Characterisation of sleep in a mouse model of CLN3 disease revealed sex-specific sleep disturbances.

The neuronal ceroid lipofuscinoses (NCLs) are a group of recessively inherited neurodegenerative diseases characterizsed by lysosomal storage of fluorescent materials. CLN3 disease, or juvenile Batten disease, is the most common NCL that is caused by mutations in the Ceroid Lipofuscinosis, Neuronal 3 (CLN3) gene. Sleep disturbances are among the most common symptoms associated with CLN3 disease that deteriorate the patients' life quality, yet this is understudied and has not been delineated in animal models of the disease.

Multimodal evaluation of network activity and optogenetic interventions in human hippocampal slices.

Seizures are made up of the coordinated activity of networks of neurons, suggesting that control of neurons in the pathologic circuits of epilepsy could allow for control of the disease. Optogenetics has been effective at stopping seizure-like activity in non-human disease models by increasing inhibitory tone or decreasing excitation, although this effect has not been shown in human brain tissue. Many of the genetic means for achieving channelrhodopsin expression in non-human models are not possible in humans, and vector-mediated methods are susceptible to species-specific tropism that may affect translational potential.

Will climate change constrain the altitudinal range of threatened species? Experimental evidence from a biodiversity hotspot.

A fundamental goal in ecology and evolution is to explain the factors that shape species' abundance and range limits. Evaluating the performance of early life-stages across an altitudinal gradient can be valuable for understanding what factors shape range limits and for predicting how plant species may respond to climate change. To experimentally evaluate the presence of local adaptation in a threatened palm (Euterpe edulis) at early life-stages, we reciprocally sowed seeds at two contrasting elevations.

The importance of including both sexes in preclinical sleep studies and analyses.

A significant effort in biomedical sciences has been made to examine relationships between sex and the mechanisms underlying various disease states and behaviors, including sleep. Here, we investigated biological sex differences in sleep using male and female C57BL/6J mice (n = 267). Physiological parameters were recorded for 48-h using non-invasive piezoelectric cages to determine total sleep, non-rapid eye movement (NREM) sleep, rapid eye movement (REM)-like sleep, and wakefulness (WAKE).

Early biological markers of post-acute sequelae of SARS-CoV-2 infection.

To understand the roles of acute-phase viral dynamics and host immune responses in post-acute sequelae of SARS-CoV-2 infection (PASC), we enrolled 136 participants within 5 days of their first positive SARS-CoV-2 real-time PCR test. Participants self-collected up to 21 nasal specimens within the first 28 days post-symptom onset; interviewer-administered questionnaires and blood samples were collected at enrollment, days 9, 14, 21, 28, and month 4 and 8 post-symptom onset. Defining PASC as the presence of any COVID-associated symptom at their 4-month visit, we compared viral markers (quantity and duration of nasal viral RNA load, infectious viral load, and plasma N-antigen level) and host immune markers (IL-6, IL-10, TNF-α, IFN-α, IFN-γ, MCP, IP-10, and Spike IgG) over the acute period.

Local Excision for Early-Stage Rectal Adenocarcinomas.

Although total mesorectal excision (TME) remains the standard of care for rectal cancer, including early-stage T1/T2 rectal adenocarcinoma, local excision may be warranted for these early-stage tumors in a select group of patients who may decline surgery or may be nonoptimal surgical candidates. Operative approaches for transanal local excision include transanal endoscopic microsurgery or transanal minimally invasive surgery for tumors <4 cm, occupying <40% of the rectal circumference and <10 cm from the dentate line. The use of preoperative chemoradiation therapy may help to downstage tumors and allow for more limited resections, and chemoradiation may also be employed postoperatively.

Using accelerometers to identify a high risk of catastrophic musculoskeletal injury in three racing Thoroughbreds.

Objective: To describe the process whereby the screening of racing Thoroughbreds with accelerometer-based inertial measurement unit (IMU) sensors followed by clinical evaluation and advanced imaging identified potentially catastrophic musculoskeletal injuries in 3 horses.

Animals: 3 Thoroughbred racehorses.

Clinical Presentation: All cases demonstrated an abnormal stride pattern either during racing (cases 1 and 2) or while breezing (case 3) and were identified as being at very high risk of catastrophic musculoskeletal injury by an algorithm derived from IMU sensor files from > 20,000 horses' race starts.

Western diet consumption impairs memory function via dysregulated hippocampus acetylcholine signaling.

Western diet (WD) consumption during early life developmental periods is associated with impaired memory function, particularly for hippocampus (HPC)-dependent processes. We developed an early life WD rodent model associated with long-lasting HPC dysfunction to investigate the neurobiological mechanisms mediating these effects. Rats received either a cafeteria-style WD (ad libitum access to various high-fat/high-sugar foods; CAF) or standard healthy chow (CTL) during the juvenile and adolescent stages (postnatal days 26-56).

Thalamocortical organoids enable in vitro modeling of 22q11.2 microdeletion associated with neuropsychiatric disorders.

Thalamic dysfunction has been implicated in multiple psychiatric disorders. We sought to study the mechanisms by which abnormalities emerge in the context of the 22q11.2 microdeletion, which confers significant genetic risk for psychiatric disorders.

Selective REM sleep restriction in mice using a device designed for tunable somatosensory stimulation.

Background: Sleep perturbation is widely used to investigate the physiological mechanisms that mediate sleep-wake dynamics, and to isolate the specific roles of sleep in health and disease. However, state-of-the-art methods to accomplish sleep perturbation in preclinical models are limited in their throughput, flexibility, and specificity.

New Method: A system was developed to deliver vibro-tactile somatosensory stimulation aimed at controlled, selective sleep perturbation.

Optimal trade-off control in machine learning-based library design, with application to adeno-associated virus (AAV) for gene therapy.

Adeno-associated viruses (AAVs) hold tremendous promise as delivery vectors for gene therapies. AAVs have been successfully engineered-for instance, for more efficient and/or cell-specific delivery to numerous tissues-by creating large, diverse starting libraries and selecting for desired properties. However, these starting libraries often contain a high proportion of variants unable to assemble or package their genomes, a prerequisite for any gene delivery goal.

An internal medicine residency preparatory curriculum for fourth-year medical students.

Background: Intern preparation courses are often broad in scope; there are few published specialty-specific programs outside of General Surgery and Obstetrics. We designed an internal medicine (IM) residency preparatory course at the University of Maryland School of Medicine, which aimed to prepare graduating medical students for the rigours of IM residency training, mapped to Entrustable Professional Activities (EPAs).

Methods: Fourteen fourth-year medical students who were matriculating into IM residency programs enrolled in a 4-week long residency preparation course.

Context-invariant socioemotional encoding by prefrontal ensembles.

The prefrontal cortex plays a key role in social interactions, anxiety-related avoidance, and flexible context- dependent behaviors, raising the question: how do prefrontal neurons represent socioemotional information across different environments? Are contextual and socioemotional representations segregated or intermixed, and does this cause socioemotional encoding to remap or generalize across environments? To address this, we imaged neuronal activity in the medial prefrontal cortex of mice engaged in social interactions or anxiety-related avoidance within different environments. Neuronal ensembles representing context and social interaction overlapped more than expected while remaining orthogonal. Anxiety-related representations similarly generalized across environments while remaining orthogonal to contextual information.

Correlations Between Quantitative EEG Parameters and Cortical Blood Flow in Patients Undergoing Extracorporeal Membrane Oxygenation With and Without Encephalopathy.

Purpose: The neurologic examination of patients undergoing extracorporeal membrane oxygenation (ECMO) is crucial for evaluating irreversible encephalopathy but is often obscured by sedation or neuromuscular blockade. Noninvasive neuromonitoring modalities including diffuse correlation spectroscopy and EEG measure cerebral perfusion and neuronal function, respectively. We hypothesized that encephalopathic ECMO patients with greater degree of irreversible cerebral injury demonstrate less correlation between electrographic activity and cerebral perfusion than those whose encephalopathy is attributable to medications.

Reciprocal associations between parental depression and child cognition: Pathways to children's internalizing and externalizing symptoms.

Parental depression is a risk factor for children's cognitive and psychological development. Literature has found reciprocal relations between parental depression and child psychopathology and effects of parental depression on children's cognition. The present study is the first to examine reciprocity among parental depression and child cognition, and pathways to child psychopathology.

Ventral hippocampus neurons encode meal-related memory.

The ability to encode and retrieve meal-related information is critical to efficiently guide energy acquisition and consumption, yet the underlying neural processes remain elusive. Here we reveal that ventral hippocampus (HPCv) neuronal activity dynamically elevates during meal consumption and this response is highly predictive of subsequent performance in a foraging-related spatial memory task. Targeted recombination-mediated ablation of HPCv meal-responsive neurons impairs foraging-related spatial memory without influencing food motivation, anxiety-like behavior, or escape-mediated spatial memory.

Dose selection for biological enzyme replacement therapy indicated for inborn errors of metabolism.

This paper summarizes key features of the dose-finding strategies used in the development of 11 approved new molecular entities that are first-in-class enzyme replacement therapy (ERT), with a goal to gain insight into the dose exploration approaches to inform efficient dose-finding in future development of biological products for Inborn Errors of Metabolism (IEM). Dose exploration should preferably begin in in vitro studies, followed by testing multiple doses in an appropriate animal disease model, when available, which can provide important information for dose assessment in humans. Performing adequate dose-finding in early phase clinical studies in a well-defined study population, including pediatric subjects, is generally critical to inform dose selection for pivotal trials; alternatively, additional dose exploration can be incorporated as part of a pivotal trial.

Gys1 Antisense Therapy Prevents Disease-Driving Aggregates and Epileptiform Discharges in a Lafora Disease Mouse Model.

Patients with Lafora disease have a mutation in EPM2A or EPM2B, resulting in dysregulation of glycogen metabolism throughout the body and aberrant glycogen molecules that aggregate into Lafora bodies. Lafora bodies are particularly damaging in the brain, where the aggregation drives seizures with increasing severity and frequency, coupled with neurodegeneration. Previous work employed mouse genetic models to reduce glycogen synthesis by approximately 50%, and this strategy significantly reduced Lafora body formation and disease phenotypes.

Viral Determinants of Acute COVID-19 Symptoms in a Nonhospitalized Adult Population in the Pre-Omicron Era.

Background: The influence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA level and presence of infectious virus on symptom occurrence is poorly understood, particularly among nonhospitalized individuals.

Methods: The study included 85 nonhospitalized, symptomatic adults, who were enrolled from September 2020 to November 2021. Data from a longitudinal cohort studied over 28 days was used to analyze the association of individual symptoms with SARS-CoV-2 viral RNA load, or the presence or level of infectious (culturable) virus.