The cover image is based on the Research Article Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features by Caleb P. Bupp et al., DOI: 10.1002/ajmg.a.40523.
Microbial Drug Resistance, Ahead of Print.
from Mary Ann Liebert, Inc. publishers via xlomafota13 on Inoreader http://bit.ly/2AKgJAB
via IFTTT
Microbial Drug Resistance, Ahead of Print.
from Mary Ann Liebert, Inc. publishers via xlomafota13 on Inoreader http://bit.ly/2SMQ2Cg
via IFTTT
The release of neurotransmitters from synaptic vesicles (SVs) at pre-synaptic release sites is the principle means by which information transfer between neurons occurs. Knowledge of the location of SVs within a neuron can thus provide valuable clues about the location of neurotransmitter release within a neuron and the downstream neurons to which a given neuron is connected, important information for understanding how neural circuits generate behavior. Here the development and characterization of four conditional tagged SV markers for Drosophila melanogaster is presented. This characterization includes evaluation of conditionality, specificity for SV localization, and sensitivity of detection in diverse neuron subtypes. These four SV markers are genome-edited variants of the synaptic vesicle-specific protein Rab3. They depend on either the B2 or FLP recombinases for conditionality, and incorporate GFP or mCherry fluorescent proteins, or FLAG or HA epitope tags, for detection.
Cerebral autoregulation is most effective in buffering against pressure fluctuations slower than 0.03 Hz (∼30 seconds). This suggests that frequency bands for characterizing cerebral autoregulation should be redefined Low cross‐spectral coherence below 0.03 Hz highlights the limitations of transfer function approaches Hemodynamic changes induced by lower body pressure could not fully explain the differences in autoregulation estimated from spontaneous vs augmented fluctuations and thus observations of spontaneous fluctuations should not be relied on whenever possible.
There is currently little empirical basis for time scales that are thought to be most significant in cerebrovascular counter‐regulation of changes in arterial pressure. While it is well established that cerebral autoregulation behaves as a "high pass" filter, recommended frequency bands have been largely arbitrarily determined. To test effectiveness of cerebral autoregulation, we refined oscillatory lower body pressure (LBP) to augment resting pressure fluctuations below 0.1 Hz by a factor of two in thirteen young male volunteers, and thoroughly characterized the time and frequency responses of cerebral autoregulation. We observed that despite a threefold increase in arterial pressure power < 0.03 Hz with oscillatory LBP, we saw no change in cerebral blood flow power, indicating near perfect counter regulation. In contrast, in the range of 0.03–0.10 Hz, both cerebral blood flow and arterial pressure power more than doubled. Our data demonstrate that cerebral autoregulation is most effective in buffering against pressure fluctuations slower than 0.03 Hz (∼30 seconds). This suggests that frequency bands of interest should be redefined and recording length should be much increased to account for this. Furthermore, low cross‐spectral coherence below 0.03 Hz, even when pressure fluctuations were augmented, highlights the uncertainty in transfer function approaches and the need to either report precision or use nonlinear approaches. Finally, hemodynamic changes induced by LBP could not fully explain the differences in autoregulation estimated from spontaneous vs augmented fluctuations and thus observations of spontaneous fluctuations should not be relied on whenever possible.
This article is protected by copyright. All rights reserved
Rubinstein‐Taybi syndrome (RSTS; OMIM 180849) is an autosomal dominant developmental disorder characterized by facial dysmorphism, broad thumbs and halluces associated with intellectual disability. RSTS is caused by alterations in CREBBP (about 60%) and EP300 genes (8%). RSTS is often diagnosed at birth or during early childhood but generally not suspected during antenatal period. We report nine cases of well‐documented fetal RSTS. Two cases were examined after death in utero at 18 and 35 weeks of gestation and seven cases after identification of ultrasound abnormalities and termination of pregnancy. On prenatal sonography, a large gallbladder was detected in two cases, and brain malformations were noted in four cases, especially cerebellar hypoplasia. However, the diagnosis of RSTS has not been suggested during pregnancy. Fetal autopsy showed that all fetuses had large thumbs and/or suggestive facial dysmorphism. A CREBBP gene anomaly was identified in all cases. Alterations were similar to those found in typical RSTS children. This report will contribute to a better knowledge of the fetal phenotype to consider the hypothesis of RSTS during pregnancy. Genotyping allows reassuring genetic counseling.
What is the central question of this study?
Greater large artery stiffness is associated with dysfunctional resistance artery vasodilatory responses, impaired memory and greater Alzheimer's disease risk. However, it is unknown if stiffer large arteries affect cerebral and skeletal muscle feed artery responses to vasoconstrictors.
What is the main finding and its importance?
In a mouse model with greater large artery stiffness (Eln+/−), we find an exacerbated vasoconstriction response to angiotensin II in cerebral arteries, but not skeletal muscle feed arteries, thus implicating altered cerebral artery angiotensin II responsiveness in the poor brain outcomes associated with greater large artery stiffness.
Greater stiffness of the large elastic arteries is associated with end‐organ damage and dysfunction. At the same time, resistance artery vasoconstrictor responsiveness influences vascular tone and organ blood flow. However, it is unknown if large elastic artery stiffness modulates the responsiveness to vasoconstrictors in resistance arteries of the cerebral or skeletal muscle circulations. We previously described the elastin haploinsufficient (Eln+/−) mouse as a model with greater aortic stiffness, but with similar cerebral and skeletal muscle feed artery stiffness to wildtype (Eln+/+) mice. Here, we utilized this model to examine the relation between large elastic artery stiffness and resistance artery vasoconstrictor responses. In middle cerebral arteries (MCAs), vasoconstriction to angiotensin II (Ang II) was ∼40% greater in Eln+/‐ compared with Eln+/+ mice (p = 0.02), and this group difference was ameliorated by losartan, indicating a role for Ang II type 1 receptors (AT1Rs). In gastrocnemius feed arteries (GFAs), Eln+/− and Eln+/+ mice did not differ in the response to Ang II. In addition, the vasoconstrictor responses to norepinephrine, endothelin‐1, and potassium chloride were not different between Eln+/− and Eln+/+ mice for either MCAs or GFAs. MCA AT1R gene expression did not differ between groups, while Ang II type 2 receptor gene expression was ∼50% lower in MCAs from Eln+/− vs. Eln+/+ (p = 0.01). In conclusion, greater large elastic artery stiffness is associated with an exacerbated vasoconstriction response to Ang II in cerebral arteries, but not associated with the responses to other vasoconstrictors in cerebral or skeletal muscle feed arteries.
This article is protected by copyright. All rights reserved
Publication date: Available online 10 January 2019
Source: Journal of Environmental Radioactivity
Author(s): Kimiaki Saito, Satoshi Mikami, Masaki Andoh, Norihiro Matsuda, Sakae Kinase, Shuichi Tsuda, Tadayoshi Yoshida, Tetsuro Sato, Akiyuki Seki, Hideaki Yamamoto, Yukihisa Sanada, Haruko Wainwright-Murakami, Hiroshi Takemiya
We summarized temporal changes in air dose rates and radionuclide deposition densities over five years in the 80 km zone based on large-scale environmental monitoring data obtained continuously after the Fukushima Nuclear Power Plant (NPP) accident, including those already reported in the present and previous special issues. After the accident, multiple radionuclides deposited on the ground were detected over a wide area; radiocesium was found to be predominantly important from the viewpoint of long-term exposure. The relatively short physical half-life of 134Cs (2.06 y) has led to considerable reductions in air dose rates. The reduction in air dose rates owing to the radioactive decay of radiocesium was more than 60% over five years. Furthermore, the air dose rates in environments associated with human lives decreased at a considerably faster rate than expected for radioactive decay. The average air dose rate originating from the radiocesium deposited in the 80 km zone was lower than that predicted from radioactive decay by a factor of 2–3 at five years after the accident. Vertical penetration of radiocesium into the ground contributed greatly to the reduction in air dose rate because of an increase in the shielding of gamma rays; the estimated average reduction in air dose rate was approximately 25% with penetration compared to that without penetration. The average air dose rate measured in undisturbed fields in the 80 km zone was estimated to be reduced owing to decontamination by approximately 20% compared to that without decontamination. The average deposition density of radiocesium in undisturbed fields has decreased owing to radioactive decay, indicating that the migration of radiocesium in the horizontal direction has generally been slow. Nevertheless, in human living environments, horizontal radiocesium movement is considered to contribute significantly to the reduction in air dose rate. The contribution of horizontal radiocesium movement to the decrease in air dose rate was estimated to vary by up to 30% on average. Massive amounts of environmental data were used in extended analyses, such as the development of a predictive model or integrated air dose rate maps according to different measurement results, which facilitated clearer characterization of the contamination conditions. Ecological half-lives were evaluated in several studies by using a bi-exponential model. Short-term ecological half-lives were shorter than one year in most cases, while long-term ecological half-lives were different across the studies. Even though the general tendency of decrease in air dose rates and deposition densities in the 80 km zone were elucidated as summarized above, their trend was found to vary significantly according to location. Therefore, site-specific analysis is an important task in the future.
Temporal changes in average air dose rates due to deposited radiocesium observed by large-scale measurements using different methods in the 80-km zone.
Publication date: Available online 10 January 2019
Source: Archives of Physical Medicine and Rehabilitation
Author(s): Allison Peipert, Rachel Bond, Edeth Engel, Linda Ehrlich-Jones
Publication date: March 2019
Source: Journal of Human Evolution, Volume 128
Author(s): Adrián Pablos, Asier Gómez-Olivencia, Bruno Maureille, Trenton W. Holliday, Stéphane Madelaine, Erik Trinkaus, Christine Couture-Veschambre
Regourdou is a well-known Middle Paleolithic site which has yielded the fossil remains of a minimum of two Neandertal individuals. The first individual (Regourdou 1) is represented by a partial skeleton while the second one is represented by a calcaneus. The foot remains of Regourdou 1 have been used in a number of comparative studies, but to date a full description and comparison of all the foot remains from the Regourdou 1 Neandertal, coming from the old excavations and from the recent reanalysis of the faunal remains, does not exist. Here, we describe and comparatively assess the Regourdou 1 tarsals, metatarsals and phalanges. They display traits observed in other Neandertal feet, which are different from some traits of the Sima de los Huesos (Atapuerca) hominins and of Middle Paleolithic, Upper Paleolithic and recent modern humans. These Neandertal features are: a rectangular talar trochlea with a large lateral malleolar facet, a broad talar head, a broad calcaneus with a projecting sustentaculum tali, a wide and wedged navicular with a projecting medial tubercle, large and wide bases of the lateral metatarsals, and mediolaterally expanded and robust phalanges that also show hallux valgus in a strongly built hallux.
Publication date: March 2019
Source: Journal of Human Evolution, Volume 128
Author(s): Emma Loftus, Julia Lee-Thorp, Melanie Leng, Curtis Marean, Judith Sealy
This study assesses the seasonal scheduling of shellfish harvesting among hunter-gatherer populations along the southernmost coast of South Africa, based on a large number of serial oxygen isotope analyses of marine mollusk shells from four archaeological sites. The south coast of South Africa boasts an exceptional record of coastal hunter-gatherer occupation spanning the Holocene, the last glacial cycle and beyond. The significance of coastal adaptations, in this region in particular, for later modern human evolution has been prominently debated. Shellfishing behaviors are an important focus for investigation given the dietary and scheduling implications and the abundant archaeological shell remains in numerous sites. Key to better understanding coastal foraging is whether it was limited to one particular season, or year-round. Yet, this has proven very difficult to establish by conventional archaeological methods. This study reconstructs seasonal harvesting patterns by calculating water temperatures from the final growth increment of shells. Results from two Later Stone Age sites, Nelson Bay Cave (together with the nearby Hoffman's Robberg Cave) and Byneskranskop 1, show a pronounced cool season signal, which is unexpected given previous ethnographic documentation of summer as the optimal season for shellfishing activities and inferences about hunter-gatherer scheduling and mobility in the late Holocene. Results from two Middle Stone Age sites, Klasies River and Pinnacle Point 5–6, show distinct seasonal patterns that likely reflect the seasonal availability of resources in the two locations. The Pinnacle Point 5–6 assemblage, which spans the MIS5-4 transition, records a marked shift in shellfishing seasonality at c. 71 ka that aligns with other indications of archaeological and environmental change at this time. We conclude that the scheduling and intensity of shellfishing in this region is affected by a suite of factors, including environmental and cultural drivers, rather than a single variable, such as population growth.
Publication date: Available online 11 January 2019
Source: Journal of Human Evolution
Author(s): Laurence Dumouchel, René Bobe
The Pliocene site of Kanapoi is key to our understanding of the environmental context of the earliest species of Australopithecus. Various approaches have been used to reconstruct the environments of this site, and here we contribute new data and analyses using mesowear and hypsodonty. The dental traits of 98 bovids, suids and rhinocerotids from Kanapoi were analyzed using these proxies. Results indicate that most of the animals analyzed had a relatively abrasive diet. Bovids in the assemblage incorporated more grass into their diet than do modern species of the same tribe or genus. Although Pliocene Kanapoi likely had complex environments, our analysis indicates that grassy habitats were a dominant component of the ecosystem, a conclusion that supports the results of previous investigations of the paleoecology of the site.
The plainfin midshipman fish (Porichthys notatus) is a species of marine teleost that produces acoustic signals that are important for mediating social behavior. The auditory sensitivity of the saccule is well established in this species, but the sensitivity and function of the midshipman's putative auditory lagena are unknown. Here, we characterize the auditory-evoked potentials from hair cells in the lagena of reproductive type I males to determine the frequency response and auditory sensitivity of the lagena to behaviorally relevant acoustic stimuli. Lagenar potentials were recorded from the caudal and medial region of the lagena, while acoustic stimuli were presented by an underwater speaker. Our results indicate that the midshipman lagena has a similar low-frequency sensitivity to that of the midshipman saccule based on sound pressure and acceleration (re: 1 µPa and 1 ms−2, respectively), but the thresholds of the lagena were higher across all frequencies tested. The relatively high auditory thresholds of the lagena may be important for encoding high levels of behaviorally relevant acoustic stimuli when close to a sound source.
Adrenal insufficiency is characterized by the deficiency of circulating adrenocortical hormones and can be primary or central.1 Primary adrenal insufficiency is due to disease of the adrenal cortex, central adrenal insufficiency to a deficit in hypothalamic/pituitary secretion of adrenocorticotropic hormone.1 Patients with adrenal insufficiency require basal steroid replacement and need supplemental glucocorticoids (GC) during periods of medical stress.
This article is protected by copyright. All rights reserved.
Using "sniffer" cell biosensors, we evaluated the effects of specific firing patterns and frequencies on activity‐dependent somatodendritic release of VP from PVN neurones. Somatodendritic release of VP was rarely observed during continuous firing but was strengthened by clustered activity. Moreover, release evoked at any given frequency was robustly potentiated by NMDAR‐mediated firing. Differently from axonal release, NMDAR activation was necessary for somatodendritic release to occur at physiological firing frequencies, acting thus as a gating mechanism by which activity‐dependent release from these two neuroneal compartments could be independently regulated. The NMDAR‐mediated potentiation was independent of a specific firing pattern and was not accompanied by increased spike broadening, but correlated with higher dendritic Ca2+ levels. Our studies provide fundamental novel information regarding stimulus‐secretion coupling at somatodendritic compartments, and shed light into mechanisms by which activity‐dependent release of neuronal signals from axonal terminals and dendrites could be regulated in a spatially compartmentalized manner.
Dendrites are now recognized to be active transmitting neuronal compartments subserving complex brain functions, including motor behaviours and homeostatic neurohumoral responses. Still, the precise mechanisms underlying activity‐dependent release of dendritic signals, and how dendritic release is regulated independently from axonal release, remains largely unknown. We used "sniffer" biosensor cells to enable the measurement and study of activity‐dependent dendritic release of vasopressin (VP) from hypothalamic neurones in brain slices. SnifferVP responses were dose‐dependent, with a threshold detection level of 0.5 nm for VP, being thus a highly sensitive tool to detect endogenous physiological levels of the neuropeptide. Somatodendritic release of VP was rarely observed in response to a burst of action potentials fired in continuous mode, but was strengthened by clustered firing activity. Moreover, release evoked at any given frequency was robustly potentiated when firing was triggered by NMDA receptor (NMDAR) activation. Differently from axonal release, NMDAR activation was necessary for dendritic release to occur at physiological firing frequencies. Thus, we propose that NMDARs may act as a gating mechanism by which activity‐dependent release from these two neuronal compartments can be independently regulated. The NMDAR‐mediated potentiation of dendritic release was independent of a particular action potential waveform, firing pattern evoked, or a more pronounced spiked broadening, but correlated with higher dendritic Ca2+ levels. Overall, our studies provide fundamental novel information regarding stimulus‐secretion coupling at neuronal dendrites, and shed light into mechanisms by which activity‐dependent release of neuronal signals from axonal terminals and dendrites can be regulated in a spatially compartmentalized manner.
This article is protected by copyright. All rights reserved
Nausea is an adverse experience characterised by alterations in autonomic and cerebral function. Susceptibility to nausea is difficult to predict, but machine learning has yet to be applied to this field of study. The severity of nausea that individuals experience is related to the underlying morphology (shape) of the subcortex; namely of the amygdala, caudate and putamen. A functional brain network related to nausea severity was identified, which included the thalamus, cingulate cortices (anterior, mid and posterior), caudate nucleus and nucleus accumbens. Sympathetic nervous system function and sympathovagal balance was closely related to both this nausea‐associated anatomical variation and functional connectivity network. Machine learning accurately predicted susceptibility or resistance to nausea. These novel anatomical and functional brain biomarkers for nausea severity may permit objective identification of individuals susceptible to nausea, using artificial intelligence/machine learning. Brain data may be useful to identify individuals more susceptible to nausea.
Nausea is a highly individual and variable experience. The central processing of nausea remains poorly understood, although numerous influential factors have been proposed including brain structure, function and autonomic nervous system (ANS) activity. We investigated the role of these factors in nausea severity and if susceptibility to nausea could be predicted using machine learning.
28 healthy participants (15 male; mean age 24 years) underwent quantification of resting sympathetic and parasympathetic nervous system activity. All were exposed to a 10‐minute motion‐sickness video during fMRI. Neuroanatomical shape differences of the subcortex and functional brain networks associated with the severity of nausea were investigated. A machine learning neural network was trained to predict nausea susceptibility, or resistance, using baseline ANS data and detected brain features.
Increasing nausea scores positively correlated with shape variation of the left amygdala, right caudate and bilateral putamen (corrected‐p = 0.05). A functional brain network active in participants reporting nausea was identified implicating the thalamus, anterior, middle and posterior cingulate cortices, caudate nucleus and nucleus accumbens (corrected‐p = 0.043). Both neuroanatomical differences and the functional nausea‐brain network were closely related to sympathetic nervous system activity. Using these data, a machine learning model predicted susceptibility to nausea with an overall accuracy of 82.1%.
Nausea severity relates to underlying subcortical morphology and a functional brain network in its experience; both measures are potential biomarkers in trials of anti‐nausea therapies. The use of machine learning should be further investigated as an objective means to develop models predicting nausea susceptibility.
This article is protected by copyright. All rights reserved
Tymothy syndrome (TS) is a multisystem disorder featuring cardiac arrhythmias, autism and adrenal gland dysfunction that originates from a de‐novo point‐mutation in the gene encoding Cav1.2 (CACNA1C) L‐type channel. To study the role of Cav1.2 channel signals on autism, the autistic TS2‐neo mouse has been generated bearing the G406R point‐mutation associated with TS type‐2. Using heterozygous TS2‐neo mice, we report that the G406R mutation reduces the rate of inactivation and shifts leftward the activation and inactivation of L‐type channels, causing marked increase of resting Ca2+‐influx ("window" Ca2+‐current). The increased "window current" causes marked reduction of NaV channel‐density, switches normal tonic firing in abnormal burst firing, reduces mitochondria metabolism, induces cell swelling and decreases catecholamine release. Overnight incubations with nifedipine rescue NaV channel‐density, the normal firing and the quantity of catecholamine released. We provide evidence that chromaffin cells malfunction derives from altered Cav1.2 channel‐gatings. L‐type voltage‐gated calcium channels (Cav1) have a key role in long‐term synaptic plasticity, sensory transduction, muscle contraction and hormone release. A point mutation in the gene encoding Cav1.2 (CACNA1C) causes Tymothy syndrome (TS), a multisystem disorder featuring cardiac arrhythmias, autism spectrum disorder (ASD) and adrenal gland dysfunction. In the more severe type‐2 form (TS2), the missense mutation G406R is on exon 8 coding for the IS6‐helix of Cav1.2 channel. The mutation causes reduced inactivation and induces autism. How this occurs and how Cav1.2 gating‐changes alter cell excitability, neuronal firing and hormone release on molecular basis is still widely unknown.
Here, using the TS2‐neo mouse model of Timothy syndrome we show that the G406R mutation alters excitability and reduces secretory activity in adrenal chromaffin cells (CCs). Specifically, the TS2‐mutation reduces the rate of voltage‐dependent inactivation and shifts leftward the activation and steady state inactivation of L‐type channels. This markedly increases the resting "window" Ca2+ current that causes an increased percentage of CCs undergoing abnormal action potential (AP) burst firing, cell swelling, reduced mitochondrial metabolism and decreased catecholamine release. The increased "window Ca2+‐current" causes also decreased NaV channel‐density and increased steady‐state inactivation that contribute to the increased abnormal burst firing. Overnight incubation with the L‐type channel blocker nifedipine rescues the normal AP firing of CCs, the density of functioning NaV channels and their steady‐state inactivation. We provide evidence that CCs malfunction derives from the altered Cav1.2 channel gating and that dihydropyridines are potential therapeutics for ASD.
This article is protected by copyright. All rights reserved
Myotonic dystrophy type 1 (DM1), the second most common muscular dystrophy and most prevalent adult form of muscular dystrophy, is characterized by muscle weakness, wasting, and myotonia. A microsatellite repeat expansion mutation results in RNA toxicity and dysregulation of mRNA processing, which are the primary downstream causes of the disorder. Recent studies with DM1 participants demonstrate that exercise is safe, enjoyable, and elicits benefits in muscle strength and function, however the molecular mechanisms of exercise adaptation in DM1 are undefined. Our results demonstrate that 7‐weeks of volitional running wheel exercise in a pre‐clinical DM1 mouse model resulted in significantly improved motor performance, muscle strength and endurance, as well as reduced myotonia. At the cellular level, chronic physical activity attenuated RNA toxicity, liberated muscleblind‐like 1 protein from myonuclear foci, and improved mRNA alternative splicing.
Myotonic dystrophy type 1 (DM1) is a trinucleotide repeat expansion neuromuscular disorder that is most prominently characterized by skeletal muscle weakness, wasting, and myotonia. Chronic physical activity is safe, satisfying, and can elicit functional benefits such as improved strength and endurance in DM1 patients, however the underlying cellular basis of exercise adaptation is undefined. Our purpose was to examine the mechanisms of exercise biology in DM1. Healthy, sedentary wild‐type (SED‐WT) mice, as well as sedentary human skeletal actin‐long repeat animals, a murine model of DM1 myopathy (SED‐DM1), and DM1 mice with volitional access to a running wheel for 7 weeks (EX‐DM1), were utilized. Chronic exercise augmented strength and endurance in vivo and in situ in DM1 mice. These alterations coincided with normalized measures of myopathy, as well as increased mitochondrial content. Electromyography revealed a 70–85% decrease in the duration of myotonic discharges in muscles from EX‐DM1 compared to SED‐DM1 animals. The exercise‐induced enhancements in muscle function corresponded at the molecular level with mitigated spliceopathy, specifically the processing of bridging integrator 1 and muscle‐specific chloride channel (CLC‐1) transcripts. CLC‐1 protein content and sarcolemmal expression were lower in SED‐DM1 versus SED‐WT animals, however they were similar between SED‐WT and EX‐DM1 groups. Chronic exercise also attenuated RNA toxicity, as indicated by reduced CUG)n foci‐positive myonuclei and sequestered muscleblind‐like 1 (MBNL1). Our data indicate that chronic exercise‐induced physiological improvements in DM1 occur in concert with mitigated primary downstream disease mechanisms, including RNA toxicity, MBNL1 loss‐of‐function, and alternative mRNA splicing.
This article is protected by copyright. All rights reserved
