Luminal breast epithelial cells of BRCA1 or BRCA2 mutation carriers and noncarriers harbor common breast cancer copy number alterations.

The prevalence and nature of somatic copy number alterations (CNAs) in breast epithelium and their role in tumor initiation and evolution remain poorly understood. Using single-cell DNA sequencing (49,238 cells) of epithelium from BRCA1 and BRCA2 carriers or wild-type individuals, we identified recurrent CNAs (for example, 1q-gain and 7q, 10q, 16q and 22q-loss) that are present in a rare population of cells across almost all samples (n = 28). In BRCA1/BRCA2 carriers, these occur before loss of heterozygosity (LOH) of wild-type alleles.

Dose-dependent effects of transcranial photobiomodulation on brain temperature in patients with major depressive disorder: a spectroscopy study.

This study aimed to evaluate the dose-dependent brain temperature effects of transcranial photobiomodulation (t-PBM). Thirty adult subjects with major depressive disorder were randomized to three t-PBM sessions with different doses (low: 50 mW/cm, medium: 300 mW/cm, high: 850 mW/cm) and a sham treatment. The low and medium doses were administered in continuous wave mode, while the high dose was administered in pulsed wave mode.

Powerful microscopy technologies decode spatially organized cellular networks that drive response to immunotherapy in humans.

In tumors, immune cells organize into networks of different sizes and composition, including complex tertiary lymphoid structures and recently identified networks centered around the chemokines CXCL9/10/11 and CCL19. New commercially available highly multiplexed microscopy using cyclical RNA in situ hybridization and antibody-based approaches have the potential to establish the organization of the immune response in human tissue and serve as a foundation for future immunology research.

Is a brief mindfulness ecological momentary intervention more efficacious than a self-monitoring app for social anxiety disorder? A randomized controlled trial.

Despite their proliferation, limited knowledge exists regarding possible benefits of brief mindfulness ecological momentary interventions (MEMIs) for social anxiety disorder (SAD). Propositions that MEMIs could alleviate SAD symptoms and related clinical outcomes remain untested. This trial evaluated a 14-day MEMI for SAD.

Neuropathic pain, mood, and stress-related disorders: A literature review of comorbidity and co-pathogenesis.

Neuropathic pain can be caused by multiple factors, and its prevalence can reach 10% of the global population. It is becoming increasingly evident that limited or short-lasting response to treatments for neuropathic pain is associated with psychological factors, which include psychiatric comorbidities known to affect quality of life. It is estimated that 60% of patients with neuropathic pain also experience depression, anxiety, and stress symptoms.

BRD2-specific inhibitor, BBC0403, inhibits the progression of osteoarthritis pathogenesis in osteoarthritis-induced C57BL/6 male mice.

Background And Purpose: The discovery of new bromo- and extra-terminal inhibitors presents new drugs to treat osteoarthritis (OA).

Experimental Approach: The new drug, BBC0403, was identified in the DNA-encoded library screening system by searching for compounds that target BRD (bromodomain-containing) proteins. The binding force with BRD proteins was evaluated using time-resolved fluorescence energy transfer (TR-FRET) and binding kinetics assays.

Facilitating the transition to residency: A resident-as-coach pilot program.

Background: The transition from medical school to residency is a critical developmental phase; coaching may help students prepare for this role transition.

Aims: We explored whether near-peer coaching could improve a specific workplace skill prior to residency.

Methods: A resident-as-coach program was piloted for the medicine sub-internship, an advanced acting internship rotation.

Precision Oncology in Melanoma and Skin Cancer Surgery.

There has been perhaps no greater advance in the prognosis of solid tumors in the last decade than for patients with metastatic melanoma. This is due to significant improvements in treatment based on two key components of melanoma tumor biology (1) the identification of driver mutations with therapeutic potential and (2) the mechanistic understanding of a tumor-specific immune response. With breakthrough findings in such a relatively short period of time, the treatment of patients with metastatic melanoma has become intensely personalized.

A transcriptional response to replication stress selectively expands a subset of Brca2-mutant mammary epithelial cells.

Germline BRCA2 mutation carriers frequently develop luminal-like breast cancers, but it remains unclear how BRCA2 mutations affect mammary epithelial subpopulations. Here, we report that monoallelic Brca2 mammary organoids subjected to replication stress activate a transcriptional response that selectively expands Brca2 luminal cells lacking hormone receptor expression (HR-). While CyTOF analyses reveal comparable epithelial compositions among wildtype and Brca2 mammary glands, Brca2 HR- luminal cells exhibit greater organoid formation and preferentially survive and expand under replication stress.

Chemically induced reprogramming to reverse cellular aging.

A hallmark of eukaryotic aging is a loss of epigenetic information, a process that can be reversed. We have previously shown that the ectopic induction of the Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals can restore youthful DNA methylation patterns, transcript profiles, and tissue function, without erasing cellular identity, a process that requires active DNA demethylation. To screen for molecules that reverse cellular aging and rejuvenate human cells without altering the genome, we developed high-throughput cell-based assays that distinguish young from old and senescent cells, including transcription-based aging clocks and a real-time nucleocytoplasmic compartmentalization (NCC) assay.

Minimum information guidelines for experiments structurally characterizing intrinsically disordered protein regions.

An unambiguous description of an experiment, and the subsequent biological observation, is vital for accurate data interpretation. Minimum information guidelines define the fundamental complement of data that can support an unambiguous conclusion based on experimental observations. We present the Minimum Information About Disorder Experiments (MIADE) guidelines to define the parameters required for the wider scientific community to understand the findings of an experiment studying the structural properties of intrinsically disordered regions (IDRs).

An Anti-Racism and Equity Initiative Improves Residency Educational Conferences.

Background: Graduate medical education curricula may reinforce systemic inequities and bias, thus contributing to health disparities. Curricular interventions and evaluation measures are needed to increase trainee awareness of bias and known inequities in health care.

Objective: This study sought to improve the content of core noontime internal medicine residency educational conferences by implementing the Department of Medicine Anti-Racism and Equity (DARE) educational initiative.

Resilient together-ALS: leveraging the NDD transdiagnostic framework to develop an early dyadic intervention for people with amyotrophic lateral sclerosis and their informal care-partners.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive weakness and eventual death, usually within 3-5 years. An ALS diagnosis is associated with substantial emotional distress for both the affected person and their family care-partners which impairs the ability to engage in important conversations about long term care planning, negatively impacts ALS symptoms for the patient, and quality of life for both patient and care-partner. Here we 1) discuss published works identified by the authors about psychosocial interventions for the ALS population, 2) identify a lack of early, dyadic interventions to support psychosocial needs of people with ALS and care-partners; 3) describe the Neurodegenerative Diseases (NDD) framework for early dyadic intervention development and 4) propose an adaptation of an evidence-based early dyadic psychosocial intervention, Recovering Together, for the unique needs of people with ALS and their care-partners (Resilient Together-ALS; RT-ALS) using the NDD framework.

Effects of Sleep Fragmentation and Estradiol Decline on Cortisol in a Human Experimental Model of Menopause.

Context: Perturbations to the hypothalamic-pituitary-adrenal (HPA) axis have been hypothesized to increase postmenopausal cardiometabolic risk. Although sleep disturbance, a known risk factor for cardiometabolic disease, is prevalent during the menopause transition, it is unknown whether menopause-related sleep disturbance and estradiol decline disturb the HPA axis.

Objective: We examined the effect of experimental fragmentation of sleep and suppression of estradiol as a model of menopause on cortisol levels in healthy young women.

Photobiomodulation: An Emerging Treatment Modality for Depression.

Major depressive disorder (MDD) is considered a global crisis. Conventional treatments for MDD consist of pharmacotherapy and psychotherapy, although a significant number of patients with depression respond poorly to conventional treatments and are diagnosed with treatment-resistant depression (TRD). Transcranial photobiomodulation (t-PBM) therapy uses near-infrared light, delivered transcranially, to modulate the brain cortex.

A roadmap for early psychosocial support in palliative care for people impacted by ALS-reducing suffering, building resiliency, and setting the stage for delivering timely transdiagnostic psychosocial care.

This commentary describes the current state of psychosocial care for people with amyotrophic lateral sclerosis and their caregivers. We provide recommendations for developing a roadmap for future research based on existing literature and our group's clinical and research experience to inform next steps to expand evidence-based psychosocial care for people with amyotrophic lateral sclerosis and their caregivers, with potential implications for a range of advanced illnesses.

Loss of epigenetic information as a cause of mammalian aging.

All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation.

Expression of IGF-1 receptor and GH receptor in hepatic tissue of patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Objective: The GH and IGF-1 axis is a candidate disease-modifying target in nonalcoholic fatty liver disease (NAFLD) given its lipolytic, anti-inflammatory and anti-fibrotic properties. IGF-1 receptor (IGF-1R) and GH receptor (GHR) expression in adult, human hepatic tissue is not well understood across the spectrum of NAFLD severity. Therefore, we sought to investigate hepatic IGF-1R and GHR expression in subjects with NAFLD utilizing gene expression analysis (GEA) and immunohistochemistry (IHC).

Integrating multi-omics data reveals function and therapeutic potential of deubiquitinating enzymes.

Deubiquitinating enzymes (DUBs), ~100 of which are found in human cells, are proteases that remove ubiquitin conjugates from proteins, thereby regulating protein turnover. They are involved in a wide range of cellular activities and are emerging therapeutic targets for cancer and other diseases. Drugs targeting USP1 and USP30 are in clinical development for cancer and kidney disease respectively.

OpenPIP: An Open-source Platform for Hosting, Visualizing and Analyzing Protein Interaction Data.

Knowing which proteins interact with each other is essential information for understanding how most biological processes at the cellular and organismal level operate and how their perturbation can cause disease. Continuous technical and methodological advances over the last two decades have led to many genome-wide systematically-generated protein-protein interaction (PPI) maps. To help store, visualize, analyze and disseminate these specialized experimental datasets via the web, we developed the freely-available Open-source Protein Interaction Platform (openPIP) as a customizable web portal designed to host experimental PPI maps.

A human breast atlas integrating single-cell proteomics and transcriptomics.

The breast is a dynamic organ whose response to physiological and pathophysiological conditions alters its disease susceptibility, yet the specific effects of these clinical variables on cell state remain poorly annotated. We present a unified, high-resolution breast atlas by integrating single-cell RNA-seq, mass cytometry, and cyclic immunofluorescence, encompassing a myriad of states. We define cell subtypes within the alveolar, hormone-sensing, and basal epithelial lineages, delineating associations of several subtypes with cancer risk factors, including age, parity, and BRCA2 germline mutation.

Emerging frontiers in virtual drug discovery: From quantum mechanical methods to deep learning approaches.

Virtual screening-based approaches to discover initial hit and lead compounds have the potential to reduce both the cost and time of early drug discovery stages, as well as to find inhibitors for even challenging target sites such as protein-protein interfaces. Here in this review, we provide an overview of the progress that has been made in virtual screening methodology and technology on multiple fronts in recent years. The advent of ultra-large virtual screens, in which hundreds of millions to billions of compounds are screened, has proven to be a powerful approach to discover highly potent hit compounds.