior in scenarios with dominant gene action. Overall, EMBV shows high potential to be a promising alternative selection criterion to GEBV for recurrent genomic selection.

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A Survey of Virus Recombination Uncovers Canonical Features of Artificial Chimeras Generated During Deep Sequencing Library Preparation

Chimeric reads can be generated by in vitro recombination during the preparation of high-throughput sequencing libraries. Our attempt to detect biological recombination between the genomes of dengue virus (DENV; +ssRNA genome) and its mosquito host using the Illumina Nextera sequencing library preparation kit revealed that most, if not all, detected host-virus chimeras were artificial. Indeed, these chimeras were not more frequent than with control RNA from another species (a pillbug), which was never in contact with DENV RNA prior to the library preparation. The proportion of chimera types merely reflected those of the three species among sequencing reads. Chimeras were frequently characterized by the presence of 1-20 bp microhomology between recombining fragments. Within-species chimeras mostly involved fragments in opposite orientations and located less than 100 bp from each other in the parental genome. We found similar features in published datasets using two other viruses: Ebola virus (EBOV; -ssRNA genome) and a herpesvirus (dsDNA genome), both produced with the Illumina Nextera protocol. These canonical features suggest that artificial chimeras are generated by intra-molecular template switching of the DNA polymerase during the PCR step of the Nextera protocol. Finally, a published Illumina dataset using the Flock House virus (FHV; +ssRNA genome) generated with a protocol preventing artificial recombination revealed the presence of 1-10 bp microhomology motifs in FHV-FHV chimeras, but very few recombining fragments were in opposite orientations. Our analysis uncovered sequence features characterizing recombination breakpoints in short-read sequencing datasets, which can be helpful to evaluate the presence and extent of artificial recombination.

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Identification of Two Distinct Classes of the Human INO80 Complex Genome-Wide

Chromatin remodeling and histone modifying enzymes play a critical role in shaping the regulatory output of a cell. Although much is known about these classes of proteins, identifying the mechanisms by which they coordinate gene expression programs remains an exciting topic of investigation. One factor that may contribute to the targeting and activity of chromatin regulators is local chromatin landscape. We leveraged genomic approaches and publically-available datasets to characterize the chromatin landscape at targets of the human INO80 chromatin remodeling complex (INO80-C). Our data revealed two classes of INO80-C targets with distinct chromatin signatures. The predominant INO80-C class was enriched for open chromatin, H3K27ac, and representative subunits from each of the three INO80-C modules (RUVBL1, RUVBL2, MCRS1, YY1). We named this class Canonical INO80. Notably, we identified an unexpected class of INO80-C targets that contained only the INO80 ATPase and harbored a repressive chromatin signature characterized by inaccessible chromatin, H3K27me3, and the methyltransferase EZH2. We named this class Non-Canonical INO80 (NC-INO80). Biochemical approaches indicated that INO80-C and the H3K27 acetyltransferase P300 physically interact, suggesting INO80-C and P300 may jointly coordinate chromatin accessibility at Canonical INO80 sites. No interaction was detected between INO80-C and EZH2, indicating INO80-C and EZH2 may engage in a separate form of regulatory crosstalk at NC-INO80 targets. Our data indicate that INO80-C is more compositionally heterogenous at its genomic targets than anticipated. Moreover, our data suggest there is an important link between INO80-C and histone modifying enzymes that may have consequences in developmental and pathological contexts.

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N-terminal Sumoylation of Centromeric Histone H3 Variant Cse4 Regulates Its Proteolysis To Prevent Mislocalization to Non-centromeric Chromatin

Stringent regulation of cellular levels of evolutionarily conserved centromeric histone H3 variant (CENP-A in humans, CID in flies, Cse4 in yeast) prevents its mislocalization to non-centromeric chromatin. Overexpression and mislocalization of CENP-A has been observed in cancers and leads to aneuploidy in yeast, flies, and human cells. Ubiquitin-mediated proteolysis of Cse4 by E3 ligases such as Psh1 and Sumo-Targeted Ubiquitin Ligase (STUbL) Slx5 prevent mislocalization of Cse4. Previously, we identified Siz1 and Siz2 as the major E3 ligases for sumoylation of Cse4. In this study, we have identified lysine 65 (K65) in Cse4 as a site that regulates sumoylation and ubiquitin-mediated proteolysis of Cse4 by Slx5. Strains expressing cse4 K65R exhibit reduced levels of sumoylated and ubiquitinated Cse4 in vivo. Furthermore, co-immunoprecipitation experiments reveal reduced interaction of cse4 K65R with Slx5, leading to increased stability and mislocalization of cse4 K65R under normal physiological conditions. Based on the increased stability of cse4 K65R in psh1 strains but not in slx5 strains, we conclude that Slx5 targets sumoylated Cse4 K65 for ubiquitination-mediated proteolysis independent of Psh1. In summary, we have identified and characterized the physiological role of Cse4 K65 in sumoylation, ubiquitin-mediated proteolysis, and localization of Cse4 for genome stability.

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Genome-Wide Association and Genomic Selection for Resistance to Amoebic Gill Disease in Atlantic Salmon

Amoebic gill disease (AGD) is one of the largest threats to salmon aquaculture, causing serious economic and animal welfare burden. Treatments can be expensive and environmentally damaging, hence the need for alternative strategies. Breeding for disease resistance can contribute to prevention and control of AGD, providing long-term cumulative benefits in selected stocks. The use of genomic selection can expedite selection for disease resistance due to improved accuracy compared to pedigree-based approaches. The aim of this work was to quantify and characterise genetic variation in AGD resistance in salmon, the genetic architecture of the trait, and the potential of genomic selection to contribute to disease control. An AGD challenge was performed in ~1,500 Atlantic salmon, using gill damage and amoebic load as indicator traits for host resistance. Both traits are heritable (h² ~ 0.25-0.30) and show high positive correlation, indicating they may be good measurements of host resistance to AGD. While the genetic architecture of resistance appeared to be largely polygenic in nature, two regions on chromosome 18 showed suggestive association with both AGD resistance traits. Using a cross-validation approach, genomic prediction accuracy was up to 18 % higher than that obtained using pedigree, and a reduction in marker density to ~2,000 SNPs was sufficient to obtain accuracies similar to those obtained using the whole dataset. This study indicates that resistance to AGD is a suitable trait for genomic selection, and the addition of this trait to Atlantic salmon breeding programs can lead to more resistant stocks.

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The Molecular and Genetic Characterization of Second Chromosome Balancers in Drosophila melanogaster

Balancer chromosomes are multiply inverted and rearranged chromosomes used in Drosophila melanogaster for many tasks, such as maintaining mutant alleles in stock and complex stock construction. Balancers were created before molecular characterization of their breakpoints was possible, so the precise locations of many of these breakpoints are unknown. Here, we report or confirm the positions of the 14 euchromatic breakpoints on the 2^nd chromosome balancers SM1, SM5, CyO, and SM6a. This total includes three breakpoints involved in a complex rearrangement on SM5 that is associated with the duplication of two genomic regions. Unbiased sequencing of several balancers allowed us to identify stocks with incorrectly identified balancers as well as single and double crossover events that had occurred between 2^nd chromosome balancers and their homologs. The crossover events that we recovered were at least 2 Mb from the closest inversion breakpoint, consistent with observations from other balancer chromosomes. Balancer chromosomes differ from one another both by large tracts of sequence diversity generated by recombination and by small differences, such as single nucleotide polymorphisms (SNPs). Therefore, we also report loss-of-function mutations carried by these chromosomes and unique SNP and InDel polymorphisms present on only single balancers. These findings provide valuable information about the structure of commonly used 2^nd chromosome balancers and extend recent work examining the structure of X and 3^rd chromosome balancers. Finally, these observations provide new insights into how the sequences of individual balancers have diverged over time.

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Multivariate Analysis of the Cotton Seed Ionome Reveals a Shared Genetic Architecture

To mitigate the effects of heat and drought stress, a better understanding of the genetic control of physiological responses to these environmental conditions is needed. To this end, we evaluated an upland cotton (Gossypium hirsutum L.) mapping population under water-limited and well-watered conditions in a hot, arid environment. The elemental concentrations (ionome) of seed samples from the population were profiled in addition to those of soil samples taken from throughout the field site to better model environmental variation. The elements profiled in seeds exhibited moderate to high heritabilities, as well as strong phenotypic and genotypic correlations between elements that were not altered by the imposed irrigation regimes. Quantitative trait loci (QTL) mapping results from a Bayesian classification method identified multiple genomic regions where QTL for individual elements colocalized, suggesting that genetic control of the ionome is highly interrelated. To more fully explore this genetic architecture, multivariate QTL mapping was implemented among groups of biochemically related elements. This analysis revealed both additional and pleiotropic QTL responsible for coordinated control of phenotypic variation for elemental accumulation. Machine learning algorithms that utilized only ionomic data predicted the irrigation regime under which genotypes were evaluated with very high accuracy. Taken together, these results demonstrate the extent to which the seed ionome is genetically interrelated and predictive of plant physiological responses to adverse environmental conditions.

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Role of Translesion Synthesis DNA Polymerases in DNA Replication in the Presence of a Weak DNA Polymerase {delta} in Saccharomyces cerevisiae

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Corrigendum

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Genetic Evidence for Roles of Yeast Mitotic Cyclins at Single-Stranded Gaps Created by DNA Replication

Paused or stalled replication forks are major threats to genome integrity; unraveling the complex pathways that contribute to fork stability and restart is crucial. Experimentally, fork stalling is induced by growing the cells in presence of hydroxyurea (HU), which depletes the pool of deoxynucleotide triphosphates (dNTPs) and slows down replication progression in yeast. Here, I report an epistasis analysis, based on sensitivity to HU, between CLB2, the principal mitotic cyclin gene in Saccharomyces cerevisiae, and genes involved in fork stability and recombination. clb2 cells are not sensitive to HU, but the strong synergistic effect of clb2 with most genes tested indicates, unexpectedly, that CLB2 has an important role in DNA replication, in the stability and restart of stalled forks, and in pathways dependent on and independent of homologous recombination. Results indicate that CLB2 functions in parallel with the SGS1 helicase and EXO1 exonuclease to allow proper Rad51 recombination, but also regulates a combined Sgs1–Exo1 activity in a pathway dependent on Mec1 and Rad53 checkpoint protein kinases. The data argue that Mec1 regulates Clb2 to prevent a deleterious Sgs1–Exo1 activity at paused or stalled forks, whereas Rad53 checkpoint activation regulates Clb2 to allow a necessary Sgs1–Exo1 activity at stalled or collapsed forks. Altogether, this study indicates that Clb2 regulates the activity of numerous nucleases at single-stranded gaps created by DNA replication. A model is proposed for the function and regulation of Clb2 at stalled forks. These data provide new perspectives on the role of mitotic cyclins at the end of S phase.

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Fine Mapping of QUICK ROOTING 1 and 2, Quantitative Trait Loci Increasing Root Length in Rice

The volume that the root system can occupy is associated with the efficiency of water and nutrient uptake from soil. Genetic improvement of root length, which is a limiting factor for root distribution, is necessary for increasing crop production. In this report, we describe identification of two quantitative trait loci (QTLs) for maximal root length, QUICK ROOTING 1 (QRO1) on chromosome 2 and QRO2 on chromosome 6, in cultivated rice (Oryza sativa L.). We measured the maximal root length in 26 lines carrying chromosome segments from the long-rooted upland rice cultivar Kinandang Patong in the genetic background of the short-rooted lowland cultivar IR64. Five lines had longer roots than IR64. By rough mapping of the target regions in BC₄F₂ populations, we detected putative QTLs for maximal root length on chromosomes 2, 6, and 8. To fine-map these QTLs, we used BC₄F₃ recombinant homozygous lines. QRO1 was mapped between markers RM5651 and RM6107, which delimit a 1.7-Mb interval on chromosome 2, and QRO2 was mapped between markers RM20495 and RM3430-1, which delimit an 884-kb interval on chromosome 6. Both QTLs may be promising gene resources for improving root system architecture in rice.

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Genomic Prediction Accuracy for Resistance Against Piscirickettsia salmonis in Farmed Rainbow Trout

Salmonid rickettsial syndrome (SRS), caused by the intracellular bacterium Piscirickettsia salmonis, is one of the main diseases affecting rainbow trout (Oncorhynchus mykiss) farming. To accelerate genetic progress, genomic selection methods can be used as an effective approach to control the disease. The aims of this study were: (i) to compare the accuracy of estimated breeding values using pedigree-based best linear unbiased prediction (PBLUP) with genomic BLUP (GBLUP), single-step GBLUP (ssGBLUP), Bayes C, and Bayesian Lasso (LASSO); and (ii) to test the accuracy of genomic prediction and PBLUP using different marker densities (0.5, 3, 10, 20, and 27 K) for resistance against P. salmonis in rainbow trout. Phenotypes were recorded as number of days to death (DD) and binary survival (BS) from 2416 fish challenged with P. salmonis. A total of 1934 fish were genotyped using a 57 K single-nucleotide polymorphism (SNP) array. All genomic prediction methods achieved higher accuracies than PBLUP. The relative increase in accuracy for different genomic models ranged from 28 to 41% for both DD and BS at 27 K SNP. Between different genomic models, the highest relative increase in accuracy was obtained with Bayes C (~40%), where 3 K SNP was enough to achieve a similar accuracy to that of the 27 K SNP for both traits. For resistance against P. salmonis in rainbow trout, we showed that genomic predictions using GBLUP, ssGBLUP, Bayes C, and LASSO can increase accuracy compared with PBLUP. Moreover, it is possible to use relatively low-density SNP panels for genomic prediction without compromising accuracy predictions for resistance against P. salmonis in rainbow trout.

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Genomic Prediction and Association Mapping of Curd-Related Traits in Gene Bank Accessions of Cauliflower

Genetic resources are an important source of genetic variation for plant breeding. Genome-wide association studies (GWAS) and genomic prediction greatly facilitate the analysis and utilization of useful genetic diversity for improving complex phenotypic traits in crop plants. We explored the potential of GWAS and genomic prediction for improving curd-related traits in cauliflower (Brassica oleracea var. botrytis) by combining 174 randomly selected cauliflower gene bank accessions from two different gene banks. The collection was genotyped with genotyping-by-sequencing (GBS) and phenotyped for six curd-related traits at two locations and three growing seasons. A GWAS analysis based on 120,693 single-nucleotide polymorphisms identified a total of 24 significant associations for curd-related traits. The potential for genomic prediction was assessed with a genomic best linear unbiased prediction model and BayesB. Prediction abilities ranged from 0.10 to 0.66 for different traits and did not differ between prediction methods. Imputation of missing genotypes only slightly improved prediction ability. Our results demonstrate that GWAS and genomic prediction in combination with GBS and phenotyping of highly heritable traits can be used to identify useful quantitative trait loci and genotypes among genetically diverse gene bank material for subsequent utilization as genetic resources in cauliflower breeding.

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Genetic Identification of Separase Regulators in Caenorhabditis elegans

Separase is a highly conserved protease required for chromosome segregation. Although observations that separase also regulates membrane trafficking events have been made, it is still not clear how separase achieves this function. Here, we present an extensive ENU mutagenesis suppressor screen aimed at identifying suppressors of sep-1(e2406), a temperature-sensitive maternal effect embryonic lethal separase mutant that primarily attenuates membrane trafficking rather than chromosome segregation. We screened nearly a million haploid genomes and isolated 68 suppressed lines. We identified 14 independent intragenic sep-1(e2406) suppressed lines. These intragenic alleles map to seven SEP-1 residues within the N-terminus, compensating for the original mutation within the poorly conserved N-terminal domain. Interestingly, 47 of the suppressed lines have novel mutations throughout the entire coding region of the pph-5 phosphatase, indicating that this is an important regulator of separase. We also found that a mutation near the MEEVD motif of HSP-90, which binds and activates PPH-5, also rescues sep-1(e2406) mutants. Finally, we identified six potentially novel suppressor lines that fall into five complementation groups. These new alleles provide the opportunity to more exhaustively investigate the regulation and function of separase.

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Differential Regulation of Zfp30 Expression in Murine Airway Epithelia Through Altered Binding of ZFP148 to rs51434084

Neutrophil chemotaxis to the airways is a key aspect of host response to microbes and a feature of multiple pulmonary diseases including asthma. Tight regulation of this recruitment is critical to prevent unwanted host tissue damage and inflammation. Using a mouse (Mus musculus) model of asthma applied to the Collaborative Cross population, we previously identified a lung gene expression quantitative trait locus (eQTL) for Zinc finger protein 30 (Zfp30) that was also a QTL for neutrophil recruitment and the hallmark neutrophil chemokine CXCL1. The Zfp30 eQTL is defined by three functionally distinct haplotypes. In this study, we searched for causal genetic variants that underlie the Zfp30 eQTL to gain a better understanding of this candidate repressor's regulation. First, we identified a putative regulatory region spanning 500 bp upstream of Zfp30, which contains 10 SNPs that form five haplotypes. In reporter gene assays in vitro, these haplotypes recapitulated the three previously identified in vivo expression patterns. Second, using site-directed mutagenesis followed by reporter gene assays, we identified a single variant, rs51434084, which explained the majority of variation in expression between two out of three haplotype groups. Finally, using a combination of in silico predictions and electrophoretic mobility shift assays, we identified ZFP148 as a transcription factor that differentially binds to the Zfp30 promoter region harboring rs51434084. In conclusion, we provide evidence in support of rs51434084 being a causal variant for the Zfp30 eQTL, and have identified a mechanism by which this variant alters Zfp30 expression, namely differential binding of ZFP148.

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Inbred or Outbred? Genetic Diversity in Laboratory Rodent Colonies

Nonmodel rodents are widely used as subjects for both basic and applied biological research, but the genetic diversity of the study individuals is rarely quantified. University-housed colonies tend to be small and subject to founder effects and genetic drift; so they may be highly inbred or show substantial genetic divergence from other colonies, even those derived from the same source. Disregard for the levels of genetic diversity in an animal colony may result in a failure to replicate results if a different colony is used to repeat an experiment, as different colonies may have fixed alternative variants. Here we use high throughput sequencing to demonstrate genetic divergence in three isolated colonies of Mongolian gerbil (Meriones unguiculatus) even though they were all established recently from the same source. We also show that genetic diversity in allegedly "outbred" colonies of nonmodel rodents (gerbils, hamsters, house mice, deer mice, and rats) varies considerably from nearly no segregating diversity to very high levels of polymorphism. We conclude that genetic divergence in isolated colonies may play an important role in the "replication crisis." In a more positive light, divergent rodent colonies represent an opportunity to leverage genetically distinct individuals in genetic crossing experiments. In sum, awareness of the genetic diversity of an animal colony is paramount as it allows researchers to properly replicate experiments and also to capitalize on other genetically distinct individuals to explore the genetic basis of a trait.

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Use of a Sibling Subtraction Method for Identifying Causal Mutations in Caenorhabditis elegans by Whole-Genome Sequencing

Whole-genome sequencing (WGS) is an indispensable tool for identifying causal mutations obtained from genetic screens. To reduce the number of causal mutation candidates typically uncovered by WGS, Caenorhabditis elegans researchers have developed several strategies. One involves crossing N2-background mutants to the polymorphic Hawaiian (HA) strain, which can be used to simultaneously identify mutant strain variants and obtain high-density mapping information. This approach, however, is not well suited for uncovering mutations in complex genetic backgrounds, and HA polymorphisms can alter phenotypes. Other approaches make use of DNA variants present in the initial background or introduced by mutagenesis. This information is used to implicate genomic regions with high densities of DNA lesions that persist after backcrossing, but these methods can provide lower resolution than HA mapping. To identify suppressor mutations using WGS, we developed an approach termed the sibling subtraction method (SSM). This method works by eliminating variants present in both mutants and their nonmutant siblings, thus greatly reducing the number of candidates. We used this method with two members of the C. elegans NimA-related kinase family, nekl-2 and nekl-3. Combining weak aphenotypic alleles of nekl-2 and nekl-3 leads to penetrant molting defects and larval arrest. We isolated ~50 suppressors of nekl-2; nekl-3 synthetic lethality using F1 clonal screening methods and a peel-1–based counterselection strategy. When applied to five of the suppressors, SSM led to only one to four suppressor candidates per strain. Thus SSM is a powerful approach for identifying causal mutations in any genetic background and provides an alternative to current methods.

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Sequencing of Linkage Region on Chromosome 12p11 Identifies PKP2 as a Candidate Gene for Left Ventricular Mass in Dominican Families

Increased left ventricular mass (LVM) is an intermediate phenotype for cardiovascular disease (CVD) and a predictor of stroke. Using families from the Dominican Republic, we have previously shown LVM to be heritable and found evidence for linkage to chromosome 12p11. Our current study aimed to further characterize the QTL by sequencing the 1 LOD unit down region in 10 families from the Dominican Republic with evidence for linkage to LVM. Within this region, we tested 5477 common variants [CVs; minor allele frequency (MAF) ≥5%] using the Quantitative Transmission-Disequilibrium Test (QTDT). Gene-based analyses were performed to test rare variants (RVs; MAF < 5%) in 181 genes using the family-based sequence kernel association test. A sample of 618 unrelated Dominicans from the Northern Manhattan Study (NOMAS) and 12 Dominican families with Exome Array data were used for replication analyses. The most strongly associated CV with evidence for replication was rs1046116 (Discovery families P = 9.0 x 10^–4; NOMAS P = 0.03; replication families P = 0.46), a missense variant in PKP2. In nonsynonymous RV analyses, PKP2 was one of the most strongly associated genes (P = 0.05) with suggestive evidence for replication in NOMAS (P = 0.05). PKP2 encodes the plakophilin 2 protein and is a desmosomal gene implicated in arrythmogenic right ventricular cardiomyopathy and recently in arrhythmogenic left ventricular cardiomyopathy, which makes PKP2 an excellent candidate gene for LVM. In conclusion, sequencing of our previously reported QTL identified common and rare variants within PKP2 to be associated with LVM. Future studies are necessary to elucidate the role these variants play in influencing LVM.

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Highly Efficient Site-Specific Mutagenesis in Malaria Mosquitoes Using CRISPR

Anopheles mosquitoes transmit at least 200 million annual malaria infections worldwide. Despite considerable genomic resources, mechanistic understanding of biological processes in Anopheles has been hampered by a lack of tools for reverse genetics. Here, we report successful application of the CRISPR/Cas9 system for highly efficient, site-specific mutagenesis in the diverse malaria vectors Anopheles albimanus, A. coluzzii, and A. funestus. When guide RNAs (gRNAs) and Cas9 protein are injected at high concentration, germline mutations are common and usually biallelic, allowing for the rapid creation of stable mutant lines for reverse genetic analysis. Our protocol should enable researchers to dissect the molecular and cellular basis of anopheline traits critical to successful disease transmission, potentially exposing new targets for malaria control.

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Had1 Is Required for Cell Wall Integrity and Fungal Virulence in Cryptococcus neoformans

Calcineurin modulates environmental stress survival and virulence of the human fungal pathogen Cryptococcus neoformans. Previously, we identified 44 putative calcineurin substrates, and proposed that the calcineurin pathway is branched to regulate targets including Crz1, Pbp1, and Puf4 in C. neoformans. In this study, we characterized Had1, which is one of the putative calcineurin substrates belonging to the ubiquitously conserved haloacid dehalogenase β-phosphoglucomutase protein superfamily. Growth of the had1 mutant was found to be compromised at 38° or higher. In addition, the had1 mutant exhibited increased sensitivity to cell wall perturbing agents, including Congo Red and Calcofluor White, and to an endoplasmic reticulum stress inducer dithiothreitol. Virulence studies revealed that the had1 mutation results in attenuated virulence compared to the wild-type strain in a murine inhalation infection model. Genetic epistasis analysis revealed that Had1 and the zinc finger transcription factor Crz1 play roles in parallel pathways that orchestrate stress survival and fungal virulence. Overall, our results demonstrate that Had1 is a key regulator of thermotolerance, cell wall integrity, and virulence of C. neoformans.

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Joint Analysis of Strain and Parent-of-Origin Effects for Recombinant Inbred Intercrosses Generated from Multiparent Populations with the Collaborative Cross as an Example

Multiparent populations (MPP) have become popular resources for complex trait mapping because of their wider allelic diversity and larger population size compared with traditional two-way recombinant inbred (RI) strains. In mice, the collaborative cross (CC) is one of the most popular MPP and is derived from eight genetically diverse inbred founder strains. The strategy of generating RI intercrosses (RIX) from MPP in general and from the CC in particular can produce a large number of completely reproducible heterozygote genomes that better represent the (outbred) human population. Since both maternal and paternal haplotypes of each RIX are readily available, RIX is a powerful resource for studying both standing genetic and epigenetic variations of complex traits, in particular, the parent-of-origin (PoO) effects, which are important contributors to many complex traits. Furthermore, most complex traits are affected by >1 genes, where multiple quantitative trait locus mapping could be more advantageous. In this paper, for MPP-RIX data but taking CC-RIX as a working example, we propose a general Bayesian variable selection procedure to simultaneously search for multiple genes with founder allelic effects and PoO effects. The proposed model respects the complex relationship among RIX samples, and the performance of the proposed method is examined by extensive simulations.

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Cell-Type Transcriptomes of the Multicellular Green Alga Volvox carteri Yield Insights into the Evolutionary Origins of Germ and Somatic Differentiation Programs

Germ–soma differentiation is a hallmark of complex multicellular organisms, yet its origins are not well understood. Volvox carteri is a simple multicellular green alga that has recently evolved a simple germ–soma dichotomy with only two cell-types: large germ cells called gonidia and small terminally differentiated somatic cells. Here, we provide a comprehensive characterization of the gonidial and somatic transcriptomes of V. carteri to uncover fundamental differences between the molecular and metabolic programming of these cell-types. We found extensive transcriptome differentiation between cell-types, with somatic cells expressing a more specialized program overrepresented in younger, lineage-specific genes, and gonidial cells expressing a more generalist program overrepresented in more ancient genes that shared striking overlap with stem cell-specific genes from animals and land plants. Directed analyses of different pathways revealed a strong dichotomy between cell-types with gonidial cells expressing growth-related genes and somatic cells expressing an altruistic metabolic program geared toward the assembly of flagella, which support organismal motility, and the conversion of storage carbon to sugars, which act as donors for production of extracellular matrix (ECM) glycoproteins whose secretion enables massive organismal expansion. V. carteri orthologs of diurnally controlled genes from C. reinhardtii, a single-celled relative, were analyzed for cell-type distribution and found to be strongly partitioned, with expression of dark-phase genes overrepresented in somatic cells and light-phase genes overrepresented in gonidial cells- a result that is consistent with cell-type programs in V. carteri arising by cooption of temporal regulons in a unicellular ancestor. Together, our findings reveal fundamental molecular, metabolic, and evolutionary mechanisms that underlie the origins of germ–soma differentiation in V. carteri and provide a template for understanding the acquisition of germ–soma differentiation in other multicellular lineages.

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In Vivo Functional Analysis of Drosophila Robo1 Fibronectin Type-III Repeats

The repellant ligand Slit and its Roundabout (Robo) family receptors regulate midline crossing of axons during development of the embryonic central nervous system (CNS). Slit proteins are produced at the midline and signal through Robo receptors to repel axons from the midline. Disruption of Slit-Robo signaling causes ectopic midline-crossing phenotypes in the CNS of a broad range of animals, including insects and vertebrates. While previous studies have investigated the roles of Drosophila melanogaster Robo1's five Immunoglobulin-like (Ig) domains, little is known about the importance of the three evolutionarily conserved Fibronectin (Fn) type-III repeats. We have individually deleted each of Drosophila Robo1's three Fn repeats, and then tested these Robo1 variants in vitro to determine their ability to bind Slit in cultured Drosophila cells and in vivo to investigate the requirement for each domain in regulating Robo1's embryonic expression pattern, axonal localization, midline repulsive function, and sensitivity to Commissureless (Comm) downregulation. We demonstrate that the Fn repeats are not required for Robo1 to bind Slit or for proper expression of Robo1 in Drosophila embryonic neurons. When expressed in a robo1 mutant background, these variants are able to restore midline repulsion to an extent equivalent to full-length Robo1. We identify a novel requirement for Fn3 in the exclusion of Robo1 from commissures and downregulation of Robo1 by Comm. Our results indicate that each of the Drosophila Robo1 Fn repeats are individually dispensable for the protein's role in midline repulsion, despite the evolutionarily conserved "5 + 3" protein structure.

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Powerful Inference with the D-Statistic on Low-Coverage Whole-Genome Data

The detection of ancient gene flow between human populations is an important issue in population genetics. A common tool for detecting ancient admixture events is the D-statistic. The D-statistic is based on the hypothesis of a genetic relationship that involves four populations, whose correctness is assessed by evaluating specific coincidences of alleles between the groups. When working with high-throughput sequencing data, calling genotypes accurately is not always possible; therefore, the D-statistic currently samples a single base from the reads of one individual per population. This implies ignoring much of the information in the data, an issue especially striking in the case of ancient genomes. We provide a significant improvement to overcome the problems of the D-statistic by considering all reads from multiple individuals in each population. We also apply type-specific error correction to combat the problems of sequencing errors, and show a way to correct for introgression from an external population that is not part of the supposed genetic relationship, and how this leads to an estimate of the admixture rate. We prove that the D-statistic is approximated by a standard normal distribution. Furthermore, we show that our method outperforms the traditional D-statistic in detecting admixtures. The power gain is most pronounced for low and medium sequencing depth (1–10x), and performances are as good as with perfectly called genotypes at a sequencing depth of 2x. We show the reliability of error correction in scenarios with simulated errors and ancient data, and correct for introgression in known scenarios to estimate the admixture rates.

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Genome-Wide Analysis of Grain Yield Stability and Environmental Interactions in a Multiparental Soybean Population

Genetic improvement toward optimized and stable agronomic performance of soybean genotypes is desirable for food security. Understanding how genotypes perform in different environmental conditions helps breeders develop sustainable cultivars adapted to target regions. Complex traits of importance are known to be controlled by a large number of genomic regions with small effects whose magnitude and direction are modulated by environmental factors. Knowledge of the constraints and undesirable effects resulting from genotype by environmental interactions is a key objective in improving selection procedures in soybean breeding programs. In this study, the genetic basis of soybean grain yield responsiveness to environmental factors was examined in a large soybean nested association population. For this, a genome-wide association to performance stability estimates generated from a Finlay-Wilkinson analysis and the inclusion of the interaction between marker genotypes and environmental factors was implemented. Genomic footprints were investigated by analysis and meta-analysis using a recently published multiparent model. Results indicated that specific soybean genomic regions were associated with stability, and that multiplicative interactions were present between environments and genetic background. Seven genomic regions in six chromosomes were identified as being associated with genotype-by-environment interactions. This study provides insight into genomic assisted breeding aimed at achieving a more stable agronomic performance of soybean, and documented opportunities to exploit genomic regions that were specifically associated with interactions involving environments and subpopulations.

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Growth of Caenorhabditis elegans in Defined Media Is Dependent on Presence of Particulate Matter

Caenorhabditis elegans are typically cultured in a monoxenic medium consisting of live bacteria. However, this introduces a secondary organism to experiments, and restricts the manipulation of the nutritional environment. Due to the intricate link between genes and environment, greater control and understanding of nutritional factors are required to push the C. elegans field into new areas. For decades, attempts to develop a chemically defined, axenic medium as an alternative for culturing C. elegans have been made. However, the mechanism by which the filter feeder C. elegans obtains nutrients from these liquid media is not known. Using a fluorescence-activated cell sorting based approach, we demonstrate growth in all past axenic C. elegans media to be dependent on the presence of previously unknown particles. This particle requirement of C. elegans led to development of liposome-based, nanoparticle culturing that allows full control of nutrients delivered to C. elegans.

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Transcriptional Profiling of Saccharomyces cerevisiae Reveals the Impact of Variation of a Single Transcription Factor on Differential Gene Expression in 4NQO, Fermentable, and Nonfermentable Carbon Sources

Cellular metabolism can change the potency of a chemical's tumorigenicity. 4-nitroquinoline-1-oxide (4NQO) is a tumorigenic drug widely used on animal models for cancer research. Polymorphisms of the transcription factor Yrr1 confer different levels of resistance to 4NQO in Saccharomyces cerevisiae. To study how different Yrr1 alleles regulate gene expression leading to resistance, transcriptomes of three isogenic S. cerevisiae strains carrying different Yrr1 alleles were profiled via RNA sequencing (RNA-Seq) and chromatin immunoprecipitation coupled with sequencing (ChIP-Seq) in the presence and absence of 4NQO. In response to 4NQO, all alleles of Yrr1 drove the expression of SNQ2 (a multidrug transporter), which was highest in the presence of 4NQO resistance-conferring alleles, and overexpression of SNQ2 alone was sufficient to overcome 4NQO-sensitive growth. Using shape metrics to refine the ChIP-Seq peaks, Yrr1 strongly associated with three loci including SNQ2. In addition to a known Yrr1 target SNG1, Yrr1 also bound upstream of RPL35B; however, overexpression of these genes did not confer 4NQO resistance. RNA-Seq data also implicated nucleotide synthesis pathways including the de novo purine pathway, and the ribonuclease reductase pathways were downregulated in response to 4NQO. Conversion of a 4NQO-sensitive allele to a 4NQO-resistant allele by a single point mutation mimicked the 4NQO-resistant allele in phenotype, and while the 4NQO resistant allele increased the expression of the ADE genes in the de novo purine biosynthetic pathway, the mutant Yrr1 increased expression of ADE genes even in the absence of 4NQO. These same ADE genes were only increased in the wild-type alleles in the presence of 4NQO, indicating that the point mutation activated Yrr1 to upregulate a pathway normally only activated in response to stress. The various Yrr1 alleles also influenced growth on different carbon sources by altering the function of the mitochondria. Hence, the complement to 4NQO resistance was poor growth on nonfermentable carbon sources, which in turn varied depending on the allele of Yrr1 expressed in the isogenic yeast. The oxidation state of the yeast affected the 4NQO toxicity by altering the reactive oxygen species (ROS) generated by cellular metabolism. The integration of RNA-Seq and ChIP-Seq elucidated how Yrr1 regulates global gene transcription in response to 4NQO and how various Yrr1 alleles confer differential resistance to 4NQO. This study provides guidance for further investigation into how Yrr1 regulates cellular responses to 4NQO, as well as transcriptomic resources for further analysis of transcription factor variation on carbon source utilization.

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Balancing tonic and phasic inhibition in hypothalamic corticotropin releasing hormone neurons

Abstract

Corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are integratory hubs that regulate the endocrine response to stress. GABA inputs provide a basal inhibitory tone that constrains this system and circulating glucocorticoids (CORT) are important feedback controllers of CRH output. Surprisingly little is known about the direct effects of CORT on GABA synapses in PVN. Here we used whole-cell patch clamp recordings from CRH neurons in mouse hypothalamic brain slices to examine the effects of CORT on synaptic and extrasynaptic GABA signalling. We show that GABA transporters (GAT) limit constitutive activation of presynaptic GABA_B receptors and ensure high release probability at GABA synapses. GATs, in combination with GABA_B receptors also curtail extrasynaptic GABA_AR signalling. CORT has no effect on synaptic GABA signalling, but increases extrasynaptic GABA tone through upregulation of postsynaptic GABA_A receptors. These data show that efficient GABA clearance and autoinhibition control the balance between synaptic (phasic) and extrasynaptic (tonic) inhibition in PVN CRH neurons. This balance is shifted towards increased extrasynaptic inhibition by CORT.

This article is protected by copyright. All rights reserved

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Genetic and Clinical Findings in a Chinese Cohort of Patients with collagen VI-Related Myopathies

Abstract

Collagen VI-related myopathy, caused by pathogenic variants in the genes encoding collagen VI, represents a clinical continuum from Ullrich congenital muscular dystrophy (UCMD) to Bethlem myopathy (BM). Clinical data of 60 probands and their family members were collected and muscle biopsies of 26 patients were analyzed. COL6A1, COL6A2 and COL6A3 exons were analyzed by direct sequencing or next generation sequencing (NGS). Sixty patients were characterized by delayed motor milestones, muscle weakness, skin and joint changes with forty UCMD and twenty BM. Muscle with biopsies revealed dystrophic changes and showed completely deficiency (CD) of collagen VI or sarcolemma specific collagen VI deficiency (SSCD). We identified 62 different pathogenic variants in these 60 patients, with 34 were first reported while 28 were previously known; 72 allelic pathogenic variants in COL6A1 (25/72, 34.7%), COL6A2 (33/72, 45.8%) and COL6A3 (14/72, 19.4%). We also found somatic mosaic variant in the parent of one proband by personal genome machine amplicon deep sequencing for mosaicism (PASM). Here we provide clinical, histological and genetic evidence of collagen VI-related myopathy in 60 Chinese patients. NGS is a valuable approach for diagnosis and accurate diagnosis provides useful information for genetic counseling of related families.

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High-intensity interval training in hypoxia does not affect muscle HIF responses to acute hypoxia in humans

Abstract

Purpose

The myocellular response to hypoxia is primarily regulated by hypoxia-inducible factors (HIFs). HIFs thus conceivably are implicated in muscular adaptation to altitude training. Therefore, we investigated the effect of hypoxic versus normoxic training during a period of prolonged hypoxia ('living high') on muscle HIF activation during acute ischaemia.

Methods

Ten young male volunteers lived in normobaric hypoxia for 5 weeks (5 days per week, ~ 15.5 h per day, F_iO₂: 16.4–14.0%). One leg was trained in hypoxia (TR_HYP, 12.3% F_iO₂) whilst the other leg was trained in normoxia (TR_NOR, 20.9% F_iO₂). Training sessions (3 per week) consisted of intermittent unilateral knee extensions at 20–25% of the 1-repetition maximum. Before and after the intervention, a 10-min arterial occlusion and reperfusion of the leg was performed. Muscle oxygenation status was continuously measured by near-infrared spectroscopy. Biopsies were taken from m. vastus lateralis before and at the end of the occlusion.

Results

Irrespective of training, occlusion elevated the fraction of HIF-1α expressing myonuclei from ~ 54 to ~ 64% (P < 0.05). However, neither muscle HIF-1α or HIF-2α protein abundance, nor the expression of HIF-1α or downstream targets selected increased in any experimental condition. Training in both TR_NOR and TR_HYP raised muscular oxygen extraction rate upon occlusion by ~ 30%, whilst muscle hyperperfusion immediately following the occlusion increased by ~ 25% in either group (P < 0.05).

Conclusion

Ten minutes of arterial occlusion increased HIF-1α-expressing myonuclei. However, neither normoxic nor hypoxic training during 'living high' altered muscle HIF translocation, stabilisation, or transcription in response to acute hypoxia induced by arterial occlusion.

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A Qualitative Assessment of Community Attitudes and Barriers to Family Planning Use in the Trifinio Region of Southwest Guatemala

Abstract

Introduction Our aim was to identify beliefs about and specific barriers to use of birth spacing methods that married and cohabitating women in the Trifinio Sur-Oeste region of Guatemala report in order to design future family planning educational programs. Methods We conducted key informant interviews with community health workers and focus groups with married or cohabitating women. We used inductive and deductive coding to identify common themes. Using these themes, we created explanatory models for decision-making context and identified barriers to family planning use, community educational needs, and potential interventions. Results Thirty-seven women, aged 20–47 years, with an average of 3.5 children and a 2nd grade education level, were included in focus groups. Women had accurate knowledge about benefits of birth spacing however had poor knowledge of family planning methods. Most common barriers included lack of spousal approval, difficulty accessing contraceptive methods, lack of knowledge, and fear of adverse effects. Women were interested in increased education for men, adolescents, and themselves. Discussion Targeted education for women, men, and adolescents is needed to improve family planning uptake in the Trifinio region. Programming should focus on increasing knowledge and acceptability of birth spacing methods and increasing constructive dialogue among couples.

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Maternal and Child Health Among Female Firefighters in the U.S.

Abstract

Objectives Despite increasing attention to the occupational impact of firefighting, little is known specific to the health of women firefighters. In particular, quantitative data is lacking on the impact firefighting has on maternal and child health for women who become pregnant while working as firefighters. Methods A total of 1821 women firefighters responded to requests to complete a self-report survey of questions about pregnancy. Women answered questions about their departments' policies and practices and their own experiences of pregnancy. Those participants who reported a pregnancy while serving as a firefighter were asked detailed questions about their pregnancy and outcomes. Results Female firefighters reported that nearly a quarter of their first pregnancies while in the fire service ended in miscarriage and that increased to a third of pregnancies by the fourth. Rates of pre-term delivery also were high among this population. Conclusions Findings have important implications for policy and practice among women who become pregnant while actively serving in the fire service.

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Association between expression levels and growth trait-related SNPs located in promoters of the MC4R and MSTN genes in Spinibarbus hollandi

Abstract

Melanocortin 4 receptor: (MC4R) and Myostatin (MSTN) are two important growth trait-related genes in animals. In this study, we showed that two SNPs, MC4R-719A>G and MSTN-519C>T, found in the promoters of the MC4R and MSTN genes, respectively, are both associated with growth traits in Spinibarbus hollandi. Furthermore, we observed that there were significant associations between the expression levels of the MC4R and MSTN genes and these two growth trait-related SNPs. The expression level of MC4R gene in brain was lower in GG genotype fish with extremely high growth performance than that in AA genotype fish with extremely low growth performance. Expression level of the MSTN gene in muscle was lower in TT genotype fish with extremely high growth performance than that in CC and CT genotype fish with lower growth performance. The results indicated that these SNPs located in the promoters of MC4R and MSTN are associated with growth-related traits through modification of gene expression levels. The MSTN and MC4R SNPs may have useful application in effective marker-assisted selection aimed to increase output in S. hollandi.

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Complete genome sequence of the sesame pathogen Ralstonia solanacearum strain SEPPX 05

Abstract

Ralstonia solanacearum is a soil-borne phytopathogen associated with bacterial wilt disease of sesame. R. solanacearum is the predominant agent causing damping-off from tropical to temperate regions. Because bacterial wilt has decreased the sesame industry yield, we sequenced the SEPPX05 genome using PacBio and Illumina HiSeq 2500 systems and revealed that R. solanacearum strain SEPPX05 carries a bipartite genome consisting of a 3,930,849 bp chromosome and a 2,066,085 bp megaplasmid with 66.84% G+C content that harbors 5,427 coding sequences. Based on the whole genome, phylogenetic analysis showed that strain SEPPX05 is grouped with two phylotype I strains (EP1 and GMI1000). Pan-genomic analysis shows that R. solanacearum is a complex species with high biological diversity and was able to colonize various environments during evolution. Despite deletions, insertions, and inversions, most genes of strain SEPPX05 have relatively high levels of synteny compared with strain GMI1000. We identified 104 genes involved in virulence-related factors in the SEPPX05 genome and eight absent genes encoding T3Es of GMI1000. Comparing SEPPX05 with other species, we found highly conserved secretion systems central to modulating interactions of host bacteria. These data may provide important clues for understanding underlying pathogenic mechanisms of R. solanacearum and help in the control of sesame bacterial wilt.

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Genetic variability comparison of cultured Israeli carp ( Cyprinus carpio ) from Korea using microsatellites

Abstract

In aquaculture, cultured fish often undergo continuous cross-fertilization without any inflow of new broodstock. This lowers genetic diversity, leading to increased disease rates and decreased survival rates. To improve the mass production and easy culture of Israeli carp, it is essential to investigate the population structure and genetic diversity of these fish. However, such a survey has not yet been performed on Korean Israeli carp. In this study, we used seven microsatellite markers to analyze the genetic diversity and association of cultured Israeli carp from Korea and China. The average numbers of alleles per locus (N_A ) for two Korean (KorA and KorB) and two Chinese (ChA and ChB) populations were as follows: KorA (10.42), KorB (14.43), ChA (20.57) and ChB (20.71). The expected heterozygosity (H_e ) ranged from 0.672 to 0.897 and from 0.827 to 0.938 in the Korean sample and Chinese sample respectively. The genetic diversity of the Korean Israeli carp was about half that of the Chinese carp. The diversity of the Korean Israeli carp was very low, suggesting that the immunity of this population could be weak, and that diversity–recovery studies are urgently needed. Therefore, our results may therefore form the foundation for future research efforts towards genetic monitoring and selective breeding, continuous research needs to be conducted in order to recover the genetic diversity of the Korean Israeli carp.

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Important Gaps in HIV Knowledge, Attitudes and Practices Among Young Asylum Seekers in Comparison to the General Population

Abstract

Migrants are disproportionately affected by HIV in many European countries, including Finland. We aimed to compare the HIV-related knowledge, attitudes and practices (KAP) of young asylum seekers to those of the general young adult population. Two cross-sectional surveys were conducted among 20- to 25-year-old young adults: The TIE study among asylum seekers (n = 47) and the World AIDS Day 2014 study among the general population (n = 485). Important gaps in HIV KAP were identified especially among the young asylum seekers. For the general young adult population, previous HIV testing was associated with female gender, better HIV knowledge and increased sexual activity. Health education concerning HIV needs to be further enforced among young adults in Finland. Due to poorer HIV knowledge, young asylum seekers might be especially vulnerable to HIV. The asylum process is a window of opportunity for health education and HIV testing.

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Effectiveness of a single session of dual-transcranial direct current stimulation in combination with upper limb robotic-assisted rehabilitation in chronic stroke patients: a randomized, double-blind, cross-over study

The impact of transcranial direct current stimulation (tDCS) is controversial in the neurorehabilitation literature. It has been suggested that tDCS should be combined with other therapy to improve their efficacy. To assess the effectiveness of a single session of upper limb robotic-assisted therapy (RAT) combined with real or sham-tDCS in chronic stroke patients. Twenty-one hemiparetic chronic stroke patients were included in a randomized, controlled, cross-over double-blind study. Each patient underwent two sessions 7 days apart in a randomized order: (a) 20 min of real dual-tDCS associated with RAT (REAL+RAT) and (b) 20 min of sham dual-tDCS associated with RAT (SHAM+RAT). Patient dexterity (Box and Block and Purdue Pegboard tests) and upper limb kinematics were evaluated before and just after each intervention. The assistance provided by the robot during the intervention was also recorded. Gross manual dexterity (1.8±0.7 blocks, P=0.008) and straightness of movement (0.01±0.03, P0.05). The assistance provided by the robot was similar during both interventions (P>0.05). The results showed a slight improvement in hand dexterity and arm movement after the REAL+RAT tDCS intervention. The observed effect after a single session was small and not clinically relevant. Repetitive sessions could increase the benefits of this combined approach. Correspondence to Stéphanie Dehem, PT, Secteur des Sciences de la Santé, Institut de Recherche Expérimentale et Clinique (IREC), Neuro Musculo Skeletal Lab (NMSK), Université Catholique de Louvain (UCL), Avenue Mounier 53, B-1200 Brussels, Belgium Tel: +32 327 645 375; e-mail: stephanie.dehem@uclouvain.be Received October 20, 2017 Accepted January 22, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Relationship Between Postpartum Depression and Psychological and Biological Variables in the Initial Postpartum Period

Abstract

Objectives The aims of this study were to evaluate the predictive relationship between psychological symptomatology 24 h postpartum and depression 4 months postpartum, and analyze the relationship between estradiol and postpartum mood. Methods Two hundred women participated in an assessment 24 h postpartum and gave a blood sample for estradiol analysis. One hundred eleven of these women completed the second assessment 4 months postpartum. The Beck Depression Inventory II and the Scale of State-Trait Anxiety were used to assess psychological symptoms. Results At 24 h postpartum, symptoms of depression, trait anxiety, and state anxiety were all significantly correlated with each other. Depression at 24 h postpartum was the only significant independent predictor of depression at 4 months postpartum, explaining 28.7% of the variance. No statistically significant relationship was found between levels of estradiol and mood. Symptoms of depression immediately postpartum thus appear to be a predictor of postpartum depression. Conclusions for Practice These results suggest that early postpartum psychological evaluation of the mother, and intervention as warranted, might prevent or lessen postpartum depression.

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Rare, genetically conditioned forms of rickets - differential diagnosis and advances in diagnostics and treatment

ABSTRACT

Apart from the classic forms of rickets, there are rare genetic disorders from the group of vitamin D-resistant rickets where the clinical picture is very similar to the classic forms.

Diagnosis of genetically conditioned rickets is often delayed. It is very important to know that a disorder of genetic background may be the cause of the failure of classic treatment in patients with rachitic symptoms. In the group of genetically conditioned rickets there are, among others, congenital hypophosphatemic rickets and vitamin D-dependent rickets type I and II.

Congenital hypophosphatemic rickets is characterised by bone mineralisation disturbances related to hypophosphatemia secondary to renal loss of phosphates. The term "hypophosphatemic rickets" covers a group of diseases with similar phenotype but with different genotypes, inheritance models and etiopathogeneses. Mutation of at least ten genes underlying this disease entity have been described.

Vitamin D-dependent rickets are caused by defects of vitamin D metabolism. There are four forms described in literature that are distinguished by their genetic causes: type 1A (VDDR1A), type 1B (VDDR1B), and type 2A (VDDR2A), type 2B (VDDR2B). A detailed family history in combination with a physical examination, biochemistry and X-ray imaging helps in differential diagnostics of rare forms of rickets.

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