A C-terminal motif containing a PKC phosphorylation site regulates γ-Protocadherin-mediated dendrite arborization in the cerebral cortex in vivo.

The Pcdhg gene cluster encodes 22 γ-Protocadherin (γ-Pcdh) cell adhesion molecules that critically regulate multiple aspects of neural development, including neuronal survival, dendritic and axonal arborization, and synapse formation and maturation. Each γ-Pcdh isoform has unique protein domains-a homophilically-interacting extracellular domain and a juxtamembrane cytoplasmic domain-as well as a C-terminal cytoplasmic domain shared by all isoforms. The extent to which isoform-specific vs. shared domains regulate distinct γ-Pcdh functions remains incompletely understood. Our previous in vitro studies identified PKC phosphorylation of a serine residue within a shared C-terminal motif as a mechanism through which γ-Pcdh promotion of dendrite arborization via MARCKS is abrogated. Here, we used CRISPR/Cas9 genome editing to generate two new mouse lines expressing only non-phosphorylatable γ-Pcdhs, due either to a serine-to-alanine mutation (PcdhgS/A) or to a 15-amino acid C-terminal deletion resulting from insertion of an early stop codon (PcdhgCTD). Both lines are viable and fertile, and the density and maturation of dendritic spines remains unchanged in both PcdhgS/A and PcdhgCTD cortex. Dendrite arborization of cortical pyramidal neurons, however, is significantly increased in both lines, as are levels of active MARCKS. Intriguingly, despite having significantly reduced levels of γ-Pcdh proteins, the PcdhgCTD mutation yields the strongest phenotype, with even heterozygous mutants exhibiting increased arborization. The present study confirms that phosphorylation of a shared C-terminal motif is a key γ-Pcdh negative regulation point, and contributes to a converging understanding of γ-Pcdh family function in which distinct roles are played by both individual isoforms and discrete protein domains.

Off Starburst Amacrine Cells in the Retina Trigger Looming-Evoked Fear Responses in Mice.

A rapidly approaching dark object evokes an evolutionarily conserved fear response in both vertebrates and invertebrates, young to old. A looming visual stimulus mimics an approaching object and triggers a similarly robust fear response in mice, resulting in freeze and flight. However, the retinal neural pathway responsible for this innate response has not been fully understood. We first explored a variety of visual stimuli that reliably induced these innate responses, and found that a looming stimulus with 2-d acclimation consistently evoked fear responses. Because the fear responses were triggered by the looming stimulus with moving edges, but not by a screen flipping from light to dark, we targeted the starburst amacrine cells (SACs), crucial neurons for retinal motion detection. We used intraocular injection of diphtheria toxin (DT) in mutant mice expressing diphtheria toxin receptors (DTR) in SACs. The looming-evoked fear responses disappeared in half of the DT-injected mice, and the other mice still exhibited the fear responses. The optomotor responses (OMRs) were reduced or eliminated, which occurred independent of the disappearance of the fear responses. A histologic examination revealed that ON SACs were reduced in both mouse groups preserved or absent fear responses. In contrast, the number of OFF SACs was different among two groups. The OFF SACs were relatively preserved in mice exhibiting continued fear responses, whereas they were ablated in mice lacking fear response to looming stimulation. These results indicate that OFF SACs and the direction-selective pathway in the retina play a role in looming-induced fear behaviors.

γ-Protocadherins control synapse formation and peripheral branching of touch sensory neurons.

Light touch sensation begins with activation of low-threshold mechanoreceptor (LTMR) endings in the skin and propagation of their signals to the spinal cord and brainstem. We found that the clustered protocadherin gamma (Pcdhg) gene locus, which encodes 22 cell-surface homophilic binding proteins, is required in somatosensory neurons for normal behavioral reactivity to a range of tactile stimuli. Developmentally, distinct Pcdhg isoforms mediate LTMR synapse formation through neuron-neuron interactions and peripheral axonal branching through neuron-glia interactions. The Pcdhgc3 isoform mediates homophilic interactions between sensory axons and spinal cord neurons to promote synapse formation in vivo and is sufficient to induce postsynaptic specializations in vitro. Moreover, loss of Pcdhgs and somatosensory synaptic inputs to the dorsal horn leads to fewer corticospinal synapses on dorsal horn neurons. These findings reveal essential roles for Pcdhg isoform diversity in somatosensory neuron synapse formation, peripheral axonal branching, and stepwise assembly of central mechanosensory circuitry.

Short-term heat acclimation protocols for an aging population: Systematic review.

INTRODUCTION: Elderly and sedentary individuals are particularly vulnerable to heat related illness. Short-term heat acclimation (STHA) can decrease both the physical and mental stress imposed on individuals performing tasks in the heat. However, the feasibility and efficacy of STHA protocols in an older population remains unclear despite this population being particularly vulnerable to heat illness. The aim of this systematic review was to investigate the feasibility and efficacy of STHA protocols (≤twelve days, ≥four days) undertaken by participants over fifty years of age. METHODS: Academic Search Premier, CINAHL Complete, MEDLINE, APA PsycInfo, and SPORTDiscus were searched for peer reviewed articles. The search terms were; (heat* or therm*) N3 (adapt* or acclimati*) AND old* or elder* or senior* or geriatric* or aging or ageing. Only studies using primary empirical data and which included participants ≥50 years of age were eligible. Extracted data includes participant demographics (sample size, gender, age, height, weight, BMI and [Formula: see text]), acclimation protocol details (acclimation activity, frequency, duration and outcome measures taken) and feasibility and efficacy outcomes. RESULTS: Twelve eligible studies were included in the systematic review. A total of 179 participants took part in experimentation, 96 of which were over 50 years old. Age ranged from 50 to 76. All twelve of the studies involved exercise on a cycle ergometer. Ten out of twelve protocols used a percentage of [Formula: see text] or [Formula: see text] to determine the target workload, which ranged from 30% to 70%. One study-controlled workload at 6METs and one implemented an incremental cycling protocol until Tre was reached +0.9°C. Ten studies used an environmental chamber. One study compared hot water immersion (HWI) to an environmental chamber while the remaining study used a hot water perfused suit. Eight studies reported a decrease in core temperature following STHA. Five studies demonstrated post-exercise changes in sweat rates and four studies showed decreases in mean skin temperature. The differences reported in physiological markers suggest that STHA is viable in an older population. CONCLUSION: There remains limited data on STHA in the elderly. However, the twelve studies examined suggest that STHA is feasible and efficacious in elderly individuals and may provide preventative protection to heat exposures. Current STHA protocols require specialised equipment and do not cater for individuals unable to exercise. Passive HWI may provide a pragmatic and affordable solution, however further information in this area is required.

A Unique Role for Protocadherin γC3 in Promoting Dendrite Arborization through an Axin1-Dependent Mechanism.

The establishment of a functional cerebral cortex depends on the proper execution of multiple developmental steps, culminating in dendritic and axonal outgrowth and the formation and maturation of synaptic connections. Dysregulation of these processes can result in improper neuronal connectivity, including that associated with various neurodevelopmental disorders. The γ-Protocadherins (γ-Pcdhs), a family of 22 distinct cell adhesion molecules that share a C-terminal cytoplasmic domain, are involved in multiple aspects of neurodevelopment including neuronal survival, dendrite arborization, and synapse development. The extent to which individual γ-Pcdh family members play unique versus common roles remains unclear. We demonstrated previously that the γ-Pcdh-C3 isoform (γC3), via its unique "variable" cytoplasmic domain (VCD), interacts in cultured cells with Axin1, a Wnt-pathway scaffold protein that regulates the differentiation and morphology of neurons. Here, we confirm that γC3 and Axin1 interact in the cortex in vivo and show that both male and female mice specifically lacking γC3 exhibit disrupted Axin1 localization to synaptic fractions, without obvious changes in dendritic spine density or morphology. However, both male and female γC3 knock-out mice exhibit severely decreased dendritic complexity of cortical pyramidal neurons that is not observed in mouse lines lacking several other γ-Pcdh isoforms. Combining knock-out with rescue constructs in cultured cortical neurons pooled from both male and female mice, we show that γC3 promotes dendritic arborization through an Axin1-dependent mechanism mediated through its VCD. Together, these data identify a novel mechanism through which γC3 uniquely regulates the formation of cortical circuitry.SIGNIFICANCE STATEMENT The complexity of a neuron's dendritic arbor is critical for its function. We showed previously that the γ-Protocadherin (γ-Pcdh) family of 22 cell adhesion molecules promotes arborization during development; it remained unclear whether individual family members played unique roles. Here, we show that one γ-Pcdh isoform, γC3, interacts in the brain with Axin1, a scaffolding protein known to influence dendrite development. A CRISPR/Cas9-generated mutant mouse line lacking γC3 (but not lines lacking other γ-Pcdhs) exhibits severely reduced dendritic complexity of cerebral cortex neurons. Using cultured γC3 knock-out neurons and a variety of rescue constructs, we confirm that the γC3 cytoplasmic domain promotes arborization through an Axin1-dependent mechanism. Thus, γ-Pcdh isoforms are not interchangeable, but rather can play unique neurodevelopmental roles.

It Is Official, They Are Different - Discrepancies Between National Statistical Agency and Register-Based State Suicide Mortality Statistics in Australia.

Background: In Australia, most state-based suicide registers now publicly release suicide mortality data alongside those the Australian Bureau of Statistics (ABS) releases annually. Aims: This study compared ABS's recorded suicides with three state-based suicide registers (Queensland, Victoria, and Tasmania). We compared their case definitions and coding approaches to assist users in choosing the most suitable data source and interpret differences between sources. Method: We collated the number of suicides by year of registration and occurrence (2006-2020). We compared the scope and coding of suicides between ABS and the registers using publicly available suicide reports and data releases. Results: The ABS's annual suicide numbers are similar to (and in Tasmania exceed) the numbers reported by state-based registers. The ABS year of occurrence data diverges substantially from the Victoria and Queensland register data in 2020, perhaps attributable to ongoing ABS revision processes. Minimal overlap exists between the case definitions and coding practices of the ABS and registers. Limitations: This is not an individual-level concordance study. Conclusion: Despite different case definitions and coding practices, the two sources produced largely consistent data. They have complementary strengths: timeliness (suicide register data) and enabling cross-jurisdictional comparisons (ABS data).

How Virtual Animal Anatomy facilitated a successful transition to online instruction and supported student learning during the coronavirus pandemic.

Anatomy faculty with cadaver-based laboratory courses were presented with a significant challenge in March 2020 to create equivalent learning experiences without cadaveric access. The undergraduate domestic animal anatomy course at the Colorado State University was halfway into a 16-week semester when COVID-19 lockdown orders and the transition to remote instruction began. The new course curriculum was critically evaluated using student surveys and course outcome data. Most students (92.5%) agreed that the transition to online learning was a success; however, students who valued face-to-face lectures prior to March were less likely to perceive the transition as a success. Qualitative and quantitative analyses of survey results suggest that the resources perceived as most helpful for the transition to online learning were not the same as those that helped facilitate animal anatomy learning. Most students (92.5%) agreed that the Virtual Animal Anatomy (VAA) helped them learn anatomy, and 82.2% indicated that the VAA was a valuable resource following the transition to online learning. Additional resources associated with transition success included course instructors, weekly quizzes, written descriptions of anatomical structures and open laboratory sessions. In contrast, those resources associated with facilitating learning included guided quizzes and asynchronous lecture recordings. These findings suggest that the VAA can support online anatomy learning when used in conjunction with other best practices for online teaching.

Effectiveness of short-term isothermic-heat acclimation (4 days) on physical performance in moderately trained males.

INTRODUCTION: A typical heat acclimation (HA) protocol takes 5-7 d of 60-90 minutes of heat exposure. Identifying the minimum dose of HA required to elicit a heat adapted phenotype could reduce financial constraints on participants and aid in the tapering phase for competition in hot countries. Therefore, the aim of this study was to investigate a 4 d HA regimen on physical performance. METHODS: Twelve moderately trained males were heat acclimated using controlled hyperthermia (Tre>38.5°C), with no fluid intake for 90 min on 4 consecutive days, with a heat stress test (HST) being completed one week prior to (HST2), and within one-week post (HST3) HA. Eleven completed the control study of HST1 versus HST2, one week apart with no intervention. Heat stress tests comprised of cycling for 90 min @ 40% Peak Power Output (PPO); 35°C; 60%RH followed by 10 minutes of passive recovery before an incremental test to exhaustion. Physical performance outcomes time to exhaustion (TTE), PPO, end rectal temperature (Tre END), and heart rate (HREND) was measured during the incremental test to exhaustion. RESULTS: Physiological markers indicated no significant changes in the heat; however descriptive statistics indicated mean resting Tre lowered 0.24°C (-0.54 to 0.07°C; d = 2.35: very large) and end-exercise lowered by 0.32°C (-0.81 to 0.16; d = 2.39: very large). There were significant improvements across multiple timepoints following HA in perceptual measures; Rate of perceived exertion (RPE), Thermal Sensation (TS), and Thermal Comfort (TC) (P<0.05). Mean TTE in the HST increased by 142 s (323±333 to 465±235s; P = 0.04) and mean PPO by 76W (137±128 to 213±77 W; P = 0.03). CONCLUSION: Short-term isothermic HA (4 d) was effective in enhancing performance capacity in hot and humid conditions. Regardless of the level of physiological adaptations, behavioural adaptations were sufficient to elicit improved performance and thermotolerance in hot conditions. Additional exposures may be requisite to ensure physiological adaptation.

Suicide numbers during the first 9-15 months of the COVID-19 pandemic compared with pre-existing trends: An interrupted time series analysis in 33 countries.

Background: Predicted increases in suicide were not generally observed in the early months of the COVID-19 pandemic. However, the picture may be changing and patterns might vary across demographic groups. We aimed to provide a timely, granular picture of the pandemic's impact on suicides globally. Methods: We identified suicide data from official public-sector sources for countries/areas-within-countries, searching websites and academic literature and contacting data custodians and authors as necessary. We sent our first data request on 22nd June 2021 and stopped collecting data on 31st October 2021. We used interrupted time series (ITS) analyses to model the association between the pandemic's emergence and total suicides and suicides by sex-, age- and sex-by-age in each country/area-within-country. We compared the observed and expected numbers of suicides in the pandemic's first nine and first 10-15 months and used meta-regression to explore sources of variation. Findings: We sourced data from 33 countries (24 high-income, six upper-middle-income, three lower-middle-income; 25 with whole-country data, 12 with data for area(s)-within-the-country, four with both). There was no evidence of greater-than-expected numbers of suicides in the majority of countries/areas-within-countries in any analysis; more commonly, there was evidence of lower-than-expected numbers. Certain sex, age and sex-by-age groups stood out as potentially concerning, but these were not consistent across countries/areas-within-countries. In the meta-regression, different patterns were not explained by countries' COVID-19 mortality rate, stringency of public health response, economic support level, or presence of a national suicide prevention strategy. Nor were they explained by countries' income level, although the meta-regression only included data from high-income and upper-middle-income countries, and there were suggestions from the ITS analyses that lower-middle-income countries fared less well. Interpretation: Although there are some countries/areas-within-countries where overall suicide numbers and numbers for certain sex- and age-based groups are greater-than-expected, these countries/areas-within-countries are in the minority. Any upward movement in suicide numbers in any place or group is concerning, and we need to remain alert to and respond to changes as the pandemic and its mental health and economic consequences continue. Funding: None.

The cross-over of statistical thinking and practices: A pandemic catalyst.

Written during the SARS-CoV-2 pandemic, and in recognition of Andy Grieve, the polymath, this article looks at an eclectic mix of topics where statistical thinking and practices should transcend typical dividing lines-with a particular focus on the areas of drug development, public health and social science. The case is made for embedding an experimental (or quasi-experimental) framework within clinical practice for vaccines and treatments following their marketing authorisation. A similar case is made for public health interventions-facilitated by pre-specification of effect size and by the greater use of data standards. A number of recommendations are made whilst noting that progress is being made in some areas.

Mouse models for the study of clustered protocadherins.

Since their first description, the clustered protocadherins (cPcdhs) have sparked interest for their potential to generate diverse cell-surface recognition cues and their widespread expression in the nervous system. Through the use of mouse models, we have learned a great deal about the functions served by cPcdhs, and how their molecular diversity is regulated. cPcdhs are essential contributors to a host of processes during neural circuit formation, including neuronal survival, dendritic and axonal branching, self-avoidance and targeting, and synapse formation. Their expression is controlled by the interplay of epigenetic marks with proximal and distal elements involving high order DNA looping, regulating transcription factor binding. Here, we will review various mouse models targeting the cPcdh locus and how they have been instructive in uncovering the regulation and function of the cPcdhs.

Retinal cadherins and the retinal cadherinopathies: Current concepts and future directions.

Cadherins are a superfamily of calcium-dependent intercellular adhesion molecules that are widely expressed in living tissues. Within the retina and retinal pigment epithelium (RPE), cadherins contribute to tissue morphogenesis, neural circuit formation, adherens junctions of the outer blood-retinal barrier, photoreceptor disc morphogenesis, maintenance and survival. Four monogenic disorders involving genes which encode cadherins have been identified as causes of inherited retinal degeneration: the retinal cadherinopathies (CDHR1, CDH23, PCDH15, CDH3). Biallelic variants in CDHR1 result in cone-rod dystrophy, rod-cone dystrophy or late-onset macular dystrophy which may be misclassified as dry age-related macular degeneration. Biallelic variants in CDH23 and PCDH15 underlie Usher Syndrome type 1D and 1F. Hypotrichosis with juvenile macular dystrophy results from biallelic variants in CDH3, which contributes to adherens tight junctions between RPE cells. In this review, we summarise the classification of cadherins, and the role of cadherins in the physiology and morphogenesis of the inner and outer retina. Cadherins expressed in primate photoreceptors (CDHR1, CDH23 and PCDH15) have evolved complex roles in outer segment disc morphogenesis and maintenance involving intracellular heterophilic interactions which are as yet incompletely characterised. We highlight what is currently unknown about the molecular function of these cadherins, and review the pathogenesis, clinical phenotype and molecular genetics of each monogenic retinal cadherinopathy. Genes regulating the expression and post-translational modification of retinal cadherins, or those coding for as yet unidentified interacting partners, are candidates for unsolved cases of retinal degeneration. This group of disorders is potentially treatable; we summarise the likely molecular therapeutic approaches and future directions for each retinal cadherinopathy.

Adapting a Federal Disaster Medical Assistance Team to Operate During a Pandemic.

After Hurricane Laura struck the southeast coast of Louisiana in August 2020, the National Disaster Medical System (NDMS), a component of the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, deployed several 35-person disaster medical assistance teams in response to requests for medical support at 3 hospital locations that had been severely damaged in the storm. This was the first natural disaster medical deployment for NDMS during the coronavirus disease (COVID-19) pandemic. This article describes the modifications to the standard operating procedures that were made at 1 site to reduce the risk of infection to our patients and NDMS responders, including changes to the physical layout of the tenting, and alterations to the triage and treatment process.

Enhancing Anatomical Instruction: Impact of a Virtual Canine Anatomy Program on Student Outcomes.

Innovative reforms in medical education will require instructional tools to support these changes and to give students more flexibility in where and how they learn. At Colorado State University, the software program Virtual Canine Anatomy (VCA) was developed to assist student learning both inside and outside the anatomical laboratory. The program includes interactive anatomical photographs of dissected canine cadavers, dissection instructions with accompanying videos and diagrams, radiographs, and three-dimensional models. There is a need to evaluate the effectiveness of instructional tools like VCA so that decisions on pedagogical delivery can be evidence-based. To measure the impact of VCA on student outcomes in a dissection laboratory, this study compared student attitudes, quiz scores, dissection quality and accuracy, and instructor reliance between students with and without access to VCA. Students with VCA needed less time with teaching assistants (P < 0.01), asked teaching assistants fewer questions (P = 0.04), felt that the dissection was easier (P = 0.02), and were in stronger agreement that they had access to adequate resources (P = 0.02). No differences were found in the dissection quality or accuracy, quiz scores, or attitudes regarding overall enjoyment of the activity between the two groups. This study shows that VCA increases student independence and can be used to enhance anatomical instruction.

Patterns of Suicide in the Context of COVID-19: Evidence From Three Australian States.

Aims: We aimed to determine whether there has been a change in the number of suicides occurring in three Australian states overall, and in age and sex subgroups, since the COVID-19 pandemic began, and to see if certain risk factors for suicide have become more prominent as likely underlying contributing factors for suicide. Method: Using real-time data from three state-based suicide registers, we ran multiple unadjusted and adjusted interrupted time series analyses to see if trends in monthly suicide counts changed after the pandemic began and whether there had been an increase in suicides where relationship breakdown, financial stressors, unemployment and homelessness were recorded. Results: Compared with the period before COVID-19, during the COVID-19 period there was no change in the number of suicides overall, or in any stratum-specific estimates except one. The exception was an increase in the number of young males who died by suicide in the COVID-19 period (adjusted RR 1.89 [95% CI 1.11-3.23]). The unadjusted analysis showed significant differences in suicide in the context of unemployment and relationship breakdown during the COVID-19 compared to the pre-COVID-19 period. Analysis showed an increase in the number of suicides occurring in the context of unemployment in the COVID-19 period (unadjusted RR 1.53 [95% CI 1.18-1.96]). In contrast, there was a decrease in the number of suicides occurring in the context of relationship breakdown in the COVID-19 period (unadjusted RR 0.82 [95% CI 0.67-0.99]). However, no significant changes were identified when the models were adjusted for possible over-dispersion, seasonality and non-linear trend. Conclusion: Although our analysis found no evidence of an overall increase in suicides after the pandemic began, the picture is complex. The identified increase in suicide in young men indicates that the impact of the pandemic is likely unevenly distributed across populations. The increase in suicides in the context of unemployment reinforces the vital need for mitigation measures during COVID-19, and for ongoing monitoring of suicide as the pandemic continues.

Suicide trends in the early months of the COVID-19 pandemic: an interrupted time-series analysis of preliminary data from 21 countries.

BACKGROUND: The COVID-19 pandemic is having profound mental health consequences for many people. Concerns have been expressed that, at their most extreme, these consequences could manifest as increased suicide rates. We aimed to assess the early effect of the COVID-19 pandemic on suicide rates around the world. METHODS: We sourced real-time suicide data from countries or areas within countries through a systematic internet search and recourse to our networks and the published literature. Between Sept 1 and Nov 1, 2020, we searched the official websites of these countries' ministries of health, police agencies, and government-run statistics agencies or equivalents, using the translated search terms "suicide" and "cause of death", before broadening the search in an attempt to identify data through other public sources. Data were included from a given country or area if they came from an official government source and were available at a monthly level from at least Jan 1, 2019, to July 31, 2020. Our internet searches were restricted to countries with more than 3 million residents for pragmatic reasons, but we relaxed this rule for countries identified through the literature and our networks. Areas within countries could also be included with populations of less than 3 million. We used an interrupted time-series analysis to model the trend in monthly suicides before COVID-19 (from at least Jan 1, 2019, to March 31, 2020) in each country or area within a country, comparing the expected number of suicides derived from the model with the observed number of suicides in the early months of the pandemic (from April 1 to July 31, 2020, in the primary analysis). FINDINGS: We sourced data from 21 countries (16 high-income and five upper-middle-income countries), including whole-country data in ten countries and data for various areas in 11 countries). Rate ratios (RRs) and 95% CIs based on the observed versus expected numbers of suicides showed no evidence of a significant increase in risk of suicide since the pandemic began in any country or area. There was statistical evidence of a decrease in suicide compared with the expected number in 12 countries or areas: New South Wales, Australia (RR 0·81 [95% CI 0·72-0·91]); Alberta, Canada (0·80 [0·68-0·93]); British Columbia, Canada (0·76 [0·66-0·87]); Chile (0·85 [0·78-0·94]); Leipzig, Germany (0·49 [0·32-0·74]); Japan (0·94 [0·91-0·96]); New Zealand (0·79 [0·68-0·91]); South Korea (0·94 [0·92-0·97]); California, USA (0·90 [0·85-0·95]); Illinois (Cook County), USA (0·79 [0·67-0·93]); Texas (four counties), USA (0·82 [0·68-0·98]); and Ecuador (0·74 [0·67-0·82]). INTERPRETATION: This is the first study to examine suicides occurring in the context of the COVID-19 pandemic in multiple countries. In high-income and upper-middle-income countries, suicide numbers have remained largely unchanged or declined in the early months of the pandemic compared with the expected levels based on the pre-pandemic period. We need to remain vigilant and be poised to respond if the situation changes as the longer-term mental health and economic effects of the pandemic unfold. FUNDING: None.

Epidemiology of functional neurological disorder, active component, U.S. Armed Forces, 2000-2018.

Functional neurological disorder (FND) is a complex neuropsychiatric disorder characterized by abnormal or atypical sensorimotor, gait, dissociative, or special sensory symptoms in the absence of structural nervous system lesions to explain the symptoms. Several factors are thought to be associated with FND, including comorbid mental health conditions; exposure to physical, emotional, or sexual trauma; young age, and low socioeconomic status. U.S. military service members may be at increased risk for FND because of the prevalence of some of these factors. The current study evaluated the incidence of FND in the U.S. Armed Forces between 2000 and 2018. The overall incidence rate was 29.5 per 100,000 person-years, with the highest rates among women and individuals less than 20 years old. The overall median annual prevalence rate was 37.2 per 100,000 persons. In addition, there were 162 medical evacuations out of the Central Command (CENTCOM) area of responsibility for FND during the study period. Most medical evacuations occurred among men and those with no history of depression or post-traumatic stress disorder (PTSD).

CRISPR/Cas9 interrogation of the mouse Pcdhg gene cluster reveals a crucial isoform-specific role for Pcdhgc4.

The mammalian Pcdhg gene cluster encodes a family of 22 cell adhesion molecules, the gamma-Protocadherins (γ-Pcdhs), critical for neuronal survival and neural circuit formation. The extent to which isoform diversity-a γ-Pcdh hallmark-is required for their functions remains unclear. We used a CRISPR/Cas9 approach to reduce isoform diversity, targeting each Pcdhg variable exon with pooled sgRNAs to generate an allelic series of 26 mouse lines with 1 to 21 isoforms disrupted via discrete indels at guide sites and/or larger deletions/rearrangements. Analysis of 5 mutant lines indicates that postnatal viability and neuronal survival do not require isoform diversity. Surprisingly, given reports that it might not independently engage in trans-interactions, we find that γC4, encoded by Pcdhgc4, is the only critical isoform. Because the human orthologue is the only PCDHG gene constrained in humans, our results indicate a conserved γC4 function that likely involves distinct molecular mechanisms.

Effectiveness of Short-Term Heat Acclimation on Intermittent Sprint Performance With Moderately Trained Females Controlling for Menstrual Cycle Phase.

INTRODUCTION: Investigate the effectiveness of short-term heat acclimation (STHA), over 5-days (permissive dehydration), on an intermittent sprint exercise protocol (HST) with females. Controlling for menstrual cycle phase. MATERIALS AND METHODS: Ten, moderately trained, females (Mean [SD]; age 22.6 [2.7] y; stature 165.3 [6.2] cm; body mass 61.5 [8.7] kg; V . ⁢ O 2 ⁢ peak 43.9 [8.6] mL⋅kg-1⋅min-1) participated. The HST (31.0°C; 50%RH) was 9 × 5 min (45-min) of intermittent exercise, based on exercise intensities of female soccer players, using a motorized treadmill and Wattbike. Participants completed HST1 vs. HST2 as a control (C) trial. Followed by 90 min, STHA (no fluid intake), for five consecutive days in 39.5°C; 60%RH, using controlled-hyperthermia (∼rectal temperature [Tre] 38.5°C). The HST3 occurred within 1 week after STHA. The HST2 vs HST3 trials were in the luteal phase, using self-reported menstrual questionnaire and plasma 17ß-estradiol. RESULTS: Pre (HST2) vs post (HST3) STHA there was a reduction at 45-min in T re by 0.20°C (95%CI -0.30 to -0.10°C; d = 0.77); T ¯ s ⁢ k (-0.50; -0.90 to -0.10°C; d = 0.80); and T ¯ b (-0.25; -0.35 to -0.15°C; d = 0.92). Cardiac frequency reduced at 45-min (-8; -16 to -1 b⋅min-1; d = 1.11) and %PV increased (7.0; -0.4 to 14.5%: d = 1.27). Mean power output increased across all nine maximal sprints by 56W (-26 to 139W; d = 0.69; n = 9). There was limited difference (P > 0.05) for these measures in HST1 vs HST2 C trial. DISCUSSION: Short-term heat acclimation (5-days) using controlled-hyperthermia, leads to physiological adaptation during intermittent exercise in the heat, in moderately trained females when controlling for menstrual cycle phase.