Discovery of BBO-8520, a first-in-class direct and covalent dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C.

Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form. This approach provides no direct target coverage of the active protein. Expectedly, adaptive resistance to KRASG12C (OFF)-only inhibitors is observed in association with increased expression and activity of KRASG12C(ON).

Experiences of adult patients living with depression-related insomnia: a qualitative systematic review.

Objective: The objective of this review was to identify and synthesize the best available evidence on how adult patients experience living with depression-related insomnia, and their experiences related to pharmacological and non-pharmacological interventions aimed at improving sleep.

Introduction: Insomnia affects 80% to 90% of patients with depression. The costs of insomnia are considerable for the individual and society alike.

Biophysical Analysis of a Minimalistic Kidney Model Expressing SGLT1 Reveals Crosstalk between Luminal and Lateral Membranes and a Plausible Mechanism of Isosmotic Transport.

We extended our model of the S1 tubular segment to address the mechanisms by which SGLT1 interacts with lateral Na/K pumps and tight junctional complexes to generate isosmotic fluid reabsorption via tubular segment S3. The strategy applied allowed for simulation of laboratory experiments. Reproducing known experimental results constrained the range of acceptable model outputs and contributed to minimizing the free parameter space.

Natural Product Graveoline Modulates Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) Membrane Association: Insights from Advanced Spectroscopic Studies.

The KRAS gene plays a pivotal role in numerous cancers by encoding a GTPase that upon association with the plasma membrane activates the MAPK pathway, promoting cellular proliferation. In our study, we investigated small molecules that disrupt KRAS's membrane interaction, hypothesizing that such disruption could in turn inhibit mutant RAS signaling. Native mass spectrometry screening of KRAS-FMe identified compounds with a preference for interacting with the hypervariable region (HVR), and surface plasmon resonance (SPR) further refined our selection to graveoline as a compound exhibiting preferential HVR binding.

The efficacy of ball blankets on insomnia in depression in outpatient clinics: A randomised crossover multicentre trial.

Many patients with depression report insomnia symptoms that profoundly affect their health and well-being. Non-pharmacological treatments of insomnia may be preferable for some patients. In this randomised crossover trial, we investigated the efficacy of the Protac Ball Blanket® on insomnia among patients with depression.

User Experiences of Ball Blankets in Adults with Depression-Related Insomnia: A Qualitative Content Analysis Study.

Insomnia is prevalent in patients suffering from depression and may itself exacerbate the disability associated with depression and impede the path to recovery. Although crucial in ensuring meaningful interactions and interventions for patients, research on patients' experiences of depression-related insomnia and its treatment is limited. The purpose of this study was therefore to investigate how adult patients with depression-related insomnia experience sleeping with a weighted Protac Ball Blanket®, focusing on how the blanket feels and works and contributes to their subjective sleep quality experience.

KRAS4b:RAF-1 Homogenous Time-Resolved Fluorescence Resonance Energy Transfer Assay for Drug Discovery.

Homogenous time-resolved FRET (HTRF) assays have become one of the most popular tools for pharmaceutical drug screening efforts over the last two decades. Large Stokes shifts and long fluorescent lifetimes of lanthanide chelates lead to robust signal to noise, as well as decreased false positive rates compared to traditional assay techniques. In this chapter, we describe an HTRF protein-protein interaction (PPI) assay for the KRAS4b G-domain in the GppNHp-bound state and the RAF-1-RBD currently used for drug screens.

Validating the efficacy and value proposition of mental fitness vocal biomarkers in a psychiatric population: prospective cohort study.

Background: The utility of vocal biomarkers for mental health assessment has gained increasing attention. This study aims to further this line of research by introducing a novel vocal scoring system designed to provide mental fitness tracking insights to users in real-world settings.

Methods: A prospective cohort study with 104 outpatient psychiatric participants was conducted to validate the "Mental Fitness Vocal Biomarker" (MFVB) score.

Sense of psychological ownership in co-design processes: A case study.

Introduction: Service users are increasingly participating in health research. Although collaborative research is assumed to give users a sense of psychological ownership, little is known about the specific psychosocial processes through which ownership develops and is displayed. The present study yields insight into a process in which service users, researchers and a website designer collaborated to design a website.

Transmembrane protein 184B (TMEM184B) promotes expression of synaptic gene networks in the mouse hippocampus.

In Alzheimer's Disease (AD) and other dementias, hippocampal synaptic dysfunction and loss contribute to the progression of memory impairment. Recent analysis of human AD transcriptomes has provided a list of gene candidates that may serve as drivers of disease. One such candidate is the membrane protein TMEM184B.

Ototoxicity associated with high-dose carboplatin for patients with previously treated germ cell tumors.

Background: High-dose carboplatin is an essential part of curative high-dose chemotherapy (HDCT) for patients with previously treated germ cell tumors (GCTs). Although hearing loss (HL) is a known side effect of HDCT, data on its severity and characteristics are limited.

Methods: Eligible patients received HDCT for GCTs from 1993 to 2017 and had audiograms before and after HDCT.

Extended High-Frequency Audiometry using the Wireless Automated Hearing Test System Compared to Manual Audiometry in Children and Adolescents.

Objectives: Reliable wireless automated audiometry that includes extended high frequencies (EHF) outside a sound booth would increase access to monitoring programs for individuals at risk for hearing loss, particularly those at risk for ototoxicity. The purpose of the study was to compare thresholds obtained with 1) standard manual audiometry to automated thresholds measured with the Wireless Automated Hearing Test System (WAHTS) inside a sound booth, and 2) automated audiometry in the sound booth to automated audiometry outside the sound booth in an office environment.

Design: Cross-sectional, repeated measures study.

Sequence and Structural Motifs Controlling the Broad Substrate Specificity of the Mycobacterial Hormone-Sensitive Lipase LipN.

has a complex life cycle transitioning between active and dormant growth states depending on environmental conditions. LipN (Rv2970c) is a conserved mycobacterial serine hydrolase with regulated catalytic activity at the interface between active and dormant growth conditions. LipN also catalyzes the xenobiotic degradation of a tertiary ester substrate and contains multiple conserved motifs connected with the ability to catalyze the hydrolysis of difficult tertiary ester substrates.

Development and Validation of a Respiratory-Responsive Vocal Biomarker-Based Tool for Generalizable Detection of Respiratory Impairment: Independent Case-Control Studies in Multiple Respiratory Conditions Including Asthma, Chronic Obstructive Pulmonary Disease, and COVID-19.

Background: Vocal biomarker-based machine learning approaches have shown promising results in the detection of various health conditions, including respiratory diseases, such as asthma.

Objective: This study aimed to determine whether a respiratory-responsive vocal biomarker (RRVB) model platform initially trained on an asthma and healthy volunteer (HV) data set can differentiate patients with active COVID-19 infection from asymptomatic HVs by assessing its sensitivity, specificity, and odds ratio (OR).

Methods: A logistic regression model using a weighted sum of voice acoustic features was previously trained and validated on a data set of approximately 1700 patients with a confirmed asthma diagnosis and a similar number of healthy controls.

Cognitive Behavioral Therapy for Chronic Insomnia in Outpatients with Major Depression-A Randomised Controlled Trial.

The aim of this randomised controlled assessor-blinded trial was to examine the effect of cognitive behavioural therapy for insomnia on sleep variables and depressive symptomatology in outpatients with comorbid insomnia and moderate to severe depression. Forty-seven participants were randomized to receive one weekly session in 6 weeks of cognitive behavioural therapy for insomnia or treatment as usual. The intervention was a hybrid between individual and group treatment.

Experiences of adult patients living with depression-related insomnia: a qualitative systematic review protocol.

Objective: The objective of this review is to identify and synthesize the best available evidence on how adult patients experience living with depression-related insomnia. In particular, the review will examine the experiences related to pharmacological and non-pharmacological interventions to improve sleep.

Introduction: Approximately 80% to 90% of patients with depression have insomnia, which is associated with substantial personal and social costs.

Association between polarity of first episode and solar insolation in bipolar I disorder.

Objective: Circadian rhythm disruption is commonly observed in bipolar disorder (BD). Daylight is the most powerful signal to entrain the human circadian clock system. This exploratory study investigated if solar insolation at the onset location was associated with the polarity of the first episode of BD I.

Reference equivalent threshold sound pressure levels for the Wireless Automated Hearing Test System.

This paper presents reference equivalent threshold sound pressure levels (RETSPLs) for the Wireless Automated Hearing Test System (WAHTS), a recently commercialized device developed for use as a boothless audiometer. Two initial studies were conducted following the ISO 389-9 standard [ISO 389-9 (2009). "Acoustics-Reference zero for the calibration of audiometric equipment.

Biomarkers of nanomaterials hazard from multi-layer data.

There is an urgent need to apply effective, data-driven approaches to reliably predict engineered nanomaterial (ENM) toxicity. Here we introduce a predictive computational framework based on the molecular and phenotypic effects of a large panel of ENMs across multiple in vitro and in vivo models. Our methodology allows for the grouping of ENMs based on multi-omics approaches combined with robust toxicity tests.

The bioactive constituents and antioxidant activities of ten selected Brazilian Cerrado fruits.

This study measured the total levels of phenolic, anthocyanin, carotenoid, and tocopherol compounds, and vitamin C in ten fruits from the Brazilian Cerrado: araçá-boi, bacaba, bacupari, biribá, cajuí, curriola, marmelada-espinho, mirindiba, murici, and puçá-preto. Five extracts were prepared from each fruit using solvents with different polarities. The Trolox equivalent antioxidant activity, oxygen radical absorbance capacity, and inhibition of β-carotene bleaching were determined for each extract.

A kink in DWORF helical structure controls the activation of the sarcoplasmic reticulum Ca-ATPase.

SERCA is a P-type ATPase embedded in the sarcoplasmic reticulum and plays a central role in muscle relaxation. SERCA's function is regulated by single-pass membrane proteins called regulins. Unlike other regulins, dwarf open reading frame (DWORF) expressed in cardiac muscle has a unique activating effect.