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Abstract Background Most western countries provide funded legal representation (LR) for involuntarily admitted psychiatric patients appearing before judicial committees. In 2004, an amendment to the Israeli Mental Health Act granted this right to involuntarily committed psychiatric patients. Psychiatrists then voiced concerns that LR may increase rates of premature discharge and compromise patients’ safety and well-being. These worries have not been sufficiently addressed to date. This study aimed to provide answers to their concerns. Methods This study included 3124 and 3434 inpatients involuntarily admitted to psychiatric facilities in 2000 and in 2010 (respectively), prior to and after the introduction of LR in Israel. Data were acquired from the Israeli National Psychiatric Hospitalization Registry. Clinical measures included percentage of discharges by the District Psychiatric Board (DPB), duration of involuntary hospitalization and rates of readmissions within thirty days and six months of discharge by treating psychiatrists (TP) or DPB. Results The odds ratio (OR) of discharge by a DPB in 2010 (n = 221) compared to 2000 (n = 93) was 2.2 [95%CI 1.72–2.82]. The OR was similar for readmissions within thirty days or six months among patients discharged by TP and a DPB (OR = 1.08, p = 0.697 and OR = 0.92, p = 0.603, respectively) as well as between the two time points (p = 0.486 and p = 0.618). The duration of hospitalizations terminated by a DPB was significantly shorter than those terminated by TP, with no difference between the study time points. The mean hospitalization duration in 2010 was 21% shorter compared to 2000 among patients discharged by TP. Conclusions The number of DPB proceedings and the number of involuntarily hospitalized psychiatric patients discharged by DPBs increased considerably after the advent of state-funded legal representation in 2004. We found that this did not compromise beneficence and non-malfeasance of patient care. Our results emphasize the feasibility of affording even the most severely mentally ill patients the rights to due process. These findings may relieve concerns about state-funded LR procedures in involuntary psychiatric hospitalizations.

During rest and sleep, memory traces replay in the brain. The dialogue between brain regions during replay is thought to stabilize labile memory traces for long-term storage. However, because replay is an internally driven, spontaneous phenomenon, it does not have a ground truth - an external reference that can validate whether a memory has truly been replayed. Instead, replay detection is based on the similarity between the sequential neural activity comprising the replay event and the corresponding template of neural activity generated during active locomotion. If the statistical likelihood of observing such a match by chance is sufficiently low, the candidate replay event is inferred to be replaying that specific memory. However, without the ability to evaluate whether replay detection methods are successfully detecting true events and correctly rejecting non-events, the evaluation and comparison of different replay methods is challenging. To circumvent this problem, we present a new framework for evaluating replay, tested using hippocampal neural recordings from rats exploring two novel linear tracks. Using this two-track paradigm, our framework selects replay events based on their temporal fidelity (sequence-based detection), and evaluates the detection performance using each event’s track discriminability, where sequenceless decoding across both tracks is used to quantify whether the track replaying is also the most likely track being reactivated.

Abstract Epilepsy is a prevalent disorder involving neuronal network hyperexcitability, yet existing therapeutic strategies often fail to provide optimal patient outcomes. Chemogenetic approaches, where exogenous receptors are expressed in defined brain areas and specifically activated by selective agonists, are appealing methods to constrain overactive neuronal activity. We developed BARNI (Bradanicline- and Acetylcholine-activated Receptor for Neuronal Inhibition), an engineered channel comprised of the α7 nicotinic acetylcholine receptor ligand-binding domain coupled to an α1 glycine receptor anion pore domain. Here we demonstrate that BARNI activation by the clinical stage α7 nicotinic acetylcholine receptor-selective agonist bradanicline effectively suppressed targeted neuronal activity, and controlled both acute and chronic seizures in male mice. Our results provide evidence for the use of an inhibitory acetylcholine-based engineered channel activatable by both exogenous and endogenous agonists as a potential therapeutic approach to treating epilepsy.

Abstract During sleep, recent memories are replayed by the hippocampus, leading to their consolidation, with a higher priority given to salient experiences. To examine the role of replay in the selective strengthening of memories, we recorded large ensembles of hippocampal place cells while male rats ran repeated spatial trajectories on two linear tracks, differing in either their familiarity or number of laps run. We observed that during sleep, the rate of replay events for a given track increased proportionally with the number of spatial trajectories run by the animal. In contrast, the rate of sleep replay events decreased if the animal was more familiar with the track. Furthermore, we find that the cumulative number of awake replay events occurring during behavior, influenced by both the novelty and duration of an experience, predicts which memories are prioritized for sleep replay, providing a more parsimonious neural correlate for the selective strengthening of memories.

Abstract Our brain’s capacity for memory storage may be vast but is still finite. Given that we cannot remember the entirety of our experiences, how does our brain select what to remember and what to forget? Much like the triage of a hospital’s emergency room, where urgent cases are prioritized and less critical patients receive delayed or even no care, the brain is believed to go through a similar process of memory triage. Recent salient memories are prioritized for consolidation, which helps create stable, long-term representations in the brain; less salient memories receive a lower priority, and are eventually forgotten if not sufficiently consolidated (Stickgold and Walker in Nat Neurosci 16(2):139–145, 2013). While rodents are a primary model for studying memory consolidation, common behavioral tests typically rely on a limited number of items or contexts, well within the memory capacity of the subject. A memory test allowing us to exceed an animal’s memory capacity is key to investigating how memories are selectively strengthened or forgotten. Here we report a new serial novel object recognition task designed to measure memory capacity and prioritization, which we test and validate using female mice.

The p53 pathway is a universal tumor suppressor mechanism that limits tumor progression by triggering apoptosis or permanent cell cycle arrest, called senescence. In recent years, efforts to reactivate p53 function in cancer have proven to be a successful therapeutic strategy in murine models and have gained traction with the development of a range of small molecules targeting mutant p53. However, knowledge of the downstream mediators of p53 reactivation in different oncogenic contexts has been limited. Here, we utilized a panel of murine cancer cell lines from three distinct tumor types susceptible to alternative outcomes following p53 restoration to define unique and shared p53 transcriptional signatures. While we found that the majority of p53-bound sites and p53-responsive transcripts are tumor-type specific, analysis of shared targets identified a core signature of genes activated by p53 across all contexts. Furthermore, we identified repression of E2F and Myc target genes as a key feature of senescence. Characterization of p53-induced transcripts revealed core and senescence-specific long noncoding RNAs (lncRNAs) that are predominantly chromatin associated and whose production is coupled to cis-regulatory activities. Functional investigation of the contributions of p53-induced lncRNAs to p53-dependent outcomes highlighted Pvt1b, the p53-dependent isoform of Pvt1, as a mediator of p53-dependent senescence via Myc repression. Inhibition of Pvt1b led to decreased activation of senescence markers and increased levels of markers of proliferation. These findings shed light on the core and outcome-specific p53 restoration signatures across different oncogenic contexts and underscore the key role of the p53-Pvt1b-Myc regulatory axis in mediating proliferative arrest.

While animals navigating the real world face a barrage of sensory input, their brains evolved to perceptually compress multidimensional information by selectively extracting the features relevant for survival. Notably, communication signals supporting social interactions in several mammalian species consist of acoustically complex sequences of vocalisations. However, little is known about what information listeners extract from such time-varying sensory streams. Here, we utilise female mice’s natural behavioural response to male courtship songs to identify the relevant acoustic dimensions used in their social decisions. We found that females were highly sensitive to disruptions of song temporal regularity and preferentially approached playbacks of intact over rhythmically irregular versions of male songs. In contrast, female behaviour was invariant to manipulations affecting the songs’ sequential organisation or the spectro-temporal structure of individual syllables. The results reveal temporal regularity as a key acoustic cue extracted by mammalian listeners from complex vocal sequences during goal-directed social behaviour.

Cross-species research is key to fully understanding brain function. Here, the authors present the ferret as a species for hippocampal research and show that, in stark contrast to rats, ferrets have robust theta oscillations during immobility.

I. INTRODUCTION II. STANDING IN ISRAEL III. DEVELOPMENT OF ISRAELI CONSTITUTIONAL AND ADMINISTRATIVE LAW AS A RESULT OF THE BROAD STANDING POLICY A. Examples of the Israeli Supreme Court Granting [...], The Article suggests that broad standing rights in Israel not only have contributed to the development of constitutional and administrative law, but also encourage the establishment of public interest organizations whose activities focus on filing petitions in those areas. Many of these petitions deal with issues that have significant political implications. This Article presents the broad standing rights in Israel, indicates the role of broad compliance in the development of Israeli constitutional and administrative law, describes the contribution of the broad standing in Israel to the establishment of public interest organizations and civic groups, and offers explanations of the dominance of these organizations and groups in filing petitions on issues which do not involve claims of violation of human rights or of individual interests.

Introduction: Severe obesity among children and adolescents has emerged as a public health concern in multiple places around the world. Methods: We searched the Medline database for articles on severe obesity rates in children published between January 1960 and January 2020. For studies with available prevalence rates for an early and a more recent time period, the relative increase in prevalence was imputed. Results: In total, 874 publications were identified, of which 38 contained relevant epidemiological data. Rates of severe obesity varied significantly according to age, gender, geographic area, and the definition of severe obesity. The highest rates of class II and III obesity in the USA according to the Centers of Disease Control cut-off were 9.5% and 4.5%, respectively. Seventeen studies reported prevalence rates in at least two time periods. Data for 9,190,718 individuals showed a 1.71 (95% CI, 1.53–1.90) greater odds for severe obesity in 2006–2017 (N = 5,029,584) versus 1967–2007 (N = 4,161,134). In an analysis limited to studies from 1980s with a minimum follow-up of 20 years, a 9.16 (95% CI, 7.76–10.80) greater odds for severe obesity in recent versus earlier time was found. An analysis limited to studies from 2000, with a follow-up of 5–15 years, a 1.09 (95% CI, 0.99–1.20) greater odds was noted when comparing (2011–2017; N = 4,991,831) versus (2000–2011; N = 4,134,340). Conclusion: Severe pediatric obesity is escalating with a marked increase from the 1980s and a slower rate from 2000.

Psychoactive compounds such as chloroquine and amphetamine act by dissipating the pH gradient across intracellular membranes, but the physiological mechanisms that normally regulate organelle pH remain poorly understood. Interestingly, recent human genetic studies have implicated the endosomal Na+/H+ exchanger NHE9 in both autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). Plasma membrane NHEs regulate cytosolic pH, but the role of intracellular isoforms has remained unclear. We now find that inactivation of NHE9 in mice reproduces behavioral features of ASD including impaired social interaction, repetitive behaviors, and altered sensory processing. Physiological characterization reveals hyperacidic endosomes, a cell-autonomous defect in glutamate receptor expression and impaired neurotransmitter release due to a defect in presynaptic Ca2+ entry. Acute inhibition of synaptic vesicle acidification rescues release but without affecting the primary defect due to loss of NHE9.

The protein α-synuclein has a central role in the pathogenesis of Parkinson's disease. Like that of other proteins that accumulate in neurodegenerative disease, however, the function of α-synuclein remains unknown. Localization to the nerve terminal suggests a role in neurotransmitter release, and overexpression inhibits regulated exocytosis, but previous work has failed to identify a clear physiological defect in mice lacking all three synuclein isoforms. Using adrenal chromaffin cells and neurons, we now find that both overexpressed and endogenous synuclein accelerate the kinetics of individual exocytotic events, promoting cargo discharge and reducing pore closure ('kiss-and-run'). Thus, synuclein exerts dose-dependent effects on dilation of the exocytotic fusion pore. Remarkably, mutations that cause Parkinson's disease abrogate this property of α-synuclein without impairing its ability to inhibit exocytosis when overexpressed, indicating a selective defect in normal function.

Increased α-synuclein (αsyn) and mitochondrial dysfunction play central roles in the pathogenesis of Parkinson's disease (PD), and lowering αsyn is under intensive investigation as a therapeutic strategy for PD. Increased αsyn levels disrupt mitochondria and impair respiration, while reduced αsyn protects against mitochondrial toxins, suggesting that interactions between αsyn and mitochondria influences the pathologic and physiologic functions of αsyn. However, we do not know if αsyn affects normal mitochondrial function or if lowering αsyn levels impacts bioenergetic function, especially at the nerve terminal where αsyn is enriched. To determine if αsyn is required for normal mitochondrial function in neurons, we comprehensively evaluated how lowering αsyn affects mitochondrial function. We found that αsyn knockout (KO) does not affect the respiration of cultured hippocampal neurons or cortical and dopaminergic synaptosomes, and that neither loss of αsyn nor all three (α, β and γ) syn isoforms decreased mitochondria-derived ATP levels at the synapse. Similarly, neither αsyn KO nor knockdown altered the capacity of synaptic mitochondria to meet the energy requirements of synaptic vesicle cycling or influenced the localization of mitochondria to dopamine (DA) synapses in vivo. Finally, αsyn KO did not affect overall energy metabolism in mice assessed with a Comprehensive Lab Animal Monitoring System. These studies suggest either that αsyn has little or no significant physiological effect on mitochondrial bioenergetic function, or that any such functions are fully compensated for when lost. These results implicate that αsyn levels can be reduced in neurons without impairing (or improving) mitochondrial bioenergetics or distribution.

Replay, the sequential reactivation within a neuronal ensemble, is a central hippocampal mechanism postulated to drive memory processing. While both rate and place representations are used by hippocampal place cells to encode behavioral episodes, replay has been largely defined by only the latter – based on the fidelity of sequential activity across neighboring place fields. Here, we show that dorsal CA1 place cells in rats can modulate their firing rate between replay events of two different contexts. This experience-dependent phenomenon mirrors the same pattern of rate modulation observed during behavior and can be used independently from place information within replay sequences to discriminate between contexts. Our results reveal the existence of two complementary neural representations available for memory processes.

Background:. Breast hypertrophy is known to be a source of both physical and psychosocial health deficits. Therefore, the ability to relieve these symptoms with surgical treatment is an important consideration for patients. The primary objective of this study was to assess the impact of patient body mass index (BMI) on postoperation complications. The secondary objective of this study was to assess patient demographics, surgical techniques, and patient comorbidities for their impact on specific postoperative complications. Methods:. A retrospective chart review of all patients who received bilateral breast reduction surgery in Nova Scotia over the past 10 years was performed. A total of 1022 patients met the inclusion criteria of the study. Logistic regression modeling was performed to identify demographic factors, surgical techniques, and patient comorbidities that impact the risk of developing specific postoperative complications. Results:. Our study population had a total complication incidence of 37.7%. BMI was not significantly different between patients who developed complications and those who did not. Logistic regression modeling showed a significant relationship that with each unit increase in BMI above the mean (25.9 kg/m2) the relative risk of patient-reported postoperative asymmetry increased by 6%. Conclusions:. The findings of this study suggest that BMI has several nonsignificant relationships to postoperative complications following bilateral breast reduction. These trends do not translate to significantly increased complaints of asymmetry, scarring‚ or revision surgeries. This study also provides valuable information on the timeline of postoperative complications and when they can commonly be identified.

Abstract Severe obesity among children and adolescents is a significant global public health concern. The prevalence has markedly increased over the last decades, becoming common in many countries. Overwhelming rates of obesity among youth have prompted efforts to identify an evidence-based immediate- and long-term cardiometabolic risk factor profile in childhood-onset severe obesity, and to highlight gaps that require further investigation. The PubMed database was systematically searched in accordance with PRISMA guidelines. The search yielded 831 results, of which 60 fulfilled stringent criteria and were summarized in this review. The definition of severe obesity was variable, with only one half the publications using the definition BMI > 120% of the 95th percentile. Point estimates of the prevalence of at least one cardiometabolic risk factor in children with severe obesity reportedly range from 67 to 86%. Cross-sectional studies indicate that children and adolescents with severe obesity are at greater risk than those with mild obesity for type 2 diabetes, hypertension, fatty liver disease and dyslipidemia, already at childhood and adolescence. Robust epidemiological data on the long-term risk and actual point estimates in adulthood are lacking for these diseases as well as for other diseases (coronary heart disease, stroke, chronic kidney disease and cancer). Recent longitudinal studies indicate an increased risk for cardiomyopathy, heart failure, cardiovascular mortality and all-cause mortality in adulthood for adolescents with severe obesity compared to those with mild obesity. Given the alarming increase in the prevalence of severe obesity, the persistence of adiposity from childhood to adulthood and the precarious course of young adults with chronic comorbidities, the economic and clinical services burden on the healthcare system is expected to rise.

Background: Cognitive function among apparently healthy adolescents has been associated with cardiovascular morbidity and mortality. We examined the relationship between global and subdomain cognitive scores in adolescence and early-onset type 2 diabetes (T2D) in men and women. Methods: A nationwide, population-based study of 971,677 Israeli born adolescents (56% men; mean age 17.4 years) who were medically examined and their cognitive performance was assessed before compulsory military service during 1992–2010. Data included global and subdomain cognitive Z-scores (problem-solving, verbal abstraction and categorization, verbal comprehension, and mathematical abilities). Data were linked to the Israeli National Diabetes Registry. The relations between global and subdomain scores and incident T2D was determined using Cox proportional hazard models and logistic regression models. Analyses were conducted separately for men and women. Findings: During 16,095,122 person-years, 3,570 individuals developed T2D. After adjustment, those in the low compared to the high quintile of global cognitive Z-score had the highest risk for T2D; HR 2.46, (95% CI 2.10–2.88) for men and 2.33 (95% CI 1.88–2.89) for women. A one-unit lower global cognitive Z-score was associated with 1.41 (95% CI 1.34–1.48) and 1.46 (95% CI 1.36–1.56) increased risks for men and women, respectively. The relationship was noted for the cognitive subdomains scores as well as for the global cognitive score, with no heterogeneity across cognitive subdomains. Interpretation: This large nationally representative cohort suggests relationship between global, as well as subdomain cognitive scores in late adolescence, and incident early onset T2D in both sexes, which was independent of socioeconomic status.

Rapid progress in technologies such as calcium imaging and electrophysiology has seen a dramatic increase in the size and extent of neural recordings. Even so, interpretation of this data requires considerable knowledge about the nature of the representation and often depends on manual operations. Decoding provides a means to infer the information content of such recordings but typically requires highly processed data and prior knowledge of the encoding scheme. Here, we developed a deep-learning framework able to decode sensory and behavioral variables directly from wide-band neural data. The network requires little user input and generalizes across stimuli, behaviors, brain regions, and recording techniques. Once trained, it can be analyzed to determine elements of the neural code that are informative about a given variable. We validated this approach using electrophysiological and calcium-imaging data from rodent auditory cortex and hippocampus as well as human electrocorticography (ECoG) data. We show successful decoding of finger movement, auditory stimuli, and spatial behaviors – including a novel representation of head direction - from raw neural activity.

This essay considers the meaning of criticality in design futures education. It identifies three such meanings - criticality as an indication of importance, as a style of reasoning, and as attentiveness to power - and argues that the latter is most suitable for seeding transformative change. By drawing connections between critical pedagogy and critical futures studies, we aim to chart a path through which design futures education can potentially grapple with the political, contentious aspects of future-making. [ABSTRACT FROM AUTHOR]