Lipid-induced condensate formation from the Alzheimer's Aβ peptide triggers amyloid aggregation.

The onset and development of Alzheimer's disease is linked to the accumulation of pathological aggregates formed from the normally monomeric amyloid-β peptide within the central nervous system. These Aβ aggregates are increasingly successfully targeted with clinical therapies at later stages of the disease, but the fundamental molecular steps in early stage disease that trigger the initial nucleation event leading to the conversion of monomeric Aβ peptide into pathological aggregates remain unknown. Here, we show that the Aβ peptide can form biomolecular condensates on lipid bilayers both in molecular assays and in living cells.

Potential Effects of Hyperglycemia on SARS-CoV-2 Entry Mechanisms in Pancreatic Beta Cells.

The COVID-19 pandemic has revealed a bidirectional relationship between SARS-CoV-2 infection and diabetes mellitus. Existing evidence strongly suggests hyperglycemia as an independent risk factor for severe COVID-19, resulting in increased morbidity and mortality. Conversely, recent studies have reported new-onset diabetes following SARS-CoV-2 infection, hinting at a potential direct viral attack on pancreatic beta cells.

Molecular mechanism of α-synuclein aggregation on lipid membranes revealed.

The central hallmark of Parkinson's disease pathology is the aggregation of the α-synuclein protein, which, in its healthy form, is associated with lipid membranes. Purified monomeric α-synuclein is relatively stable , but its aggregation can be triggered by the presence of lipid vesicles. Despite this central importance of lipids in the context of α-synuclein aggregation, their detailed mechanistic role in this process has not been established to date.

A solid beta-sheet structure is formed at the surface of FUS droplets during aging.

Phase transitions are important to understand cell dynamics, and the maturation of liquid droplets is relevant to neurodegenerative disorders. We combined NMR and Raman spectroscopies with microscopy to follow, over a period of days to months, droplet maturation of the protein fused in sarcoma (FUS). Our study reveals that the surface of the droplets plays a critical role in this process, while RNA binding prevents it.

Racial Disparities Among Clinical High-Risk and First-Episode Psychosis Multisite Research Participants: A Systematic Review.

Objective: The NIH has mandated equal representation of Black, Indigenous, and people of color (BIPOC) individuals in clinical research, but it is unclear whether such inclusion has been achieved in multisite research studies of individuals at clinical high risk for psychosis or with first-episode psychosis (FEP). An assessment of inclusion rates is important for understanding the social determinants of psychosis and psychosis risk that specifically affect BIPOC individuals.

Methods: The authors conducted a systematic review of the literature published between 1993 and 2022 of multisite research studies of clinical high risk for psychosis and FEP in North America to determine ethnoracial inclusion rates.

Racial and ethnic inequities in psychiatric inpatient building and unit assignment.

Racism is a social determinant of mental health which has a disproportionally negative impact on the experiences of psychiatric inpatients of color. Distinct differences in the physical space and clinical settings of two inpatient buildings at a hospital system in the tristate (New York, New Jersey, Connecticut) area of the United States led to the present investigation of racial inequities in the assignment of patients to specific buildings and units. Archival electronic medical record data were analyzed from over 18,000 unique patients over a period of six years.

Race-Based Disparities in the Frequency and Duration of Restraint Use in a Psychiatric Inpatient Setting.

Objective: Patients' race and age have each been identified as risk factors for experiencing restraint events during psychiatric hospitalization. Restraint duration is also an important variable in determining disparities in treatment. To the authors' knowledge, no studies to date have examined the effect of the interaction of race and age on restraint use and duration in inpatient psychiatric settings.

Introducing desirable patches to initiate ecosystem transitions and accelerate ecosystem restoration.

Meeting restoration targets may require active strategies to accelerate natural regeneration rates or overcome the resilience associated with degraded ecosystem states. Introducing desired ecosystem patches in degraded landscapes constitutes a promising active restoration strategy, with various mechanisms potentially causing these patches to become foci from which desired species can re-establish throughout the landscape. This study considers three mechanisms previously identified as potential drivers of introduced patch dynamics: autocatalytic nucleation, directed dispersal, and resource concentration.

Understanding and controlling the molecular mechanisms of protein aggregation in mAb therapeutics.

In antibody development and manufacturing, protein aggregation is a common challenge that can lead to serious efficacy and safety issues. To mitigate this problem, it is important to investigate its molecular origins. This review discusses (1) our current molecular understanding and theoretical models of antibody aggregation, (2) how various stress conditions related to antibody upstream and downstream bioprocesses can trigger aggregation, and (3) current mitigation strategies employed towards inhibiting aggregation.

Investigating the Role of Amazonian Mesoscale Wind Patterns and Strength on the Spatial Distribution of Martian Bedrock Exposures.

The Martian highlands contain Noachian-aged areally-extensive (>225 km) bedrock exposures that have been mapped using thermal and visible imaging datasets. Given their age, crater density and impact gardening should have led to the formation of decameter scale layers of regolith that would overlie and bury these outcrops if composed of competent materials like basaltic lavas. However, many of these regions lack thick regolith layers and show clear exposures of bedrock materials with elevated thermal inertia values compared to the global average.

Ethnoracial discrimination and the development of suspiciousness symptoms in individuals at clinical high-risk for psychosis.

Background And Hypothesis: While individuals at clinical high-risk (CHR) for psychosis experience higher levels of discrimination than healthy controls, it is unclear how these experiences contribute to the etiology of attenuated positive symptoms. The present study examined the association of perceived discrimination with positive symptoms in a cohort from the North American Prodrome Longitudinal Study (NAPLS2). It predicted that CHR individuals will report higher levels of lifetime and past year perceived discrimination related to their race and ethnicity (ethnoracial discrimination) and that this form of discrimination will be significantly associated with baseline positive symptoms.

The weaponization of medicine: Early psychosis in the Black community and the need for racially informed mental healthcare.

There is a notable disparity between the observed prevalence of schizophrenia-spectrum disorders in racialized persons in the United States and Canada and White individuals in these same countries, with Black people being diagnosed at higher rates than other groups. The consequences thereof bring a progression of lifelong punitive societal implications, including reduced opportunities, substandard care, increased contact with the legal system, and criminalization. Other psychological conditions do not show such a wide racial gap as a schizophrenia-spectrum disorder diagnosis.

Spontaneous nucleation and fast aggregate-dependent proliferation of α-synuclein aggregates within liquid condensates at neutral pH.

The aggregation of α-synuclein into amyloid fibrils has been under scrutiny in recent years because of its association with Parkinson's disease. This process can be triggered by a lipid-dependent nucleation process, and the resulting aggregates can proliferate through secondary nucleation under acidic pH conditions. It has also been recently reported that the aggregation of α-synuclein may follow an alternative pathway, which takes place within dense liquid condensates formed through phase separation.

Aggregation controlled by condensate rheology.

Biomolecular condensates in living cells can exhibit a complex rheology, including viscoelastic and glassy behavior. This rheological behavior of condensates was suggested to regulate polymerization of cytoskeletal filaments and aggregation of amyloid fibrils. Here, we theoretically investigate how the rheological properties of condensates can control the formation of linear aggregates.

Spatiotemporal properties of glutamate input support direction selectivity in the dendrites of retinal starburst amacrine cells.

The asymmetric summation of kinetically distinct glutamate inputs across the dendrites of retinal 'starburst' amacrine cells is one of the several mechanisms that have been proposed to underlie their direction-selective properties, but experimentally verifying input kinetics has been a challenge. Here, we used two-photon glutamate sensor (iGluSnFR) imaging to directly measure the input kinetics across individual starburst dendrites. We found that signals measured from proximal dendrites were relatively sustained compared to those measured from distal dendrites.

From Macro- to Microscale: A combined modelling approach for near-surface wind flow on Mars at sub-dune length-scales.

The processes that initiate and sustain sediment transport which contribute to the modification of aeolian deposits in Mars' low-density atmosphere are still not fully understood despite recent atmospheric modelling. However, detailed microscale wind flow modelling, using Computational Fluid Dynamics at a resolution of <2 m, provides insights into the near-surface processes that cannot be modeled using larger-scale atmospheric modeling. Such Computational Fluid Dynamics simulations cannot by themselves account for regional-scale atmospheric circulations or flow modifications induced by regional km-scale topography, although realistic fine-scale mesoscale atmospheric modeling can.

Distinct Mechanisms of Mismatch-Repair Deficiency Delineate Two Modes of Response to Anti-PD-1 Immunotherapy in Endometrial Carcinoma.

Unlabelled: Mismatch repair-deficient (MMRd) cancers have varied responses to immune-checkpoint blockade (ICB). We conducted a phase II clinical trial of the PD-1 inhibitor pembrolizumab in 24 patients with MMRd endometrial cancer (NCT02899793). Patients with mutational MMRd tumors (6 patients) had higher response rates and longer survival than those with epigenetic MMRd tumors (18 patients).

Transcriptional dynamics of murine motor neuron maturation in vivo and in vitro.

Neurons born in the embryo can undergo a protracted period of maturation lasting well into postnatal life. How gene expression changes are regulated during maturation and whether they can be recapitulated in cultured neurons remains poorly understood. Here, we show that mouse motor neurons exhibit pervasive changes in gene expression and accessibility of associated regulatory regions from embryonic till juvenile age.

Analytical Solution to the Flory-Huggins Model.

A self-consistent analytical solution for binodal concentrations of the two-component Flory-Huggins phase separation model is derived. We show that this form extends the validity of the Ginzburg-Landau expansion away from the critical point to cover the whole phase space. Furthermore, this analytical solution reveals an exponential scaling law of the dilute phase binodal concentration as a function of the interaction strength and chain length.

Uncovering the universality of self-replication in protein aggregation and its link to disease.

Fibrillar protein aggregates are a hallmark of a range of human disorders, from prion diseases to dementias, but are also encountered in several functional contexts. Yet, the fundamental links between protein assembly mechanisms and their functional or pathological roles have remained elusive. Here, we analyze the aggregation kinetics of a large set of proteins that self-assemble by a nucleated-growth mechanism, from those associated with disease, over those whose aggregates fulfill functional roles in biology, to those that aggregate only under artificial conditions.

Ethnoracial Inclusion in Clinical Trials of Ketamine in the Treatment of Mental Health Disorders.

Objective: Despite strong evidence for the safety and efficacy of ketamine in the treatment of mood disorders, the enrollment of Black, Indigenous, and People of Color (BIPOC) has not been a focus of this research. Health disparities in the treatment of mood disorders in BIPOC indicate a strong need to understand the clinical, social, and pharmacological aspects of this novel treatment in people of color.

Method: A comprehensive methodological search for double-blind, placebo-controlled, randomized ketamine clinical trials published from 1993 to 2020 was conducted across several databases to analyze the demographics of trial participants.