Small molecule protein assembly modulators with pan-cancer therapeutic efficacy.

Two structurally unrelated small molecule chemotypes, represented by compounds PAV-617 and PAV-951, with antiviral activity in cell culture against Mpox virus (formerly known as monkeypox virus) and human immunodeficiency virus (HIV) respectively, were studied for anti-cancer efficacy. Each exhibited apparent pan-cancer cytotoxicity with reasonable pharmacokinetics. Non-toxicity is demonstrated in a non-cancer cell line and in mice at doses achieving drug exposure at active concentrations.

The protective roles of coping self-efficacy and social support for posttraumatic stress during the COVID-19 pandemic.

Objective: This study examined the roles of social support and coping self-efficacy (CSE) in attenuating posttraumatic stress (PTS) symptoms during the COVID-19 pandemic among a nonclinical university student sample.

Method: Participants ( = 610; 59% female) completed questionaries assessing psychological distress (Kessler Psychological Distress Scale) at baseline and 6-month follow-up, and social support (Interpersonal Support Evaluation List-12), CSE Scale, and PTS symptoms (Impact of Event Scale-Revised) at 6 months. A path analysis was conducted using SPSS Amos to examine the direct and indirect pathways from psychological distress to PTS symptoms that are accounted for by social support and CSE, controlling for gender.

Food Insecurity Predicts Magnitude of Early BMI Change in a Pediatric Weight Management Intervention.

Objective: The aim of this study was to estimate the prevalence of food insecurity among children with overweight/obesity presenting for weight management treatment and examine whether food insecurity predicts early change in body mass index (BMI), expressed as a percentage of the 95th percentile (%BMIp95).

Method: Children (N = 69; ages 3-18 years) presenting to a hospital-based pediatric weight management intervention and 1 parent/guardian per child (N = 69) were included. At the first appointment, parents/guardians completed the US Household Food Security Survey Module: Six-item Short Form and a demographics questionnaire.

Disrupted-in-schizophrenia 1 protein aggregates in cerebrospinal fluid are elevated in patients with first-episode psychosis.

Aim: The disrupted-in-schizophrenia 1 (DISC1) protein is a key regulator at the intersection of major signaling pathways relevant for adaptive behavior. It is prone to posttranslational changes such as misassembly and aggregation but the significance of such transformations for human mental illness has remained unclear. We aimed to demonstrate the occurrence of DISC1 protein aggregates in patients with first-episode psychosis (FEP).

Age moderates change in disease-related stress among congenital heart disease survivors: a 6-year follow-up.

Aims: As congenital heart disease (CHD) survivors age, they are confronted with elevated risk of cardiovascular morbidity and increasingly complex disease self-management demands. Given that stress is associated with poor physical and psychosocial outcomes, it is crucial to examine how disease-related stress changes over time in this population. However, this outcome has received little research attention to date.

50-kHz ultrasonic vocalizations do not signal social anhedonia in transgenic DISC1 rats.

Patients diagnosed with neuropsychiatric disorders, such as autism and schizophrenia, suffer from disorganized speech. The disrupted-in-schizophrenia 1 (DISC1) protein pathway is considered a risk factor for the development of several psychiatric disorders and plays an important role in the dysregulation of dopamine (DA), which in turn plays an important role in the regulation of ultrasonic vocalizations (USVs) in rats. Moreover, the DISC1 protein pathway has been identified as a cause of social anhedonia, that is, a decrease in the drive for social interactions.

TRIOBP-1 Protein Aggregation Exists in Both Major Depressive Disorder and Schizophrenia, and Can Occur through Two Distinct Regions of the Protein.

The presence of proteinopathy, the accumulation of specific proteins as aggregates in neurons, is an emerging aspect of the pathology of schizophrenia and other major mental illnesses. Among the initial proteins implicated in forming such aggregates in these conditions is Trio and F-actin Binding Protein isoform 1 (TRIOBP-1), a ubiquitously expressed protein involved in the stabilization of the actin cytoskeleton. Here we investigate the insolubility of TRIOBP-1, as an indicator of aggregation, in brain samples from 25 schizophrenia patients, 25 major depressive disorder patients and 50 control individuals (anterior cingulate cortex, BA23).

Social anhedonia as a Disrupted-in-Schizophrenia 1-dependent phenotype.

Deficits in social interaction or social cognition are key phenotypes in a variety of chronic mental diseases, yet, their modeling and molecular dissection are only in their infancy. The Disrupted-in-Schizophrenia 1 (DISC1) signaling pathway is considered to play a role in different psychiatric disorders such as schizophrenia, depression, and biopolar disorders. DISC1 is involved in regulating the dopaminergic neurotransmission in, among others, the mesolimbic reward system.

New Mothers' Perceptions of Pressure to Breastfeed.

Purpose: Develop a measure to quantitatively assess perceived pressure to breastfeed and examine associations between perceived pressure, emotional distress, and the breastfeeding experience and self-efficacy among women with 2- to 6-month-old infants.

Study Design And Methods: A cross-sectional study using an online survey to assess perceived pressure to breastfeed, emotional distress, and the breastfeeding experience and self-efficacy was conducted. Participants were recruited through ResearchMatch, a national online service that matches potential participants to research studies, and online community forums (e.

Disrupted-in-schizophrenia 1 Protein Misassembly Impairs Cognitive Flexibility and Social Behaviors in a Transgenic Rat Model.

Alterations in cognitive functions, social behaviors and stress reactions are commonly diagnosed in chronic mental illnesses (CMI). Animal models expressing mutant genes associated to CMI represent either rare mutations or those contributing only minimally to genetic risk. Non-genetic causes of CMI can be modeled by disturbing downstream signaling pathways, for example by inducing protein misassembly or aggregation.

A Randomized Clinical Trial Demonstrating Feasibility and Preliminary Efficacy of a Videoconference-Delivered Physical Activity Lifestyle Intervention Among Adolescents With a Congenital Heart Defect.

Background: Individuals with congenital heart defects are at increased risk for developing further cardiovascular complications, which can be mitigated by increasing physical activity. Given that positive health behaviors begin declining during older adolescence, it is vital to promote lifestyle changes in this population.

Purpose: The current study aims to (a) determine the feasibility/acceptability of the Congenital Heart Disease Physical Activity Lifestyle (CHD-PAL) intervention among adolescents (ages 15-18) with moderate and complex congenital heart defects, and (b) estimate the preliminary efficacy of CHD-PAL for increasing time spent in moderate-to-vigorous physical activity (MVPA) and cardiorespiratory fitness and decreasing sedentary behavior.

A Pan-Respiratory Antiviral Chemotype Targeting a Host Multi-Protein Complex.

We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity of PAV-431, a representative compound from the series, has been validated against infectious virus in multiple cell culture models for all six families of viruses causing most respiratory disease in humans. In animals this chemotype has been demonstrated efficacious for Porcine Epidemic Diarrhea Virus (a coronavirus) and Respiratory Syncytial Virus (a paramyxovirus).

A Randomized Phase 1 Evaluation of Deupirfenidone, a Novel Deuterium-Containing Drug Candidate for Interstitial Lung Disease and Other Inflammatory and Fibrotic Diseases.

LYT-100 (deupirfenidone) is a selectively deuterated form of pirfenidone under development for the treatment of inflammatory and fibrotic diseases, including interstitial lung disease. Adverse events associated with antifibrotics can be a barrier to adoption and persistence in patients with interstitial lung diseases, most of whom are not on standard-of-care therapy. LYT-100 is designed to have a differentiated pharmacokinetic (PK) profile from pirfenidone and could offer a differentiated safety profile compared to current standard-of-care drugs while retaining the biochemical potency and specificity of pirfenidone.

Gender Differences in Physical Activity Engagement Among Adolescents With Congenital Heart Disease.

Objective: The current study aimed to (a) describe moderate-to-vigorous physical activity (MVPA), sedentary behavior (SB), and cardiorespiratory fitness (VO2Peak) via objective assessment among adolescents with congenital heart disease (CHD), (b) examine gender differences on MVPA, SB, VO2Peak, and the Theory of Planned Behavior elements, and (c) identify whether gender moderates the relationships between the Theory of Planned Behavior elements and MVPA, SB, and VO2Peak.

Methods: Adolescent CHD survivors (N = 86; ages 15-18 years) wore an accelerometer to assess MVPA and SB, underwent an exercise stress test to assess VO2Peak, and completed a survey of the Theory of Planned Behavior elements as measured by perceived benefits (attitudes), family/friend support and perceived norms (social norms), and self-efficacy and barriers (perceived behavioral control) to engaging in physical activity.

Results: On average, CHD survivors engaged in 22.

Ultrasensitive immunoassay allows measurement of serum neurofilament heavy in multiple sclerosis.

Background: Neurofilament heavy (NfH) is a promising biomarker for neuro-axonal damage in Multiple Sclerosis (MS). We compared the performance of high-sensitivity serum-NfH immunoassays, with as aim to investigate the value of serum-NfH as biomarker for MS.

Methods: We measured serum-NfH in 76 MS patients with Simoa (one commercial, one in-house) or Luminex assays.

The interaction of insoluble Amyloid-β with soluble Amyloid-β dimers decreases Amyloid-β plaque numbers.

Objectives: The heterogeneity of Amyloid-beta (Aβ) plaque load in patients with Alzheimer's disease (AD) has puzzled neuropathology. Since brain Aβ plaque load does not correlate with cognitive decline, neurotoxic soluble Aβ oligomers have been championed as disease-causing agents in early AD. So far, investigating molecular interactions between soluble oligomeric Aβ and insoluble Aβ in vivo has been difficult because of the abundance of Aβ oligomer species and the kinetic equilibrium in which they coexist.

Viruses as 'Truffle Hounds': Molecular Tools for Untangling Brain Cellular Pathology.

The ability of viruses to evolve several orders of magnitude faster than their host cells has enabled them to exploit host cellular machinery by selectively recruiting multiprotein complexes (MPCs) for their catalyzed assembly and replication. This hijacking may depend on alternative, 'moonlighting' functions of host proteins that deviate from their canonical functions thereby inducing cellular pathology. Here, we posit that if virus-induced cellular pathology is similar to that of other, unknown (non-viral) causes, the identification and molecular characterization of the host proteins involved in virus-mediated cellular pathology can be leveraged to decipher the non-viral disease-relevant mechanisms.

Health-Related Quality of Life and Emotional Distress Among Mothers of Sons With Muscular Dystrophy as Compared to Sex- and Age Group-Matched Controls.

The health-related quality of life and emotional distress among mothers of sons with Duchenne or Becker muscular dystrophies (n = 82) were compared to sex- and age group-matched controls (n = 26). Participants self-reported health-related quality of life for themselves and their son(s), emotional distress, and mood/anxiety-related medication. Mothers reported poorer health-related quality of life across all domains of their health-related quality of life, as well as higher levels of emotional distress.

SARS-CoV-2 targets neurons of 3D human brain organoids.

COVID-19 pandemic caused by SARS-CoV-2 infection is a public health emergency. COVID-19 typically exhibits respiratory illness. Unexpectedly, emerging clinical reports indicate that neurological symptoms continue to rise, suggesting detrimental effects of SARS-CoV-2 on the central nervous system (CNS).

Tools as "petrified memes": A duality.

Tools are generated by defined steps, fulfill distinct uses, and elicit affordances or mental representations. When the latter are recombined, they are perceived as "technical reasoning," resulting in novel tools when executed. They can be exchanged, varied, and selected between individuals in a cumulative social process.

IPSC-Derived Neuronal Cultures Carrying the Alzheimer's Disease Associated R47H Variant Enables the Construction of an Aβ-Induced Gene Regulatory Network.

Genes associated with immune response and inflammation have been identified as genetic risk factors for late-onset Alzheimer´s disease (LOAD). The rare R47H variant within triggering receptor expressed on myeloid cells 2 (TREM2) has been shown to increase the risk for developing Alzheimer's disease (AD) 2-3-fold. Here, we report the generation and characterization of a model of late-onset Alzheimer's disease (LOAD) using lymphoblast-derived induced pluripotent stem cells (iPSCs) from patients carrying the TREM2 R47H mutation, as well as from control individuals without dementia.

Blood tests to diagnose schizophrenia: self-imposed limits in psychiatry.

The naturalisation of mental disorders-ie, their translation into measurable and preferably molecular variables-has not progressed despite breath-taking discoveries in the neurosciences. We ask whether self-inflicted limits exist among psychiatrists that would prevent them from supporting an imaginary perfect blood test with diagnostic specificity, sensitivity, and validity, which was able to replace clinical diagnosis completely. Although relevant for many mental disorders, we use the clinical disease category schizophrenia here as an example to discuss factors that oppose the naturalisation of clinical disease categories.

Disruption of cellular proteostasis by H1N1 influenza A virus causes α-synuclein aggregation.

Neurodegenerative diseases feature specific misfolded or misassembled proteins associated with neurotoxicity. The precise mechanisms by which protein aggregates first arise in the majority of sporadic cases have remained unclear. Likely, a first critical mass of misfolded proteins starts a vicious cycle of a prion-like expansion.