Cortical ensembles orchestrate social competition through hypothalamic outputs.

Most social species self-organize into dominance hierarchies1,2, which decreases aggression and conserves energy3,4, but it is not clear how individuals know their social rank. We have only begun to learn how the brain represents social rank5-9 and guides behaviour on the basis of this representation. The medial prefrontal cortex (mPFC) is involved in social dominance in rodents7,8 and humans10,11. Yet, precisely how the mPFC encodes relative social rank and which circuits mediate this computation is not known. We developed a social competition assay in which mice compete for rewards, as well as a computer vision tool (AlphaTracker) to track multiple, unmarked animals. A hidden Markov model combined with generalized linear models was able to decode social competition behaviour from mPFC ensemble activity. Population dynamics in the mPFC predicted social rank and competitive success. Finally, we demonstrate that mPFC cells that project to the lateral hypothalamus promote dominance behaviour during reward competition. Thus, we reveal a cortico-hypothalamic circuit by which the mPFC exerts top-down modulation of social dominance.

Forging the microbiome to help us live long and prosper.

Aging is often accompanied by an increased risk of an array of diseases spanning the cardiovascular, nervous, and immune systems, among others. Despite remarkable progress in understanding the cellular and molecular mechanisms involved in aging, the role of the microbiome remains understudied. In this Essay, we highlight recent progress towards understanding if and how the microbiome contributes to aging and age-associated diseases. Furthermore, we discuss the need to consider sexually dimorphic phenotypes in the context of aging and the microbiome. We also highlight the broad implications for this emerging area of interdisciplinary research to address long-standing questions about host-microbiome interactions across the life span.

Newborn screening algorithm distinguishing potential symptomatic isovaleric acidemia from asymptomatic newborns.

Newborn screening (NBS) for isovaleric acidemia (IVA) reduces mortality and morbidity; however, it has also resulted in the detection of individuals with an asymptomatic or mild presentation for which early detection via newborn screening has not been proven to alter neurological outcome. We reevaluated biochemical and molecular data for newborns flagged positive for IVA in aim of developing a new screening algorithm to exclude the latter from positive screening. Among 2 794 365 newborns underwent routine newborn screening in Israel, 412 flagged positive for IVA, of which, 371 were false positives on recall sample testing and 41 positive newborns were referred to the clinic. 38/41 have biochemical and molecular confirmation in keeping with IVA. Among the 38 patients, 32% (12/38) were classified as symptomatic while, 68% (26/38) were classified as asymptomatic. 69% of the latter group harbor the known variant associated with mild potentially asymptomatic phenotype, c.932C>T; p. Ala311Val. Among asymptomatic patients, only 46% (12/26) are currently treated. Two novel variants have been detected in the IVD gene: c.487G>A; p. Ala163Thr and c.985A>G; p. Met329Val. Cut-off recalculation, of referred newborns' initial biochemical results, after classifying the referred patients to two binary groups of symptomatic and asymptomatic, resulted in an improved NBS algorithm comprising of C5 >5 µM and C5/C2>0.2 and C5/C3>4 flagging only those likely to have the classic symptomatic phenotype.

Population differences in antibody response to SARS-CoV-2 infection and BNT162b2 vaccination.

The concentration of SARS-CoV-2-specific serum antibodies, elicited by vaccination or infection, is a primary determinant of anti-viral immunity, which correlates with protection against infection and COVID-19. Serum samples were obtained from 25 897 participants and assayed for anti-SARS-CoV-2 spike protein RBD IgG antibodies. The cohort was composed of newly vaccinated BNT162b2 recipients, in the first month or 6 months after vaccination, COVID-19 patients and a general sample of the Israeli population. Antibody levels of BNT162b2 vaccine recipients were negatively correlated with age, with a prominent decrease in recipients over 55 years old, which was most significant in males. This trend was observable within the first month and 6 months after vaccination, while younger participants were more likely to maintain stable levels of serum antibodies. The antibody concentration of participants previously infected with SARS-CoV-2 was lower than the vaccinated and had a more complex, non-linear relation to age, sex and COVID-19 symptoms. Taken together, our data supports age and sex as primary determining factors for both the magnitude and durability of humoral response to SARS-CoV-2 infection and the COVID-19 vaccine. Our results could inform vaccination policies, prioritizing the most susceptible populations for repeated vaccination.

Addition of galactose-1-phosphate measurement enhances newborn screening for classical galactosemia.

Galactosemia is an inborn disorder of carbohydrate metabolism of which early detection can prevent severe illness. Although the assay for galactose-1-phosphate uridyltransferase (GALT) enzyme activity has been available since the 1960s, many issues prevented it from becoming universal. In order to develop the Israeli newborn screening pilot algorithm for galactosemia, flow injection analysis tandem mass spectrometry measurement of galactose-1-phosphate in archived dried blood spots from newborns with classical galactosemia, galactosemia variants, epimerase deficiency, and normal controls, was conducted. Out of 431 330 newborns screened during the pilot study (30 months), two with classical galactosemia and four with epimerase deficiency were identified and confirmed. Five false positives and no false negatives were recorded. Following this pilot study, the Israeli final and routine newborn screening algorithm, as recommended by the Advisory Committee to the National Newborn Screening Program, now consists of galactose-1-phosphate measurement integrated into the routine tandem mass spectrometry panel as the first-tier screening test, and GALT enzyme activity as the second-tier performed to identify only newborns suspected to be at risk for classical galactosemia. The GALT enzyme activity cut-off used in the final algorithm was lowered in order to avoid false positives.

Factors to consider in evaluating the appropriateness of restraints during forensic evaluations.

Forensic examiners frequently conduct evaluations with individuals who may be regarded as dangerous. To manage this situation, forensic examiners may prefer examinees to wear restraints. Available literature indicates that the use of restraints may be both physically and psychologically detrimental and thus possibly both reduces the yield and limits the utility of psychological test data. Although there is a lack of research addressing this concern, one must use the available information to inform the decision on utilization of restraints during forensic evaluations. In addition, professional ethics, test standards and norms, the reported adverse effects of restraints on both psychiatric patients and inmates, and the concept of forced medication are reviewed to help assess the appropriateness of restraints during forensic evaluations. This analysis provides forensic examiners with insight and recommendations to determine if the use of restraints is best practice during forensic evaluations, particularly within the United States.

The yield of genetic workup for middle-aged and elderly patients with neurological disorders in a real-world setting.

Genetic workup is becoming increasingly common in the clinical assessment of neurological disorders. We evaluated its yield among middle-aged and elderly neurological patients, in a real-world context. This retrospective study included 368 consecutive Israeli patients aged 50 years and older (202 [54.9%] males), who were referred to a single neurogenetics clinic between 2017 and mid-2023. All had neurological disorders, without a previous molecular diagnosis. Demographic, clinical and genetic data were collected from medical records. The mean age at first genetic counseling at the clinic was 62.3 ± 7.8 years (range 50-85 years), and the main indications for referral were neuromuscular, movement and cerebrovascular disorders, as well as cognitive impairment and dementia. Out of the 368 patients, 245 (66.6%) underwent genetic testing that included exome sequencing (ES), analysis of nucleotide repeat expansions, detection of specific mutations, targeted gene panel sequencing or chromosomal microarray analysis. Overall, 80 patients (21.7%) received a molecular diagnosis due to 36 conditions, accounting for 32.7% of the patients who performed genetic testing. The diagnostic rates were highest for neuromuscular (58/186 patients [31.2%] in this group, 39.2% of 148 tested individuals) and movement disorders (14/79 [17.7%] patients, 29.2% of 48 tested), but lower for other disorders. Testing of nucleotide repeat expansions and ES provided a diagnosis to 28/73 (38.4%) and 19/132 (14.4%) individuals, respectively. Based on our findings, genetic workup and testing are useful in the diagnostic process of neurological patients aged ≥50 years, in particular for those with neuromuscular and movement disorders.

Concurrent and predictive validity of psychopathy in a batterers' intervention sample.

Domestic violence is a serious problem in the United States, with almost two million incidents occurring every year. Although several risk factors have been identified, psychopathy has been understudied in this area. The current study investigated the association between psychopathy and successful treatment completion and reoffending in 483 convicted male batterers undergoing treatment. Findings showed that both overall psychopathy and the specific facet of impulsive antisociality were positively associated with treatment failure and recidivism at 1-year follow-up. Furthermore, results also indicated that the psychopathy facet of fearless dominance positively moderated the association between impulsive antisociality and treatment failure. Thus, individuals high on fearless dominance are bold and narcissistic, and reject the notion that they need treatment, and when coupled with impulsive antisociality, this combination of traits increases the likelihood of treatment failure. In addition, relative risk-ratio analyses indicated that individuals with elevated scores on global psychopathy and impulsive antisociality were at a greater risk for treatment failure and recidivism.

Childhood trauma and compulsive buying.

OBJECTIVE: Childhood trauma has been empirically associated with various types of self-regulatory difficulties in adulthood. However, according to the extant literature, no study has examined relationships between various types of childhood trauma and compulsive buying behavior in adulthood. METHODS: Using a self-report survey methodology in a cross-sectional consecutive sample of 370 obstetrics/gynecology patients, we examined five types of childhood trauma before the age of 12 years (i.e. witnessing violence, physical neglect, emotional abuse, physical abuse, sexual abuse) in relationship to compulsive buying as assessed by the Compulsive Buying Scale (CBS). RESULTS: All forms of trauma demonstrated statistically significant correlations with the CBS. Using a linear regression analysis, both witnessing violence and emotional abuse significantly contributed to CBS scores. Further analyses indicated that race did not moderate the relationship between childhood trauma and compulsive buying. CONCLUSIONS: Findings indicate that various forms of childhood trauma are correlated with compulsive buying behavior, particularly witnessing violence and emotional abuse.

AlphaTracker: a multi-animal tracking and behavioral analysis tool.

Computer vision has emerged as a powerful tool to elevate behavioral research. This protocol describes a computer vision machine learning pipeline called AlphaTracker, which has minimal hardware requirements and produces reliable tracking of multiple unmarked animals, as well as behavioral clustering. AlphaTracker pairs a top-down pose-estimation software combined with unsupervised clustering to facilitate behavioral motif discovery that will accelerate behavioral research. All steps of the protocol are provided as open-source software with graphic user interfaces or implementable with command-line prompts. Users with a graphical processing unit (GPU) can model and analyze animal behaviors of interest in less than a day. AlphaTracker greatly facilitates the analysis of the mechanism of individual/social behavior and group dynamics.

A diet-dependent host metabolite shapes the gut microbiota to protect from autoimmunity.

Diet can protect from autoimmune disease; however, whether diet acts via the host and/or microbiome remains unclear. Here, we use a ketogenic diet (KD) as a model to dissect these complex interactions. A KD rescued the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis in a microbiota-dependent fashion. Dietary supplementation with a single KD-dependent host metabolite (ß-hydroxybutyrate, ßHB) rescued EAE whereas transgenic mice unable to produce ßHB in the intestine developed more severe disease. Transplantation of the ßHB-shaped gut microbiota was protective. Lactobacillus sequence variants were associated with decreased T helper 17 (Th17) cell activation in vitro . Finally, we isolated a L. murinus strain that protected from EAE, which was phenocopied by the Lactobacillus metabolite indole lactic acid. Thus, diet alters the immunomodulatory potential of the gut microbiota by shifting host metabolism, emphasizing the utility of taking a more integrative approach to study diet-host-microbiome interactions.

Hereditary orotic aciduria identified by newborn screening.

Introduction: Hereditary orotic aciduria is an extremely rare, autosomal recessive disease caused by deficiency of uridine monophosphate synthase. Untreated, affected individuals may develop refractory megaloblastic anemia, neurodevelopmental disabilities, and crystalluria. Newborn screening has the potential to identify and enable treatment of affected individuals before they become significantly ill. Methods: Measuring orotic acid as part of expanded newborn screening using flow injection analysis tandem mass spectrometry. Results: Since the addition of orotic acid measurement to the Israeli routine newborn screening program, 1,492,439 neonates have been screened. The screen has identified ten Muslim Arab newborns that remain asymptomatic so far, with DBS orotic acid elevated up to 10 times the upper reference limit. Urine organic acid testing confirmed the presence of orotic aciduria along with homozygous variations in the UMPS gene. Conclusion: Newborn screening measuring of orotic acid, now integrated into the routine tandem mass spectrometry panel, is capable of identifying neonates with hereditary orotic aciduria.

Evaluation of the moderated-expression and differential configuration hypotheses in the context of "successful" or "noncriminal" psychopathy.

The concept of "successful" psychopathy has intrigued the field, yet relatively little actual science exists to understand what makes those high in psychopathic traits more or less successful, or even what constitutes "success." In the current study, we examined the validity of the moderated expression hypothesis, including an elaborated version that considers differential configuration of psychopathy traits, as accounting for differences in criminal and noncriminal (the most common operationalization of "success") expressions of psychopathy. The latter was conceptualized from the perspective of the triarchic psychopathy model. We recruited a community sample (n = 212) that had been overweighted toward psychopathic personality traits. The triarchic psychopathy domains of boldness, meanness, and disinhibition were modeled as latent constructs based on scores from multiple psychopathy measures. We examined affective processing dysfunction, various executive cognitive deficits, substance misuse, and socioeconomic indicators (income, education) as potential moderators of associations between psychopathy and criminality. We estimated a series of latent regression models in which we tested interaction effects between hypothesized moderators and a latent criminality variable. We found that affective processing dysfunction, substance misuse, and the triarchic psychopathy domain of disinhibition all moderated the association between meanness and criminality, in that the latter association was stronger as these moderators increased in severity. Disinhibition was also moderated by substance misuse and boldness by both personal income and commission errors from a go/no-go task, though in the case of the latter domain, these moderators served as protective factors against criminality. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Vici syndrome in Israel: Clinical and molecular insights.

Introduction: Vici Syndrome is a rare, severe, neurodevelopmental/neurodegenerative disorder with multi-systemic manifestations presenting in infancy. It is mainly characterized by global developmental delay, seizures, agenesis of the corpus callosum, hair and skin hypopigmentation, bilateral cataract, and varying degrees of immunodeficiency, among other features. Vici Syndrome is caused by biallelic pathogenic variants in EPG5, resulting in impaired autophagy. Thus far, the condition has been reported in less than a hundred individuals. Objective and Methods: We aimed to characterize the clinical and molecular findings in individuals harboring biallelic EPG5 variants, recruited from four medical centers in Israel. Furthermore, we aimed to utilize a machine learning-based tool to assess facial features of Vici syndrome. Results: Eleven cases of Vici Syndrome from five unrelated families, one of which was diagnosed prenatally with subsequent termination of pregnancy, were recruited. A total of five disease causing variants were detected in EPG5: two novel: c.2554-5A>G and c.1461delC; and 3 previously reported: c.3447G>A, c.5993C>G, and c.1007A>G, the latter previously identified in several patients of Ashkenazi-Jewish (AJ) descent. Amongst 140,491 individuals screened by the Dor Yeshorim Program, we show that the c.1007A>G variant has an overall carrier frequency of 0.45% (1 in 224) among AJ individuals. Finally, based on two-dimensional facial photographs of individuals with Vici syndrome (n = 19), a composite facial mask was created using the DeepGestalt algorithm, illustrating facial features typical of this disorder. Conclusion: We report on ten children and one fetus from five unrelated families, affected with Vici syndrome, and describe prenatal and postnatal characteristics. Our findings contribute to the current knowledge regarding the molecular basis and phenotypic features of this rare syndrome. Additionally, the deep learning-based facial gestalt adds to the clinician's diagnostic toolbox and may aid in facilitating identification of affected individuals.

Clinical impact of exome sequencing in the setting of a general pediatric ward for hospitalized children with suspected genetic disorders.

Background: Genetic conditions contribute a significant portion of disease etiologies in children admitted to general pediatric wards worldwide. While exome sequencing (ES) has improved clinical diagnosis and management over a variety of pediatric subspecialties, it is not yet routinely used by general pediatric hospitalists. We aim to investigate the impact of exome sequencing in sequencing-naive children suspected of having monogenic disorders while receiving inpatient care. Methods: We prospectively employed exome sequencing in children admitted to the general pediatric inpatient service at a large tertiary medical center in Israel. Genetic analysis was triggered by general and/or subspecialist pediatricians who were part of the primary inpatient team. We determined the diagnostic yield among children who were referred for exome sequencing and observed the effects of genetic diagnosis on medical care. Results: A total of fifty probands were evaluated and exome sequenced during the study period. The most common phenotypes included were neurodevelopmental (56%), gastrointestinal (34%), and congenital cardiac anomalies (24%). A molecular diagnosis was reached in 38% of patients. Among seven patients (37%), the molecular genetic diagnosis influenced subsequent clinical management already during admission or shortly following discharge. Conclusion: We identified a significant fraction of genetic etiologies among undiagnosed children admitted to the general pediatric ward. Our results support that early application of exome sequencing may be maximized by pediatric hospitalists' high index of suspicion for an underlying genetic etiology, prompting an in-house genetic evaluation. This framework should include a multidisciplinary co-management approach of the primary care team working alongside with subspecialties, geneticists and bioinformaticians.

Agar Art: a CURE for the Microbiology Laboratory.

We previously developed and assessed "The Art of Microbiology," a course-based undergraduate research experience (CURE) which uses agar art to spur student experimentation, where we found student outcomes related to science persistence. However, these outcomes were not correlated with specific activities and gains were not reported from more than one class. In this study, we explored which of the three major activities in this CURE-agar art, experimental design, or poster presentations-affected student engagement and outcomes associated with improved understanding of the nature of science (NOS). The Art of Microbiology was studied in three microbiology teaching laboratories: at a research university with either the CURE developer (18 students) or a CURE implementer (39 students) and at a community college with a CURE implementer (25 students). Our quasi-experimental mixed methods study used pre/post-NOS surveys and semi-structured class-wide interviews. Community college students had lower baseline NOS responses but had gains in NOS similar to research university students post-CURE. We surveyed research university students following each major activity using the Assessing Student Perspective of Engagement in Class Tool (ASPECT) survey but did not find a correlation between NOS and activity engagement. Of the three activities, we found the highest engagement with agar art, especially in the CURE developer class. Interviewed students in all classes described agar art as a fun, relevant, and low-stakes assignment. This work contributes to the evidence supporting agar art as a curricular tool, especially in ways that can add research to classrooms in and beyond the research university.

Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1.

BACKGROUND AND OBJECTIVES: To expand the clinical knowledge of GPAA1-related glycosylphosphatidylinositol (GPI) deficiency. METHODS: An international case series of 7 patients with biallelic GPAA1 variants were identified. Clinical, biochemical, and neuroimaging data were collected for comparison. Where possible, GPI-anchored proteins were assessed using flow cytometry. RESULTS: Ten novel variants were identified in 7 patients. Flow cytometry samples of 3 available patients confirmed deficiency of several GPI-anchored proteins on leukocytes. Extensive phenotypic information was available for each patient. The majority experienced developmental delay, seizures, and hypotonia. Neuroimaging revealed cerebellar anomalies in the majority of the patients. Alkaline phosphatase was within the normal range in 5 individuals and low in 1 individual, as has been noted in other transamidase defects. We notably describe individuals either less affected or older than the ones published previously. DISCUSSION: Clinical features of the cases reported broaden the spectrum of the known phenotype of GPAA1-related GPI deficiency, while outlining the importance of using functional studies such as flow cytometry to aid in variant classification.

Interdisciplinary STEM education reform: dishing out art in a microbiology laboratory.

In the modern educational framework, life science and visual art are usually presented as mutually exclusive subjects. Despite this perceived disciplinary contrast, visual art has the ability to engage and provoke students in ways that can have important downstream effects on scientific discovery, especially when applied in a practical setting such as a laboratory course. This review broadly examines the benefit of interdisciplinary fusions of science and art as well as recent ways in which art strategies have been used in undergraduate biology classrooms. In a case study, we found that undergraduate students in an introductory microbiology laboratory course who participated in open-inquiry activities involving agar art had greater confidence in their personal efficacy as scientists compared to a control class. Collectively, these observations suggest that visual art can be a useful enhancement in the course-based undergraduate research setting, and science educators at all levels should consider incorporating artistic creativity in their own classroom strategies.

The use of psychometrists in clinical neuropsychology: history, current status, and future directions.

In recent years, the National Academy of Neuropsychology and other professional neuropsychological organizations have published a number of articles and position papers regarding the use, education, and training of psychometrists ("technicians"). Although these documents provide guidelines for the suggested qualifications and training procedures of psychometrists, none make any mention of the need for a standardized credentialing process, which is commonly required of technicians in similar fields, especially in medical settings. Given the recent changes in current procedural Terminology codes used to bill for neuropsychological services and the interpretation of legislation disallowing the use of psychometrists in New York, the need for a standard credential for psychometrists is apparent. This article will review the history and current use of psychometrists in clinical neuropsychology and highlight the need and rationale for the credentialing of psychometrists.