A brain-wide map of descending inputs onto spinal V1 interneurons.

Motor output results from the coordinated activity of neural circuits distributed across multiple brain regions that convey information to the spinal cord via descending motor pathways. Yet the organizational logic through which supraspinal systems target discrete components of spinal motor circuits remains unclear. Here, using viral transsynaptic tracing along with serial two-photon tomography, we have generated a whole-brain map of monosynaptic inputs to spinal V1 interneurons, a major inhibitory population involved in motor control.

Synaptic plasticity in human thalamocortical assembloids.

Synaptic plasticities, such as long-term potentiation (LTP) and depression (LTD), tune synaptic efficacy and are essential for learning and memory. Current studies of synaptic plasticity in humans are limited by a lack of adequate human models. Here, we modeled the thalamocortical system by fusing human induced pluripotent stem cell-derived thalamic and cortical organoids.

Synaptic plasticity in human thalamocortical assembloids.

Synaptic plasticities, such as long-term potentiation (LTP) and depression (LTD), tune synaptic efficacy and are essential for learning and memory. Current studies of synaptic plasticity in humans are limited by a lack of adequate human models. Here, we modeled the thalamocortical system by fusing human induced pluripotent stem cell-derived thalamic and cortical organoids.

Selective chemogenetic inactivation of corticoaccumbal projections disrupts trait choice impulsivity.

Impulsive choice has enduring trait-like characteristics and is defined by preference for small immediate rewards over larger delayed ones. Importantly, it is a determining factor in the development and persistence of substance use disorder (SUD). Emerging evidence from human and animal studies suggests frontal cortical regions exert influence over striatal reward processing areas during decision-making in impulsive choice or delay discounting (DD) tasks.

Alzheimer's disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment.

Recent proteome and transcriptome profiling of Alzheimer's disease (AD) brains reveals RNA splicing dysfunction and U1 small nuclear ribonucleoprotein (snRNP) pathology containing U1-70K and its N-terminal 40-KDa fragment (N40K). Here we present a causative role of U1 snRNP dysfunction to neurodegeneration in primary neurons and transgenic mice (N40K-Tg), in which N40K expression exerts a dominant-negative effect to downregulate full-length U1-70K. N40K-Tg recapitulates N40K insolubility, erroneous splicing events, neuronal degeneration and cognitive impairment.

Patterns in Tacrolimus Variability and Association with Donor-Specific Antibody Formation in Pediatric Kidney Transplant Recipients.

Background And Objectives: High tacrolimus intrapatient variability has been associated with inferior graft outcomes in patients with kidney transplants. We studied baseline patterns of tacrolimus intrapatient variability in pediatric patients with kidney transplants and examined these patterns in relation to C1q-binding donor-specific antibodies.

Design, Setting, Participants, & Measurements: All tacrolimus levels in participants who underwent kidney-only transplantation at a single pediatric center from 2004 to 2018 (with at least 12-month follow-up, followed until 2019) were analyzed to determine baseline variability.

Physiotherapists Both Reproduce and Resist Biomedical Dominance when Working With People With Low Back Pain: A Qualitative Study Towards New Praxis.

Despite recommendations to incorporate physical and psychosocial factors when providing care for people with back pain, research suggests that physiotherapists continue to focus on biological aspects. This study investigated how interpersonal and institutional norms influence this continued enactment of the biological aspects of management. We used theoretically-driven analysis, drawing from Foucauldian notions of power, to analyse 28 ethnographic observations of consultations and seven group discussions with physiotherapists.

Cortical control of striatal fast-spiking interneuron synchrony.

Inhibitory fast-spiking interneurons in the dorsal striatum regulate actions and action strategies, including habits. Fast-spiking interneurons are widely believed to synchronize their firing due to the electrical synapses formed between these neurons. However, neuronal modelling data suggest convergent cortical input may also drive synchrony in fast-spiking interneuron networks.

A Case for Thalamic Mechanisms of Schizophrenia: Perspective From Modeling 22q11.2 Deletion Syndrome.

Schizophrenia is a severe, chronic psychiatric disorder that devastates the lives of millions of people worldwide. The disease is characterized by a constellation of symptoms, ranging from cognitive deficits, to social withdrawal, to hallucinations. Despite decades of research, our understanding of the neurobiology of the disease, specifically the neural circuits underlying schizophrenia symptoms, is still in the early stages.

Hypoxia alters the release and size distribution of extracellular vesicles in pancreatic cancer cells to support their adaptive survival.

Pancreatic tumors are highly desmoplastic and poorly-vascularized, and therefore must develop adaptive mechanisms to sustain their survival under hypoxic condition. Extracellular vesicles (EV) play vital roles in pancreatic tumor pathobiology by facilitating intercellular communication. Here we studied the effect of hypoxia on the release of EVs and examined their role in adaptive survival of pancreatic cancer (PC) cells.

Exosomal markers (CD63 and CD9) expression and their prognostic significance using immunohistochemistry in patients with pancreatic ductal adenocarcinoma.

Background: Exosomes are important mediators of intercellular communications and play pivotal roles in cancer progression, metastasis and chemoresistance. CD63 and CD9 are widely accepted exosomal markers. In patients with pancreatic ductal adenocarcinoma (PDAC), positive correlation between CD9 expression and overall survival (OS) was reported.

Understanding functional and social risk characteristics of frail older adults: a cross-sectional survey study.

Background: Frailty is a condition of increasing importance, given the aging adult population. With an anticipated shortage of geriatricians, primary care physicians will increasingly need to manage care for frail adults with complex functional risks and social-economic circumstances.

Methods: We used cross-sectional data from 4551 adults ages 65-90 who responded to the 2014/2015 cycle of the Kaiser Permanente Northern California Member Health Survey (MHS), a self-administered survey that covers multiple health and social characteristics, to create a deficits accumulation model frailty index, classify respondents as frail or non-frail, and then compare prevalence of functional health issues including Activities of Daily Living (ADL)/Instrumental Activities of Daily Living (IADL) and social determinants of health (SDOHs) by frailty status.

An Aplysia-like synaptic switch for rapid protection against ethanol-induced synaptic inhibition in a mammalian habit circuit.

Decades of work in Aplysia californica established the general rule that principles of synaptic plasticity and their molecular mechanisms are evolutionarily conserved from mollusks to mammals. However, an exquisitely sensitive, activity-dependent homosynaptic mechanism that protects against the depression of neurotransmitter release in Aplysia sensory neuron terminals has, to date, not been uncovered in other animals, including mammals. Here, we discover that depression at a mammalian synapse that is implicated in habit formation and habit learning acceleration by ethanol, the fast-spiking interneuron (FSI) to medium spiny principal projection neuron (MSN) synapse of the dorsolateral striatum, is subject to this type of synaptic protection.

Rejuvenation of plasticity in the brain: opening the critical period.

Cortical circuits are particularly sensitive to incoming sensory information during well-defined intervals of postnatal development called 'critical periods'. The critical period for cortical plasticity closes in adults, thus restricting the brain's ability to indiscriminately store new sensory information. For example, children acquire language in an exposure-based manner, whereas learning language in adulthood requires more effort and attention.

Complex Control of Striatal Neurotransmission by Nicotinic Acetylcholine Receptors via Excitatory Inputs onto Medium Spiny Neurons.

The prevalence of nicotine dependence is higher than that for any other substance abuse disorder; still, the underlying mechanisms are not fully established. To this end, we studied acute effects by nicotine on neurotransmission in the dorsolateral striatum, a key brain region with respect to the formation of habits. Electrophysiological recordings in acutely isolated brain slices from rodent showed that nicotine (10 nm to 10 μm) produced an LTD of evoked field potentials.

Drp1 Mitochondrial Fission in D1 Neurons Mediates Behavioral and Cellular Plasticity during Early Cocaine Abstinence.

Altered brain energy homeostasis is a key adaptation occurring in the cocaine-addicted brain, but the effect of cocaine on the fundamental source of energy, mitochondria, is unknown. We demonstrate an increase of dynamin-related protein-1 (Drp1), the mitochondrial fission mediator, in nucleus accumbens (NAc) after repeated cocaine exposure and in cocaine-dependent individuals. Mdivi-1, a demonstrated fission inhibitor, blunts cocaine seeking and locomotor sensitization, while blocking c-Fos induction and excitatory input onto dopamine receptor-1 (D1) containing NAc medium spiny neurons (MSNs).

Incidence, duration and cost of futile treatment in end-of-life hospital admissions to three Australian public-sector tertiary hospitals: a retrospective multicentre cohort study.

Objectives: To estimate the incidence, duration and cost of futile treatment for end-of-life hospital admissions.

Design: Retrospective multicentre cohort study involving a clinical audit of hospital admissions.

Setting: Three Australian public-sector tertiary hospitals.

Exosomal Markers (CD63 and CD9) Expression Pattern Using Immunohistochemistry in Resected Malignant and Nonmalignant Pancreatic Specimens.

Objectives: Exosomes are important mediators in intercellular communications and play a role in cancer progression and metastasis. Exosomal membranes are enriched in endosome-specific tetraspanins (CD9 and CD63). Here, we explored the expression of CD63 and CD9 utilizing immunohistochemistry in malignant and nonmalignant cells in 29 resected pancreatic specimens (RPSs) of mixed racial background.

Incidence of Sinusitis in Burn Victims and Association With Inhalational Injury.

The purpose of this study is to determine the incidence of sinusitis in mechanically ventilated burn victims and to examine if the presence of inhalational injury increases the likelihood of developing sinusitis. The authors hypothesize that the incidence of sinusitis will be increased in burn victims who have concomitant inhalational injury. A retrospective chart analysis was performed on all patients who were admitted to the Nathan Speare Regional Burn Treatment Center over a 24-month time frame.

Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK.

Background: Chemoresistance is a significant clinical problem in pancreatic cancer (PC) and underlying molecular mechanisms still remain to be completely understood. Here we report a novel exosome-mediated mechanism of drug-induced acquired chemoresistance in PC cells.

Methods: Differential ultracentrifugation was performed to isolate extracellular vesicles (EVs) based on their size from vehicle- or gemcitabine-treated PC cells.

Experience of clinical supervisors of international medical graduates in an Australian district hospital.

Objective Herein we record the experience of clinical supervisors of international medical graduates (IMGs) working as junior staff in a district hospital by examining supervisor perspectives on IMG performance, the factors affecting their performance and the requirements of supervision under these circumstances. Methods The present study had an open-ended exploratory qualitative design. Thirteen 13 open-ended, in-depth interviews were undertaken with supervisors of IMGs employed in a public district hospital in Queensland, Australia.