The view of organelles and how they operate together has changed dramatically over the last two decades. The textbook view of organelles was that they operated largely independently and were connected by vesicular trafficking and the diffusion of signals through the cytoplasm. We now know that all organelles make functional close contacts with one another, often called membrane contact sites. The study of these sites has moved to center stage in cell biology as it has become clear that they play critical roles in healthy and developing cells and during cell stress and disease states. Contact sites have important roles in intracellular signaling, lipid metabolism, motor-protein-mediated membrane dynamics, organelle division, and organelle biogenesis. Here, we summarize the major conceptual changes that have occurred in cell biology as we have come to appreciate how contact sites integrate the activities of organelles.

Cell death supports morphogenesis during development and homeostasis after birth by removing damaged or obsolete cells. It also curtails the spread of pathogens by eliminating infected cells. Cell death can be induced by the genetically programmed suicide mechanisms of apoptosis, necroptosis, and pyroptosis, or it can be a consequence of dysregulated metabolism, as in ferroptosis. Here, we review the signaling mechanisms underlying each cell-death pathway, discuss how impaired or excessive activation of the distinct cell-death processes can promote disease, and highlight existing and potential therapies for redressing imbalances in cell death in cancer and other diseases.

Although social interactions are known to drive pathogen transmission, the contributions of socially transmissible host-associated mutualists and commensals to host health and disease remain poorly explored. We use the concept of the social microbiome-the microbial metacommunity of a social network of hosts-to analyze the implications of social microbial transmission for host health and disease. We investigate the contributions of socially transmissible microbes to both eco-evolutionary microbiome community processes (colonization resistance, the evolution of virulence, and reactions to ecological disturbance) and microbial transmission-based processes (transmission of microbes with metabolic and immune effects, inter-specific transmission, transmission of antibiotic-resistant microbes, and transmission of viruses). We consider the implications of social microbial transmission for communicable and non-communicable diseases and evaluate the importance of a socially transmissible component underlying canonically non-communicable diseases. The social transmission of mutualists and commensals may play a significant, under-appreciated role in the social determinants of health and may act as a hidden force in social evolution.

Mounting evidence suggests metabolism instructs stem cell fate decisions. However, how fetal metabolism changes during development and how altered maternal metabolism shapes fetal metabolism remain unexplored. We present a descriptive atlas of in vivo fetal murine metabolism during mid-to-late gestation in normal and diabetic pregnancy. Using 13C-glucose and liquid chromatography-mass spectrometry (LC-MS), we profiled the metabolism of fetal brains, hearts, livers, and placentas harvested from pregnant dams between embryonic days (E)10.5 and 18.5. Our analysis revealed metabolic features specific to a hyperglycemic environment and signatures that may denote developmental transitions during euglycemic development. We observed sorbitol accumulation in fetal tissues and altered neurotransmitter levels in fetal brains isolated from hyperglycemic dams. Tracing 13C-glucose revealed disparate fetal nutrient sourcing depending on maternal glycemic states. Regardless of glycemic state, histidine-derived metabolites accumulated in late-stage fetal tissues. Our rich dataset presents a comprehensive overview of in vivo fetal tissue metabolism and alterations due to maternal hyperglycemia.

RNA sequencing in situ allows for whole-transcriptome characterization at high resolution, while retaining spatial information. These data present an analytical challenge for bioinformatics-how to leverage spatial information effectively? Properties of data with a spatial dimension require special handling, which necessitate a different set of statistical and inferential considerations when compared to non-spatial data. The geographical sciences primarily use spatial data and have developed methods to analye them. Here we discuss the challenges associated with spatial analysis and examine how we can take advantage of practice from the geographical sciences to realize the full potential of spatial information in transcriptomic datasets.

Opioids are used for pain management despite the side effects that contribute to the opioid crisis. The pursuit of non-addictive opioid analgesics remains unattained due to the unresolved intricacies of opioid actions, receptor signaling cascades, and neuronal plasticity. Advancements in structural, molecular, and computational tools illuminate the dynamic interplay between opioids and opioid receptors, as well as the molecular determinants of signaling pathways, which are potentially interlinked with pharmacological responses. Here, we review the molecular basis of opioid receptor signaling with a focus on the structures of opioid receptors bound to endogenous peptides or pharmacological agents. These insights unveil specific interactions that dictate ligand selectivity and likely their distinctive pharmacological profiles. Biochemical analysis further unveils molecular features governing opioid receptor signaling. Simultaneously, the synergy between computational biology and medicinal chemistry continues to expedite the discovery of novel chemotypes with the promise of yielding more efficacious and safer opioid compounds.

Ribonucleoprotein (RNP) granules are diverse membrane-less organelles that form through multivalent RNA-RNA, RNA-protein, and protein-protein interactions between RNPs. RNP granules are implicated in many aspects of RNA physiology, but in most cases their functions are poorly understood. RNP granules can be described through four key principles. First, RNP granules often arise because of the large size, high localized concentrations, and multivalent interactions of RNPs. Second, cells regulate RNP granule formation by multiple mechanisms including posttranslational modifications, protein chaperones, and RNA chaperones. Third, RNP granules impact cell physiology in multiple manners. Finally, dysregulation of RNP granules contributes to human diseases. Outstanding issues in the field remain, including determining the scale and molecular mechanisms of RNP granule function and how granule dysfunction contributes to human disease.

Alzheimer's disease (AD) research has entered a new era with the recent positive phase 3 clinical trials of the anti-Aβ antibodies lecanemab and donanemab. Why did it take 30 years to achieve these successes? Developing potent therapies for reducing fibrillar amyloid was key, as was selection of patients at relatively early stages of disease. Biomarkers of the target pathologies, including amyloid and tau PET, and insights from past trials were also critical to the recent successes. Moving forward, the challenge will be to develop more efficacious therapies with greater efficiency. Novel trial designs, including combination therapies and umbrella and basket protocols, will accelerate clinical development. Better diversity and inclusivity of trial participants are needed, and blood-based biomarkers may help to improve access for medically underserved groups. Incentivizing innovation in both academia and industry through public-private partnerships, collaborative mechanisms, and the creation of new career paths will be critical to build momentum in these exciting times.

Plant-associated microbiota can extend plant immune system function, improve nutrient acquisition and availability, and alleviate abiotic stresses. Thus, naturally beneficial microbial therapeutics are enticing tools to improve plant productivity. The basic definition of plant microbiota across species and ecosystems, combined with the development of reductionist experimental models and the manipulation of plant phenotypes with microbes, has fueled interest in its translation to agriculture. However, the great majority of microbes exhibiting plant-productivity traits in the lab and greenhouse fail in the field. Therapeutic microbes must reach détente, the establishment of uneasy homeostasis, with the plant immune system, invade heterogeneous pre-established plant-associated communities, and persist in a new and potentially remodeled community. Environmental conditions can alter community structure and thus impact the engraftment of therapeutic microbes. We survey recent breakthroughs, challenges, and opportunities in translating beneficial microbes from the lab to the field.

ADP-ribosylation is a ubiquitous modification of biomolecules, including proteins and nucleic acids, that regulates various cellular functions in all kingdoms of life. The recent emergence of new technologies to study ADP-ribosylation has reshaped our understanding of the molecular mechanisms that govern the establishment, removal, and recognition of this modification, as well as its impact on cellular and organismal function. These advances have also revealed the intricate involvement of ADP-ribosylation in human physiology and pathology and the enormous potential that their manipulation holds for therapy. In this review, we present the state-of-the-art findings covering the work in structural biology, biochemistry, cell biology, and clinical aspects of ADP-ribosylation.

Recent Aβ-immunotherapy trials have yielded the first clear evidence that removing aggregated Aβ from the brains of symptomatic patients can slow the progression of Alzheimer's disease. The clinical benefit achieved in these trials has been modest, however, highlighting the need for both a deeper understanding of disease mechanisms and the importance of intervening early in the pathogenic cascade. An immunoprevention strategy for Alzheimer's disease is required that will integrate the findings from clinical trials with mechanistic insights from preclinical disease models to select promising antibodies, optimize the timing of intervention, identify early biomarkers, and mitigate potential side effects.

The TGF-β regulatory system plays crucial roles in the preservation of organismal integrity. TGF-β signaling controls metazoan embryo development, tissue homeostasis, and injury repair through coordinated effects on cell proliferation, phenotypic plasticity, migration, metabolic adaptation, and immune surveillance of multiple cell types in shared ecosystems. Defects of TGF-β signaling, particularly in epithelial cells, tissue fibroblasts, and immune cells, disrupt immune tolerance, promote inflammation, underlie the pathogenesis of fibrosis and cancer, and contribute to the resistance of these diseases to treatment. Here, we review how TGF-β coordinates multicellular response programs in health and disease and how this knowledge can be leveraged to develop treatments for diseases of the TGF-β system.

Menopause is the cessation of ovarian function, with loss of reproductive hormone production and irreversible loss of fertility. It is a natural part of reproductive aging. The physiology of the menopause is complex and incompletely understood. Globally, menopause occurs around the age of 49 years, with geographic and ethnic variation. The hormonal changes of the menopause transition may result in both symptoms and long-term systemic effects, predominantly adverse effects on cardiometabolic and musculoskeletal health. The most effective treatment for bothersome menopausal symptoms is evidence-based, menopausal hormone therapy (MHT), which reduces bone loss and may have cardiometabolic benefits. Evidence-based non-hormonal interventions are also available for symptom relief. Treatment should be individualized with shared decision-making. Most MHT regimens are not regulator approved for perimenopausal women. Studies that include perimenopausal women are needed to determine the efficacy and safety of treatment options. Further research is crucial to improve menopause care, along with research to guide policy and clinical practice.

With the rapid expansion of aging biology research, the identification and evaluation of longevity interventions in humans have become key goals of this field. Biomarkers of aging are critically important tools in achieving these objectives over realistic time frames. However, the current lack of standards and consensus on the properties of a reliable aging biomarker hinders their further development and validation for clinical applications. Here, we advance a framework for the terminology and characterization of biomarkers of aging, including classification and potential clinical use cases. We discuss validation steps and highlight ongoing challenges as potential areas in need of future research. This framework sets the stage for the development of valid biomarkers of aging and their ultimate utilization in clinical trials and practice.

A human embryo's legal definition and its entitlement to protection vary greatly worldwide. Recently, human pluripotent stem cells have been used to form in vitro models of early embryos that have challenged legal definitions and raised questions regarding their usage. In this light, we propose a refined legal definition of an embryo, suggest "tipping points" for when human embryo models could eventually be afforded similar protection to that of embryos, and then revisit basic ethical principles that might help to draft a roadmap for the gradual, justified usage of embryo models in a manner that aims to maximize benefits to society.

Applying to graduate school can be particularly challenging for students from historically minoritized backgrounds due to a hidden curriculum in the graduate admissions process. To address this issue, a team of volunteer STEM trainees established the Científico Latino Graduate Student Mentorship Initiative (CL-GSMI) in 2019 to support applicants from historically minoritized backgrounds. CL-GSMI is designed to improve access to critical resources, including information, mentorship, and financial support, and has assisted 443 students in applying and matriculating to graduate school. Using program evaluation data from 2020 to 2021, we highlight areas in graduate school admissions that can be improved to promote equity and inclusion.

The cerebral cortex is the brain's outermost layer. It is responsible for processing motor and sensory information that support high-level cognitive abilities and shape personality. Its development and functional organization strongly rely on cell communication that is established via an intricate system of diffusible signals and physical contacts during development. Interfering with this cellular crosstalk can cause neurodevelopmental disorders. Here, we review how crosstalk between migrating cells and their environment influences cerebral cortex development, ranging from neurogenesis to synaptogenesis and assembly of cortical circuits.

We are 52 Black scientists. Here, we establish the context of Juneteenth in STEMM and discuss the barriers Black scientists face, the struggles they endure, and the lack of recognition they receive. We review racism's history in science and provide institutional-level solutions to reduce the burdens on Black scientists.

Inflammasomes are critical sentinels of the innate immune system that respond to threats to the host through recognition of distinct molecules, known as pathogen- or damage-associated molecular patterns (PAMPs/DAMPs), or disruptions of cellular homeostasis, referred to as homeostasis-altering molecular processes (HAMPs) or effector-triggered immunity (ETI). Several distinct proteins nucleate inflammasomes, including NLRP1, CARD8, NLRP3, NLRP6, NLRC4/NAIP, AIM2, pyrin, and caspases-4/-5/-11. This diverse array of sensors strengthens the inflammasome response through redundancy and plasticity. Here, we present an overview of these pathways, outlining the mechanisms of inflammasome formation, subcellular regulation, and pyroptosis, and discuss the wide-reaching effects of inflammasomes in human disease.

Phenotypic sex-based differences exist for many complex traits. In other cases, phenotypes may be similar, but underlying biology may vary. Thus, sex-aware genetic analyses are becoming increasingly important for understanding the mechanisms driving these differences. To this end, we provide a guide outlining the current best practices for testing various models of sex-dependent genetic effects in complex traits and disease conditions, noting that this is an evolving field. Insights from sex-aware analyses will not only teach us about the biology of complex traits but also aid in achieving the goals of precision medicine and health equity for all.