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.

Highlights From the 2023 Revision of Pediatric Tactical Emergency Casualty Care Guidelines.

ABSTRACT: In 2023 the Committee for Tactical Emergency Casualty Care (C-TECC) issued updated Pediatric Tactical Emergency Casualty Care (TECC) Guidelines (Guidelines) that focus on the delivery of stabilizing care of children who are the victims of high-threat incidents such as an active shooter event. The Guidelines provide evidence-based and best practice recommendations to those individuals and departments that specifically provide operational medical support to law enforcement agencies caring for children in this uniquely dangerous environment where traditional resources may not be available. This article highlights key takeaway points from the Guidelines, including several updates since the first version was released in 2013.The evidence base for the care of children in this environment is lacking, and medical care delivered in the high-threat environment is inconsistent and often not optimized for the care of infants and children. The Guidelines are supported from the existing literature base where possible, and where it is not, by consensus as to the current best practices as determined by iterative deliberations among the diverse and experienced group of stakeholders who are members of C-TECC. The Guidelines provide patient assessment and management information specific to the care of children in the following 3 dynamic phases of the high-threat environment: Direct Threat, Indirect Threat, and Evacuation. The phases represent a continuum of risk to the patient and the responder ranging from extreme (such as ongoing gunfire) to minimal (during movement toward definitive medical care).The high-threat environment is dynamic and there is competing safety, tactical/operational, and patient care priorities for responders when infants and children are injured. The Guidelines provide recommendations on the type of medical and psychological care that should be considered under each phase of threat and establishes the context for how and why to deliver (or potentially defer) certain interventions under some circumstances in order the maximize the opportunity for a good outcome for an injured pediatric patient. The Guidelines also emphasize the importance of synergizing hospital-based pediatric trauma care with those law enforcement and fire/emergency medical services that may provide field care to children under high-threat circumstances.

The repeatability of a cycling exercise-heat stress test in a male population.

INTRODUCTION: There is considerable inter-individual variability in the physiological responses to environmental stressors and so to accurately assess and monitor changes in an individual's ability to cope with exercise-heat stress, a reliable protocol is required. The aim of this study was to examine the repeatability of a 90-min steady-state heat exercise bout with physiological and subjective variables, and performance during an incremental test to exhaustion post 90-min steady-state exercise. METHOD: Sixteen mixed ability males (Age: 39 ± 15yrs; Height: 176.5 ± 4.8 cm; BM: 79.7 ± 10.3 kg; V˙O2peak: 46.2 ± 8.6 ml/kg/min; PPO: 309 ± 39W) who trained at least three times a week undertook two 90-min steady-state - followed by an incremental protocol to exhaustion - cycling heat stress tests (HSTs) in a hot-humid environment (35 °C, 60%RH). Heart rate (HR), rectal (T‾re) and skin temperature (T‾sk), rating of perceived exertion (RPE), thermal sensation (TS), and thermal comfort (TC) were measured throughout. Data was analysed using Intraclass Correlation Coefficients (ICC), technical error of measurement (TEM), Bland-Altman plots, t-tests, and Cohen's d to indicate magnitude of change. RESULTS: Physiological variables indicated good repeatability evident through moderate to strong ICC ratings, low magnitudes of change (d), lower mean biases compared to their respective calculated TEMs, and statistical non-significance, except HR90, ₸sk90, and ₸sk. Hydration status showed good repeatability except for urine osmolality (osmu90) and resting urine colour (colu). Perceptual variables showed encouraging repeatability apart from resting TS and mean TS. Performance data showed good repeatability overall, however 11 participants progressed to the incremental test to exhaustion in the second visit compared to 7 in the first. CONCLUSION: Current data demonstrated favourable physiological, perceptual, and performance repeatability during repeated cycling HSTs in hot-humid conditions. However, given more participants progressed to the incremental trial to exhaustion protocol in the second visit, at least one familiarisation trial may improve the reliability of exercise capacity assessment.

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.

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.

DSCAM promotes self-avoidance in the developing mouse retina by masking the functions of cadherin superfamily members.

During neural development, self-avoidance ensures that a neuron's processes arborize to evenly fill a particular spatial domain. At the individual cell level, self-avoidance is promoted by genes encoding cell-surface molecules capable of generating thousands of diverse isoforms, such as Dscam1 (Down syndrome cell adhesion molecule 1) in Drosophila Isoform choice differs between neighboring cells, allowing neurons to distinguish "self" from "nonself". In the mouse retina, Dscam promotes self-avoidance at the level of cell types, but without extreme isoform diversity. Therefore, we hypothesize that DSCAM is a general self-avoidance cue that "masks" other cell type-specific adhesion systems to prevent overly exuberant adhesion. Here, we provide in vivo and in vitro evidence that DSCAM masks the functions of members of the cadherin superfamily, supporting this hypothesis. Thus, unlike the isoform-rich molecules tasked with self-avoidance at the individual cell level, here the diversity resides on the adhesive side, positioning DSCAM as a generalized modulator of cell adhesion during neural development.

Environmental effects of ambient temperature and relative humidity on insulin pharmacodynamics in adults with type 1 diabetes mellitus.

OBJECTIVE: This study aimed to explore the effects of ambient temperature and relative humidity on insulin pharmacodynamics in adults with type 1 diabetes. MATERIALS AND METHODS: A three-way, cross-over, randomised study was performed in adults with type 1 diabetes mellitus (n = 10). The pharmacodynamics profile of a single dose of short-acting insulin (insulin lispro) was investigated, using a controlled environmental chamber, under three environmental conditions: (a) temperature: 15°C and humidity: 10%; (b) temperature: 30°C and humidity: 10%; and (c) temperature: 30°C and humidity: 60%. A euglycaemic glucose clamp technique ensured constant blood glucose of 100 mg/dL (5.5 mmol/L). The following pharmacodynamic endpoints were calculated: maximum glucose infusion rate (GIRmax ), time to GIRmax (tGIRmax ), total area under the curve (AUC) for GIR from 0-6 hours (AUCGIR.0-6h ), and partial AUCs (AUCGIR.0-1h , AUCGIR.0-2h and AUCGIR.2-6h ). RESULTS: Higher temperature (30°C) under 10% fixed humidity conditions resulted in greater GIRmax (P = 0.04) and a later tGIR.max (P = 0.049) compared to lower temperature (15°C). Humidity did not affect any pharmacodynamic parameter. When the combined effects of temperature and humidity were explored, tGIR.max (P = 0.008) occurred earlier, with a lower late insulin pharmacodynamic effect (AUCGIR.2-6h ; P = 0.017) at a temperature of 15°C and humidity of 10% compared to a temperature of 30°C and humidity of 60%. CONCLUSIONS: High ambient temperature resulted in a greater insulin peak effect compared to low ambient temperature, with the contribution of high relative humidity apparent only at high ambient temperature. This suggests that patients with type 1 diabetes mellitus who are entering higher environmental temperatures, with or without high humidity, could experience more hypoglycaemic events.

Relative Age, Maturation and Physical Biases on Position Allocation in Elite-Youth Soccer.

This study assessed the contribution of relative age, anthropometry, maturation, and physical fitness characteristics on soccer playing position (goalkeeper [GK], central-defender [CD], lateral-defender [LD], central-midfield [CM], lateral-midfielder [LM], and forward [FWD]) for 465 elite-youth players (U13-U18's). U13-14 CD were relatively older than LD and CM (likely small effects). CD and GK were generally taller and heavier (likely small to very-likely moderate effects) than other players at each developmental stage and were advanced maturers at U13-14 (very-likely small to likely moderate effects). GK had inferior agility (very-likely small to likely moderate effects), endurance (very-likely small to likely moderate effects), and sprint capacities (likely small-moderate effects) vs. outfield positions at U13-14, but deficits in anaerobic phenotypes were diminished in U15-16 and U17-18. Position specific fitness characteristics were distinguished at U15-16 (likely small) and U17-18 (likely moderate), where LM were faster than their central counterparts. In summary, relative age, maturation and anthropometric characteristics appear to bias the allocation of players into key defensive roles from an early development stage, whereas position-specific physical attributes do not become apparent until the latter stages of talent development in outfield players. Given the inter-individual trajectories of physical development according to biological maturation, playing position allocation might be considered 'plastic' by selectors, until complete-maturity is achieved.

Estimands: discussion points from the PSI estimands and sensitivity expert group.

ICH E9 Statistical Principles for Clinical Trials was issued in 1998. In October 2014, an addendum to ICH E9 was proposed relating to estimands and sensitivity analyses. In preparation for the release of the addendum, Statisticians in the Pharmaceutical Industry held a 1-day expert group meeting in February 2015. Topics debated included definition, development, implementation, education and communication challenges associated with estimands and sensitivity analyses. The topic of estimands is an important and relatively new one in clinical development. A clear message from the meeting was that estimands bridge the gap between study objectives and statistical methods. When defining estimands, an iterative process linking trial objectives, estimands, trial design, statistical and sensitivity analysis needs to be established. Each objective should have at least one distinct estimand, supported by sensitivity analyses. Because clinical trials are multi-faceted and expensive, it is unrealistic to restrict a study to a single objective and associated estimand. The actual set of estimands and sensitivity analyses for a study will depend on the study objectives, the disease setting and the needs of the various stakeholders. Copyright © 2016 John Wiley & Sons, Ltd.

Accelerometery and Heart Rate Responses of Professional Fast-Medium Bowlers in One-Day and Multi-Day Cricket.

The physical demands of fast-medium bowling are increasingly being recognised, yet comparative exploration of the differing demands between competitive formats (i.e. one-day [OD] versus multi-day [MD] matches) remain minimal. The aim of this study was to describe in-match physiological profiles of professional fast-medium bowlers from England across different versions of competitive matches using a multivariable wearable monitoring device. Seven professional cricket fast-medium bowlers wore the BioharnessTM monitoring device during matches, over three seasons (>80 hours in-match). Heart Rate (HR) and Acceleromety (ACC) was compared across match types (OD, MD) and different in-match activity states (Bowling, Between over bowling, Fielding). Peak acceleration during OD bowling was significantly higher in comparison to MD cricket ([OD vs. MD] 234.1 ± 57.9 vs 226.6 ± 32.9 ct·episode-1, p < 0.05, ES = 0.11-0.30). Data for ACC were also higher during OD than MD fielding activities (p < 0.01, ES = 0.11-.30). OD bowling stimulated higher mean HR responses (143 ± 14 vs 137 ± 16 beats·min-1, p < 0.05, ES = 0.21) when compared to MD matches. This increase in OD cricket was evident for both between over (129 ± 9 vs 120 ± 13 beats·min-1,p < 0.01, ES = 0.11-0.50) and during fielding (115 ± 12 vs 106 ± 12 beats·min-1, p < 0.01, ES = 0.36) activity. The increased HR and ACC evident in OD matches suggest greater acute physical loads than MD formats. Therefore, use of wearable technology and the findings provided give a valuable appreciation of the differences in match loads, and thus required physiological preparation and recovery in fast-medium bowlers.

Impact of a Hurricane Shelter Viral Gastroenteritis Outbreak on a Responding Medical Team.

UNLABELLED: Introduction In late October of 2012, Hurricane Sandy struck the northeast United States and shelters were established throughout the impacted region. Numerous cases of infectious viral gastroenteritis occurred in several of these shelters. Such outbreaks are common and have been well described in the past. Early monitoring for, and recognition of, the outbreak allowed for implementation of aggressive infection control measures. However, these measures required intensive medical response team involvement. Little is known about how such outbreaks affect the medical teams responding to the incident. Hypothesis/Problem Describe the impact of an infectious viral gastroenteritis outbreak within a single shelter on a responding medical team. METHODS: The number of individuals staying in the single shelter each night (as determined by shelter staff) and the number of patients treated for symptoms of viral gastroenteritis were recorded each day. On return from deployment, members of a single responding medical team were surveyed to determine how many team members became ill during, or immediately following, their deployment. RESULTS: The shelter population peaked on November 5, 2012 with 811 individuals sleeping in the shelter. The first patients presented to the shelter clinic with symptoms of viral gastroenteritis on November 4, 2012, and the last case was seen on November 21, 2012. A total of 64 patients were treated for nausea, vomiting, or diarrhea over the 17-day period. A post-deployment survey was sent to 66 deployed medical team members and 45 completed the survey. Twelve (26.7%) of the team members who responded to the survey experienced symptoms of probable viral gastroenteritis. Team members reported onset of symptoms during deployment as well as after returning home. Symptoms started on days 4-8, 8-14, on the trip home, and after returning home in four, four, two, and two team members, respectively. CONCLUSION: Medical teams providing shelter care during viral gastroenteritis outbreaks are susceptible to contracting the virus while caring for patients. When responding to similar incidents in the future, teams should not only be ready to implement aggressive infectious control measures but also be prepared to care for team members who become ill.

Creation and Delphi-method refinement of pediatric disaster triage simulations.

OBJECTIVE: There is a need for rigorously designed pediatric disaster triage (PDT) training simulations for paramedics. First, we sought to design three multiple patient incidents for EMS provider training simulations. Our second objective was to determine the appropriate interventions and triage level for each victim in each of the simulations and develop evaluation instruments for each simulation. The final objective was to ensure that each simulation and evaluation tool was free of bias toward any specific PDT strategy. METHODS: We created mixed-methods disaster simulation scenarios with pediatric victims: a school shooting, a school bus crash, and a multiple-victim house fire. Standardized patients, high-fidelity manikins, and low-fidelity manikins were used to portray the victims. Each simulation had similar acuity of injuries and 10 victims. Examples include children with special health-care needs, gunshot wounds, and smoke inhalation. Checklist-based evaluation tools and behaviorally anchored global assessments of function were created for each simulation. Eight physicians and paramedics from areas with differing PDT strategies were recruited as Subject Matter Experts (SMEs) for a modified Delphi iterative critique of the simulations and evaluation tools. The modified Delphi was managed with an online survey tool. The SMEs provided an expected triage category for each patient. The target for modified Delphi consensus was ≥85%. Using Likert scales and free text, the SMEs assessed the validity of the simulations, including instances of bias toward a specific PDT strategy, clarity of learning objectives, and the correlation of the evaluation tools to the learning objectives and scenarios. RESULTS: After two rounds of the modified Delphi, consensus for expected triage level was >85% for 28 of 30 victims, with the remaining two achieving >85% consensus after three Delphi iterations. To achieve consensus, we amended 11 instances of bias toward a specific PDT strategy and corrected 10 instances of noncorrelation between evaluations and simulation. CONCLUSIONS: The modified Delphi process, used to derive novel PDT simulation and evaluation tools, yielded a high degree of consensus among the SMEs, and eliminated biases toward specific PDT strategies in the evaluations. The simulations and evaluation tools may now be tested for reliability and validity as part of a prehospital PDT curriculum.

Subgroups: time to go back to basic statistical principles?

Exploratory subgroup analyses are an increasing source of controversy as part of the interpretation of the results of clinical trials. In this article, we review the major challenges of multiplicity, statistical methods available to assess consistency of effect, and the part appropriate design plays in mitigating the risk of false conclusions from subgroup analyses. We discuss the problems associated with using definitions of consistency based on effect sizes in specific subgroups. We argue that what is required is a return to basic statistical principles, including more use of modeling techniques.

Disease-specific predictive formulas for energy expenditure in the dialysis population.

OBJECTIVE: Metabolic rate is poorly understood in advanced kidney disease because direct measurement is expensive and time-consuming. Predictive equations for resting energy expenditure (REE) are needed based on simple bedside parameters. Algorithms derived for normal individuals may not be valid in the renal population. We aimed to develop predictive equations for REE specifically for the dialysis population. DESIGN: Two-hundred subjects on maintenance dialysis underwent a comprehensive metabolic assessment including REE from indirect calorimetry. Parameters predicting REE were identified, and regression equations developed and validated in 20 separate subjects. RESULTS: Mean REE was 1,658 ± 317 kCal/day (males) and 1,380 ± 287 kCal/day (females). Weight and height correlated positively with REE (r(2) = 0.54 and 0.31) and negatively with age older than 65 years (r(2) = 0.18). The energy cost of a unitary kilogram of body weight increased nonlinearly for lower body mass index (BMI). Existing equations derived in normal individuals underestimated REE (bias 50-114 kCal/day for 3 equations). The novel derived equation was REE(kCal/day) = -2.497·Age·Factorage+0.011·height(2.023) + 83.573·Weight(0.6291) + 68.171·Factorsex, where Factorage = 1 if 65 years or older and 0 if younger than 65, and Factorsex = 1 if male and 0 if female. This algorithm performed at least as well as those developed for normals in terms of limits of agreement and reduced bias. In validation with the Bland-Altman technique, bias was not significant for our algorithm (-22 ± 96 kCal/day). The 95% limits of agreement were +380 to -424 kCal/day. CONCLUSION: Existing equations for REE derived from normal individuals are not valid in the dialysis population. The relatively increased REE in those with low BMI implies the need for higher dialysis doses in this subgroup. This disease-specific algorithm may be useful clinically and as a research tool to predict REE.

The athletic profile of fast bowling in cricket: a review.

Cricket is a global sport played in over 100 countries with elite performers attracting multimillion dollar contracts. Therefore, performers maintaining optimum physical fitness and remaining injury free is important. Fast bowlers have a vital position in a cricket team, and there is an increasing body of scientific literature that has reviewed this role over the past decade. Previous research on fast bowlers has tended to focus on biomechanical analysis and injury prevention in performers. However, this review aims to critically analyze the emerging contribution of physiological-based literature linked to fast bowling in cricket, highlight the current evidence related to simulated and competitive in-match performance, and relate this practically to the conditioning coach. Furthermore, the review considers limitations with past research and possible avenues for future investigation. It is clear with the advent of new applied mobile monitoring technology that there is scope for more ecologically valid and longitudinal exploration capturing in-match data, providing quantification of physiological workloads, and analysis of the physical demands across the differing formats of the game. Currently, strength and conditioning specialists do not have a critical academic resource with which to shape professional practice, and this review aims to provide a starting point for evidence in the specific area.

Relationship between the relative timing of prosection and dissection experiences and laboratory examination performance in a gross anatomy course.

Reduced hours of instruction are reported within the gross anatomy education literature. Anatomy instruction continues to be challenged with motivating and inspiring learners to value the contribution of gross anatomy knowledge to their career development alongside increased organizational demands for efficiency and effectiveness. To address these demands, this retrospective study sought to understand how the relative timing and amount of gross anatomy instruction were related to examination performance. Undergraduate and graduate students between 2018 and 2022 were assigned to three cohorts determined by enrollment in prosection-based anatomy only (n = 334), concurrent enrollment in prosection- and dissection-based anatomy in the same semester (n = 67), or consecutive enrollment in the courses one year apart (n = 43). Concurrent students had higher prosection-based anatomy examination scores than prosection-only and consecutive students. Consecutively, enrolled students outperformed concurrently enrolled students on the first two dissection examinations but showed no performance differences on the third and fourth dissection examinations. While the results on the timing and presentation of anatomical instruction were inconclusive, the results do support increased instructional time using both prosection and dissection modalities concurrently to improve performance on identification-based gross anatomy examinations.

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.

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 versus shared domains regulate distinct γ-Pcdh functions remains incompletely understood. Our previous in vitro studies identified protein kinase C (PKC) phosphorylation of a serine residue within a shared C-terminal motif as a mechanism through which γ-Pcdh promotion of dendrite arborization via myristoylated alanine-rich C-kinase substrate (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 remain 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.

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).

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.