Τρίτη, 30 Ιανουαρίου 2018

CrossTalk proposal: CNNM proteins are Na+/Mg2+ exchangers playing a central role in transepithelial Mg2+ (re)absorption



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CrossTalk opposing view: CNNM proteins are not Na+/Mg2+ exchangers but Mg2+ transport regulators playing a central role in transepithelial Mg2+ (re)absorption



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Rebuttal from Yosuke Funato, Kazuharu Furutani, Yoshihisa Kurachi and Hiroaki Miki



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Rebuttal from Francisco J. Arjona and Jeroen H. F. de Baaij



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Ca2+ signalling in mouse urethral smooth muscle in situ: role of Ca2+ stores and Ca2+ influx mechanisms

Abstract

Urethral smooth muscle cells (USMC) generate myogenic tone and contribute to urinary continence. Currently, little is known about Ca2+ signalling in USMC in situ, and therefore little is known about the source(s) of Ca2+ required for excitation-contraction coupling. We characterized Ca2+ signalling in USMC within intact urethral muscles using a genetically encoded Ca2+ sensor, GCaMP3, expressed selectively in USMC. USMC fired spontaneous intracellular Ca2+ waves that did not propagate cell-to-cell across muscle bundles. Ca2+ waves increased dramatically in response to the α1-adrenoceptor agonist, phenylephrine (PE, 10 μm) and to ATP (10 μm). Ca2+ waves were inhibited by DEA-NONOate (10 μm). Ca2+ influx and release from SR stores contributed to Ca2+ waves, as Ca2+ free bathing solution and blocking the sarcoplasmic Ca2+-ATPase abolished activity. Intracellular Ca2+ release involved cooperation between RyRs and IP3Rs, as tetracaine and ryanodine (100 μm) and xestospongin C (1 μm) reduced Ca2+ waves. Ca2+ waves were insensitive to L-type Ca2+ channel modulators nifedipine (1 μm), nicardipine (1 μm), isradipine (1 μm) and FPL (1 μm), and were unaffected by the T-type Ca2+ channel antagonists NNC 55–0396 (1 μm) and TTA-A2 (1 μm). Ca2+ waves were reduced by the store operated Ca2+ entry (SOCE) blocker SKF 96365 (10 μm) and by an Orai antagonist, GSK-7975A (1 μm). The latter also reduced urethral contractions induced by PE, suggesting that Orai can function effectively as a receptor-operated channel. In conclusion, Ca2+ waves in mouse USMC are a source of Ca2+ for excitation-contraction coupling in urethral muscles.

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Impact of Multiple Single-Nucleotide Polymorphisms Within mprF on Daptomycin Resistance in Staphylococcus aureus

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


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Kinase-independent function of E-type cyclins in liver cancer [Genetics]

E-type cyclins (cyclins E1 and E2) are components of the core cell cycle machinery and are overexpressed in many human tumor types. E cyclins are thought to drive tumor cell proliferation by activating the cyclin-dependent kinase 2 (CDK2). The cyclin E1 gene represents the site of recurrent integration of the...

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Enhancer adoption caused by genomic insertion elicits interdigital Shh expression and syndactyly in mouse [Genetics]

Acquisition of new cis-regulatory elements (CREs) can cause alteration of developmental gene regulation and may introduce morphological novelty in evolution. Although structural variation in the genome generated by chromosomal rearrangement is one possible source of new CREs, only a few examples are known, except for cases of retrotransposition. In this...

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MAFA missense mutation causes familial insulinomatosis and diabetes mellitus [Genetics]

The β-cell–enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No disease-causing MAFA variants have been previously described. We investigated a large pedigree with autosomal dominant inheritance of diabetes mellitus or insulinomatosis, an adult-onset condition of recurrent hyperinsulinemic...

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Large genomic insertion at the Shh locus results in hammer toes through enhancer adoption [Genetics]

Enhancers are cis-regulatory elements which control the expression of genes in a defined spatiotemporal pattern, enabling the normal morphogenesis of organs and structures during embryogenesis. Enhancers control their target genes independently of their orientation or distance through chromosomal looping and are thought to evolve through various mutational mechanisms (1). A...

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Patient-Centered Values and Experiences with Emergency Department and Mental Health Crisis Care

Abstract

Little is known about what patients value in psychiatric crisis services or how they compare community-based services with those received in the emergency department. Three focus groups (n = 27) were held of participants who had received psychiatric crisis services in emergency departments or a community mental health center. Participants described care experiences and preferences. Focus groups were audio recorded, transcribed, and coded using a value-based lens. Themes included appreciation for feeling respected, basic comforts, and shared decision-making as foundations of quality care. Participants preferred the community mental health center. Research should address long-term outcomes to motivate change in psychiatric crisis care.



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Genomic structure of the native inhabitants of Peninsular Malaysia and North Borneo suggests complex human population history in Southeast Asia

Abstract

Southeast Asia (SEA) is enriched with a complex history of peopling. Malaysia, which is located at the crossroads of SEA, has been recognized as one of the hubs for early human migration. To unravel the genomic complexity of the native inhabitants of Malaysia, we sequenced 12 samples from 3 indigenous populations from Peninsular Malaysia and 4 native populations from North Borneo to a high coverage of 28–37×. We showed that the Negritos from Peninsular Malaysia shared a common ancestor with the East Asians, but exhibited some level of gene flow from South Asia, while the North Borneo populations exhibited closer genetic affinity towards East Asians than the Malays. The analysis of time of divergence suggested that ancestors of Negrito were the earliest settlers in the Malay Peninsula, whom first separated from the Papuans ~ 50–33 thousand years ago (kya), followed by East Asian (~ 40–15 kya), while the divergence time frame between North Borneo and East Asia populations predates the Austronesian expansion period implies a possible pre-Neolithic colonization. Substantial Neanderthal ancestry was confirmed in our genomes, as was observed in other East Asians. However, no significant difference was observed, in terms of the proportion of Denisovan gene flow into these native inhabitants from Malaysia. Judging from the similar amount of introgression in the Southeast Asians and East Asians, our findings suggest that the Denisovan gene flow may have occurred before the divergence of these populations and that the shared similarities are likely an ancestral component.



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Vitamin D and the Athlete: Current Perspectives and New Challenges

Abstract

The last decade has seen a dramatic increase in general interest in and research into vitamin D, with many athletes now taking vitamin D supplements as part of their everyday dietary regimen. The most recognized role of vitamin D is its regulation of calcium homeostasis; there is a strong relationship between vitamin D and bone health in non-athletic individuals. In contrast, data have consistently failed to demonstrate any relationship between serum 25[OH]D and bone health, which may in part be due to the osteogenic stimulus of exercise. Vitamin D may interact with extra-skeletal tissues such as muscle and the immune system to modulate recovery from damaging exercise and infection risk. Given that many athletes now engage in supplementation, often consuming extreme doses of vitamin D, it is important to assess whether excessive vitamin D can be detrimental to health. It has been argued that toxic effects only occur when serum 25[OH]D concentrations are greater than 180 nmol·l−1, but data from our laboratory have suggested high-dose supplementation could be problematic. Finally, there is a paradoxical relationship between serum 25[OH]D concentration, ethnicity, and markers of bone health: Black athletes often present with low serum 25[OH]D without physiological consequences. One explanation for this could be genetic differences in vitamin D binding protein due to ethnicity, resulting in greater concentrations of bioavailable (or free) vitamin D in some ethnic groups. In the absence of any pathology, screening may be unnecessary and could result in incorrect supplementation. Data must now be re-examined, taking into consideration bioavailable or "free" vitamin D in ethnically diverse groups to enable new thresholds and target concentrations to be established; perhaps, for now, it is time to "set vitamin D free".



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Administration of Caffeine in Alternate Forms

Abstract

There has been recent interest in the ergogenic effects of caffeine delivered in low doses (~ 200 mg or ~ 3 mg/kg body mass) and administered in forms other than capsules, coffee and sports drinks, including chewing gum, bars, gels, mouth rinses, energy drinks and aerosols. Caffeinated chewing gum is absorbed quicker through the buccal mucosa compared with capsule delivery and absorption in the gut, although total caffeine absorption over time is not different. Rapid absorption may be important in many sporting situations. Caffeinated chewing gum improved endurance cycling performance, and there is limited evidence that repeated sprint cycling and power production may also be improved. Mouth rinsing with caffeine may stimulate nerves with direct links to the brain, in addition to caffeine absorption in the mouth. However, caffeine mouth rinsing has not been shown to have significant effects on cognitive performance. Delivering caffeine with mouth rinsing improved short-duration, high-intensity, repeated sprinting in normal and depleted glycogen states, while the majority of the literature indicates no ergogenic effect on aerobic exercise performance, and resistance exercise has not been adequately studied. Studies with caffeinated energy drinks have generally not examined the individual effects of caffeine on performance, making conclusions about this form of caffeine delivery impossible. Caffeinated aerosol mouth and nasal sprays may stimulate nerves with direct brain connections and enter the blood via mucosal and pulmonary absorption, although little support exists for caffeine delivered in this manner. Overall, more research is needed examining alternate forms of caffeine delivery including direct measures of brain activation and entry of caffeine into the blood, as well as more studies examining trained athletes and female subjects.



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Assessing the Role of Muscle Protein Breakdown in Response to Nutrition and Exercise in Humans

Abstract

Muscle protein breakdown (MPB) is an important metabolic component of muscle remodeling, adaptation to training, and increasing muscle mass. Degradation of muscle proteins occurs via the integration of three main systems—autophagy and the calpain and ubiquitin-proteasome systems. These systems do not operate independently, and the regulation is complex. Complete degradation of a protein requires some combination of the systems. Determination of MPB in humans is technically challenging, leading to a relative dearth of information. Available information on the dynamic response of MPB primarily comes from stable isotopic methods with expression and activity measures providing complementary information. It seems clear that resistance exercise increases MPB, but not as much as the increase in muscle protein synthesis. Both hyperaminoacidemia and hyperinsulinemia inhibit the post-exercise response of MPB. Available data do not allow a comprehensive examination of the mechanisms behind these responses. Practical nutrition recommendations for interventions to suppress MPB following exercise are often made. However, it is likely that some degree of increased MPB following exercise is an important component for optimal remodeling. At this time, it is not possible to determine the impact of nutrition on any individual muscle protein. Thus, until we can develop and employ better methods to elucidate the role of MPB following exercise and the response to nutrition, recommendations to optimize post exercise nutrition should focus on the response of muscle protein synthesis. The aim of this review is to provide a comprehensive examination of the state of knowledge, including methodological considerations, of the response of MPB to exercise and nutrition in humans.



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Protection Before Impact: the Potential Neuroprotective Role of Nutritional Supplementation in Sports-Related Head Trauma

Abstract

Even in the presence of underreporting, sports-related concussions/mild traumatic brain injuries (mTBI) are on the rise. In the absence of proper diagnosis, an athlete may return to play prior to full recovery, increasing the risk of second-impact syndrome or protracted symptoms. Recent evidence has demonstrated that sub-concussive impacts, those sustained routinely in practice and competition, result in a quantifiable pathophysiological response and the accumulation of both concussive and sub-concussive impacts sustained over a lifetime of sports participation may lead to long-term neurological impairments and an increased risk of developing neurodegenerative diseases. The pathophysiological, neurometabolic, and neurochemical cascade that initiates subsequent to the injury is complex and involves multiple mechanisms. While pharmaceutical treatments may target one mechanism, specific nutrients and nutraceuticals have been discovered to impact several pathways, presenting a broader approach. Several studies have demonstrated the neuroprotective effect of nutritional supplementation in the treatment of mTBI. However, given that many concussions go unreported and sub-concussive impacts result in a pathophysiological response that, too, may contribute to long-term brain health, protection prior to impact is warranted. This review discusses the current literature regarding the role of nutritional supplements that, when provided before mTBI and traumatic brain injury, may provide neurological protection.



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Imbalance of synaptic actin dynamics as a key to the Fragile X syndrome?

Abstract

Our experiences and memories define who we are and evidence accumulates that memory formation is dependent on functional and structural adaptations of synaptic structures in our brain. Especially dendritic spines, the postsynaptic compartments of synapses, show a strong structure-to-function relationship and a high degree of structural plasticity. Although the molecular mechanisms are not completely understood, it is known that these modifications are highly dependent on the actin-cytoskeleton, the major cytoskeletal component of the spine. Given the crucial involvement of actin in these mechanisms, dysregulations of spine actin dynamics (reflected by alterations in dendritic spine morphology) can be found in a variety of neurological disorders ranging from schizophrenia to several forms of autism spectrum disorders like the Fragile X Syndrome (FXS). FXS is caused by a single mutation leading to an inactivation of the X-linked fragile X mental retardation 1 gene and loss of its gene product, the RNA-binding protein Fragile X Mental Retardation Protein 1 (FMRP) which normally can be found both pre- and postsynaptically. FMRP is involved in mRNA transport as well as regulation of local translation at the synapse and although hundreds of FMRP-target mRNAs could be identified only very few interactions between FMRP and actin-regulating proteins were reported and validated. In this review we want to give an overview about recent work by our lab and others providing evidence that dysregulated actin dynamics might indeed be at the very base of a deeper understanding of neurological disorders ranging from cognitive impairment to the autism spectrum.

This article is protected by copyright. All rights reserved



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Fat feeding facilitates hot bodies, but is resistance futile?

Abstract

High-fat diets (HFD) result in metabolic dysregulation and cardiometabolic abnormalities which contribute to the development of obesity and cardiovascular disease.

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Anatomic Relationship between the Hook of the Hamate and the Distal Transverse Carpal Ligament: Implications for Ultrasound Guided Carpal Tunnel Release

ABSTRACTObjectiveDuring ultrasound guided carpal tunnel release (USCTR), osseous landmarks may supplement direct visualization of the distal transverse carpal ligament (dTCL) to ensure a complete release. The purpose of this study was to determine the relationship between the apex of the hook of the hamate (aHH) and the dTCL within the transverse safe zone (TSZ) of the carpal tunnel.DesignTwenty unembalmed cadaveric specimens were dissected to determine the aHH-dTCL distance and the aHH-SPA distance (the distance between the aHH and the superficial palmar arch) at the ulnar and radial limits of the TSZ (the distance between the hook of the hamate or ulnar artery to the median nerve).ResultsThe aHH-dTCL distance averaged 11-12 mm across the TSZ (maximum 18.2 mm), whereas the aHH-SPA distance was significantly greater on the radial side of the TSZ compared to the ulnar side (22.6 ± 3.6 mm versus 14.0 ± 4.0 mm).ConclusionsThe dTCL lies approximately 11-12 mm distal to the aHH across the TSZ, with an upper limit of 18.2 mm. Along with direct sonographic visualization of the dTCL, the aHH can be used with other osseous landmarks to estimate the position of the dTCL during USCTR. Objective During ultrasound guided carpal tunnel release (USCTR), osseous landmarks may supplement direct visualization of the distal transverse carpal ligament (dTCL) to ensure a complete release. The purpose of this study was to determine the relationship between the apex of the hook of the hamate (aHH) and the dTCL within the transverse safe zone (TSZ) of the carpal tunnel. Design Twenty unembalmed cadaveric specimens were dissected to determine the aHH-dTCL distance and the aHH-SPA distance (the distance between the aHH and the superficial palmar arch) at the ulnar and radial limits of the TSZ (the distance between the hook of the hamate or ulnar artery to the median nerve). Results The aHH-dTCL distance averaged 11-12 mm across the TSZ (maximum 18.2 mm), whereas the aHH-SPA distance was significantly greater on the radial side of the TSZ compared to the ulnar side (22.6 ± 3.6 mm versus 14.0 ± 4.0 mm). Conclusions The dTCL lies approximately 11-12 mm distal to the aHH across the TSZ, with an upper limit of 18.2 mm. Along with direct sonographic visualization of the dTCL, the aHH can be used with other osseous landmarks to estimate the position of the dTCL during USCTR. Please send correspondence to: Jay Smith, M.D. Department of PM&R, W14 Mayo Building, 200 1st ST, SW, Rochester, MN 55905, Email: smith.jay@mayo.edu Acknowledgement of Funding Sources Funding provided by Mayo Clinic Institutional Funds. This project was supported by Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Neither funding source had a role in the study design, the collection, analysis and interpretation of data, the writing of the report or the decision to submit for publication. Declaration of Conflicting Interests Dr. Smith is Co-Founder and Chief Medical Officer for Sonex Health, LLC. Dr. Kakar is on the Medical Advisory Board for Sonex Health, LLC and is a consultant for Arthrex, Inc. and Skeletal Dynamics, LLC. Previous Presentation Results were presented in abbreviated form as a poster at the American Academy of Physical Medicine and Rehabilitation in October 2016. They have not been published, nor are they under consideration for publication elsewhere. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Effects of Different Exercise Modes on Arterial Stiffness and Nitric Oxide Synthesis

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AbstractPurposeAerobic training (AT) and high-intensity intermittent training (HIIT) reduce arterial stiffness, whereas resistance training (RT) induces deterioration of or no change in arterial stiffness. However, the molecular mechanism of these effects of different exercise modes remains unclear. This study aimed to clarify the difference of different exercise effects on endothelial nitric oxide synthase (eNOS) signaling pathway and arterial stiffness in rats and humans.MethodsIn the animal study, forty 10-week-old male Sprague-Dawley rats were randomly divided into 4groups: sedentary control (CON), AT (treadmill running, 60min at 30m/min, 5days/wk for 8weeks), RT (ladder-climbing, 8-10sets/day, 3days/wk for 8weeks), and HIIT (14repeats of 20-sec swimming session with 10-sec pause between sessions, 4days/wk for 6weeks from 12-week-old) groups (n=10 in each group). In the human study, we confirmed the effects of 6-week HIIT and 8-week AT interventions on central arterial stiffness and plasma nitrite/nitrate (NOx) level in untrained healthy young men in randomized controlled trial (HIIT, AT, and CON; n=7 in each group).ResultsIn the animal study, the effect on aortic pulse wave velocity (PWV), as an index of central arterial stiffness, following HIIT was the same as the decrease in aortic PWV and increase in arterial eNOS/Akt phosphorylation following AT, which was not changed by RT. Negative correlation between aortic PWV and eNOS phosphorylation was observed (r=-0.38, p

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Exercise Effects on Adipose Tissue Postprandial Lipolysis and Blood Flow in Children

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AbstractPoor suppression of lipolysis and blunted increase in blood flow following meal ingestion in obese adults may indicate resistance to the antilipolytic action of insulin. Exercise may be used to normalize lipolytic responses to food intake by increasing insulin sensitivity.PurposeTo determine if acute bouts of aerobic exercise and/or excise training alter lipolytic and blood flow responses to food intake in lean (LN) and obese (OB) children.MethodsSixty-five children (9-11 yrs) were randomized into acute exercise (EX: 16 LN and 28 OB) or control (CON: 9 LN and 12 OB) groups that exercised (EX), or rested (CON) between standardized breakfast and lunch. Microdialysis probes were inserted into the subcutaneous abdominal adipose tissue to monitor interstitial glycerol (lipolysis) and blood flow. Changes in interstitial glycerol and nutritive flow were calculated from dialysate samples before and after each meal. A subgroup (OB=15 and LN=9) from the acute exercise group underwent 16 weeks of aerobic exercise training.ResultsPoor suppression of lipolysis and a blunted increase in adipose tissue nutritive blood flow in response to breakfast was associated with BMI percentile (r=0.3, p

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Comparison of Two Generations of ActiGraph Accelerometers: The CARDIA Study

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AbstractPurposeTo examine the comparability of the ActiGraph 7164 and wGT3X-BT wear time, count-based estimates, and average time/day in physical activity of different intensities.MethodsWe studied 87 Coronary Artery Risk Development in Young Adults (CARDIA) participants, aged 48-60 years, who simultaneously wore the 7164 and wGT3X-BT accelerometers at the waist in 2015-16, with wear time ≥4 of 7 days, ≥10 hours/day for both monitors. Freedson cutpoints (counts/min) were used to define sedentary (

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Video-Recorded Validation of Wearable Step Counters under Free-living Conditions

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AbstractPurposeThe purpose of this study was to determine the accuracy of 14 step counting methods under free-living conditions. MethodsTwelve adults (mean±SD, age: 35±13 yr) wore a chest harness that held a GoPro camera pointed down at the feet during all waking hours for one day. The GoPro continuously recorded video of all steps taken throughout the day. Simultaneously, participants wore two StepWatch [SW] devices on each ankle (all programmed with different settings), one activPAL [AP] on each thigh, four devices at the waist (Fitbit Zip [FZ], Yamax Digi-Walker SW-200 [DW], New Lifestyles NL-2000 [NL], and ActiGraph GT9X [AG]), and two devices on the dominant and non-dominant wrists (Fitbit Charge [FC] and AG). The GoPro videos were downloaded to a computer and researchers counted steps using a hand tally device, which served as the criterion method.ResultsThe SW devices recorded between 95.3% to 102.8% of actual steps taken throughout the day (P>0.05). Eleven step counting methods estimated less than 100% of actual steps; FZ, DW, and AG with the Moving Average Vector Magnitude algorithm (MAVM) on both wrists recorded 71% to 91% of steps (P>0.05), while the AP, NL, AG (without Low Frequency Extension [no-LFE], MAVM) worn on the hip, and FC recorded 69% to 84% of steps (P0.05), while the AG (LFE) on both wrists and the hip recorded 128% to 220% of steps (P0.05). Eleven step counting methods estimated less than 100% of actual steps; FZ, DW, and AG with the Moving Average Vector Magnitude algorithm (MAVM) on both wrists recorded 71% to 91% of steps (P>0.05), while the AP, NL, AG (without Low Frequency Extension [no-LFE], MAVM) worn on the hip, and FC recorded 69% to 84% of steps (P0.05), while the AG (LFE) on both wrists and the hip recorded 128% to 220% of steps (P

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Cloud computing for genomic data analysis and collaboration

Cloud computing for genomic data analysis and collaboration

Cloud computing for genomic data analysis and collaboration, Published online: 30 January 2018; doi:10.1038/nrg.2017.113

Next-generation sequencing technologies have fuelled a rapid rise in data, which require vast computational resources to store and analyse. This Review discusses the role of cloud computing in genomics research to facilitate data sharing and new analyses of archived sequencing data, as well as large-scale international collaborations.

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Plant genetics: Parasites plant microRNAs in the host

Plant genetics: Parasites plant microRNAs in the host

Plant genetics: Parasites plant microRNAs in the host, Published online: 30 January 2018; doi:10.1038/nrg.2018.3

Plant genetics: Parasites plant microRNAs in the host

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Endothelial immune activation programs cell-fate decisions and angiogenesis by inducing DLL4 through TLR4-ERK-FOXC2 signalling

Abstract

Endothelial cells (EC) mediate a specific and robust immune response to bacteria in sepsis through the activation of Toll-Like Receptor (TLR) signalling. The mechanisms by which bacterial ligands released during sepsis program endothelial cell (EC) specification and altered angiogenesis remain unclear. We postulated that the Forkhead box protein C2 (FOXC2) transcriptional factor directs EC cell-fate decisions and angiogenesis during TLR signalling. In human lung EC, LPS induced ERK phosphorylation, FOXC2, and DLL4 expression in a TLR4-dependent manner. LPS mediated ERK phosphorylation resulted in FOXC2-ERK protein ligation, ERK-dependent FOXC2 serine and threonine phosphorylation, and subsequent activation of DLL4 gene expression. Chemical inhibition of ERK or ERK-2 dominant negative transfection disrupted LPS-mediated FOXC2 phosphorylation and transcriptional activation of FOXC2. FOXC2-siRNA or ERK-inhibition attenuated LPS-induced DLL4 expression and angiogenic sprouting in vitro. In vivo, intraperitoneal LPS induced ERK and FOXC2 phosphorylation, FOXC2 binding to DLL4 promoter, and FOXC2/DLL4 expression in the lung. ERK-inhibition suppressed LPS-induced FOXC2 phosphorylation, FOXC2-DLL4 promoter binding, and induction of FOXC2 and DLL4 in mouse lung EC. LPS induced aberrant retinal angiogenesis and DLL4 expression in neonatal mice, which was attenuated with ERK-inhibition. FOXC2+/- mice treated with LPS showed a mitigated increase in FOXC2 and DLL4 compared to FOXC2+/+ mice. These data reveal a new mechanism (TLR4-ERK-FOXC2-DLL4) by which sepsis-induced EC TLR signalling programs EC specification and altered angiogenesis.

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