The rockefeller university

The molecular mechanisms that enable memories to persist over long timescales from days to weeks and months are still poorly understood1. Here, to develop insights into this process, we created a behavioural task in which mice formed multiple memories but only consolidated some, while forgetting others, over the span of weeks. We then monitored circuit-specific molecular programs that diverged between consolidated and forgotten memories. We identified multiple distinct waves of transcription, that is, cellular macrostates, in the thalamocortical circuit that defined memory persistence. Of note, a small set of transcriptional regulators orchestrated broad molecular programs that enabled entry into these macrostates. Targeted CRISPR-knockout studies revealed that although these transcriptional regulators had no effects on memory formation, they had prominent, causal and strikingly time-dependent roles in memory stabilization. In particular, the calmodulin-dependent transcription factor CAMTA1 was required for initial memory maintenance over days, whereas the transcription factor TCF4 and the histone methyltransferase ASH1L were required later to maintain memory over weeks. These results identify a critical CAMTA1-TCF4-ASH1L thalamocortical transcriptional cascade that is required for memory stabilization and put forth a model in which the sequential recruitment of circuit-specific transcriptional programs enables memory maintenance over progressively longer timescales.

Sensory compensation occurs when loss of one sense leads to enhanced perception by another sense. We have identified a previously undescribed mechanism of sensory compensation in female Aedes aegypti mosquitoes. Odorant receptor co-receptor (Orco) mutants show enhanced attraction to human skin temperature and increased heat-evoked neuronal activity in foreleg sensory neurons. Ir140, a foreleg-enriched member of the ionotropic receptor (IR) superfamily of sensory receptors, is up-regulated in Orco mutant legs. Ir140, Orco double mutants do not show the enhanced heat seeking seen in Orco single mutants, suggesting that up-regulation of Ir140 in the foreleg is a key mechanism underlying sensory compensation in Orco mutants. Because Orco expression is sparse in legs, this sensory compensation requires an indirect, long-range mechanism. Our findings highlight how female Aedes aegypti mosquitoes, despite suffering olfactory sensory loss, maintain the overall effectiveness of their host-seeking behavior by up-regulating attraction to human skin temperature, further enhancing their status as the most dangerous predator of humans.

Decades of research into human neurodegenerative diseases have revealed important similarities as well as dissimilarities between diseases. While investigations of specific mechanistic aspects of diseases have been aided by cell and animal models, true advances in the understanding of neurodegeneration require that we deal with the daunting complexities of the human brain. In this review, we discuss novel molecular profiling methods that have been applied to human postmortem brain tissue during the last decade and highlight insights into cell type-specific molecular characteristics and disease-associated changes in both vulnerable and resilient cell types in Huntington's disease, Parkinson's disease, and Alzheimer's disease. We also illustrate how these approaches can complement human genetic analyses and studies of animal models to advance our understanding of human neurodegeneration.

Aims This narrative expert review aims to elucidate the role of biomarkers in the diagnosis and treatment of interstitial cystitis/bladder pain syndrome (IC/BPS), highlighting their potential to enhance patient care by enabling more precise and individualized therapeutic strategies.Methods and Results We performed a comprehensive review of literature focused on biomarkers relevant to IC/BPS, including bladder capacity, symptom intensity, bladder wall thickness, as well as serum and urinary inflammatory cytokines and other biomarkers of inflammation, oxidative stress, and urothelial and extracellular matrix remodeling. Evidence indicates that biomarkers such as TNF-alpha, IL-8, and bladder capacity can differentiate between Hunner lesion and non-Hunner lesion IC subtypes, predict treatment responses, and guide effective interventions. Furthermore, advanced statistical methods and machine learning applications show promise in improving diagnostic accuracy and treatment outcome predictions through clustering of the biomarker data.Conclusions Reliable biomarkers are vital for improving diagnostic precision and tailoring therapies for IC/BPS patients. Ongoing research and validation of these biomarkers are essential for advancing understanding, guiding treatment decisions, and enhancing the quality of life for individuals affected by this complex syndrome. The need for integrated biomarker profiles and multipronged research approaches is crucial for the future of IC/BPS management.

Background and Aims:Hepatitis B virus (HBV) and hepatitis C virus (HCV) share transmission routes and often coinfect the liver, leading to accelerated liver disease progression. In the era of direct-acting antivirals (DAAs) for HCV, the clinical impact of coinfection is further complicated by reports of HBV reactivation following HCV cure. While HCV-induced interferon (IFN) responses are known to suppress HBV, the underlying mechanisms remain incompletely understood. This study aimed to investigate how HCV modulates HBV infection in the setting of coinfection and to identify strategies to prevent HBV reactivation post-HCV clearance.Approach and Results:We utilized a multicellular liver culture model composed of human-induced pluripotent stem cell (hiPSC)-derived hepatocytes, hepatic stellate cells, and macrophages, which supports productive HBV and HCV infection and recapitulates clinical coinfection dynamics. We found that IL1 beta derived from HCV-activated macrophage suppresses HBV replication independent of IFN signaling. Mechanistically, IL1 beta downregulated the HBV receptor SLC10A1 in hepatocytes via induction of a truncated C/EBP beta isoform that negatively regulates the full-length variant. Concurrently, IL1 beta induced ISG20 expression through USF1 phosphorylation, further inhibiting HBV replication. A combination treatment of DAAs and an HBV entry inhibitor effectively prevented HBV reactivation in the model.Conclusions:Our findings reveal a macrophage-derived, IFN-independent mechanism by which HCV suppresses HBV infection, mediated through IL1 beta. These insights highlight the complex crosstalk between hepatotropic viruses during coinfection and suggest that targeting IL1 beta-regulated pathways may offer therapeutic potential to prevent HBV reactivation in DAA-treated patients.

Choline is an essential micronutrient critical for cellular and organismal homeostasis. As a core component of phospholipids and sphingolipids, it is indispensable for membrane architecture and function. Additionally, choline is a precursor for acetylcholine, a key neurotransmitter, and betaine, a methyl donor important for epigenetic regulation. Consistent with its pleiotropic role in cellular physiology, choline metabolism contributes to numerous developmental and physiological processes in the brain, liver, kidney, lung and immune system, and both choline deficiency and excess are implicated in human disease. Mutations in the genes encoding choline metabolism proteins lead to inborn errors of metabolism, which manifest in diverse clinical pathologies. While the identities of many enzymes involved in choline metabolism were identified decades ago, only recently has the field begun to understand the diverse mechanisms by which choline availability is regulated and fuelled via metabolite transport/recycling and nutrient acquisition. This review provides a comprehensive overview of choline metabolism, emphasizing emerging concepts and their implications for human health and disease.

Methods for describing and reporting the clinical and histologic characteristics of cutaneous tissue samples from patients with hidradenitis suppurativa (HS) are not currently standardized, limiting clinicians' and scientists' ability to uniformly record, report, and communicate about the characteristics of tissue used in translational experiments. A recently published consensus statement outlined morphological definitions of typical HS lesions, but no consensus has been reached regarding clinical characterization and examination of HS tissue samples. In this study, we aimed to establish a protocol for reporting histopathologic and clinical characteristics of HS tissue specimens. This study was conducted from May 2023 to August 2023. Experts in clinical care, dermatopathology, and translational research were recruited, and a modified Delphi technique was used to develop a protocol for histologic reporting and clinical characterization of submitted tissue specimens from patients with HS. A total of 27 experts participated (14 dermatologists, 3 fellowship-trained dermatopathologists, 3 plastic surgeons, 3 general surgeons, and 4 research scientists) in creating and reviewing protocols for the clinical and histopathological examination of HS tissue specimens. The protocols were formatted as a synoptic report and will help to consistently classify specimens in biobanks on the basis of histologic features and more accurately report and select samples used in translational research projects.

Multidrug resistance-associated protein 2 (MRP2) is an ATP-powered exporter important for maintaining liver homeostasis and a potential contributor to chemotherapeutic resistance. Using cryogenic electron microscopy (cryo-EM), we determine the structures of human MRP2 in three conformational states: an autoinhibited state, a substrate-bound pre-translocation state, and an ATP-bound post-translocation state. In the autoinhibited state, the cytosolic regulatory (R) domain plugs into the transmembrane substrate-binding site and extends into the cytosol to form a composite ATP-binding site at the surface of nucleotide-binding domain 2. Substrate displaces the R domain, permitting conformational changes necessary for transport. These observations suggest that the R domain functions as a selectivity gauge, where only at sufficiently high concentrations can the substrate effectively initiate transport. Comparative structural analyzes of MRP2 bound to various substrates, as determined in this study and others, reveal how MRP2 recognizes a diverse array of compounds, supporting its role in multidrug resistance.

BackgroundAdvanced practice nursing (APN) and advanced practice midwifery (APM) in Kenya are critical in healthcare system strengthening by expanding access to quality care, particularly in underserved regions. Globally, the International Council of Nurses (ICN) defines APN as a level of nursing practice that requires a minimum of a master's degree, along with advanced clinical training and competency. Similarly, APM involves midwives with advanced training to provide specialized maternal and neonatal care. In Kenya, the APN and APM concepts were launched in 2020 and are still nascent, and their practice is determined by the context as provided by the country credentialing the practice. Despite the strides made in developing the advanced roles, there is an eminent gap in understanding stakeholders' perceptions of the roles, scope of practice, and regulation.AimTo explore stakeholders' perceptions of the roles and regulations of APN and APM in Kenya.DesignAn exploratory qualitative study was undertaken as part of a larger formative research conducted between January 2022 and November 2023, utilizing a multimethod design that included a gap analysis of the scopes of practice for APN and APM in Kenya. Data collection was conducted among purposively sampled participants using a total of 7 focus group discussions (FGDs), with three of them conducted among 14 APN and APM students and 4 FGDs among 16 members of the Kenyan-based nursing and midwifery associations. Seven key informant interviews (KIIs) were also held with 2 medical doctors (OBGYN), two faculty, and 3 students (practicing APN). A thematic analysis approach was employed, and reporting was done according to the Standards for Reporting Qualitative Research.FindingsParticipant's perspectives were reflected in 5 themes: definition of APN/APM and scope; entry qualifications into APN/APM practice; roles of APN/APM; barriers to enacting APN/APM roles; the national policy and regulatory landscape for advanced practice roles.ConclusionThere were varied viewpoints on how APNs/APMs are defined in the Kenyan context. Similarly, views on the entry level qualifications into APN/APM were diverse. Many participants emphasized the importance of licensure, autonomy of practice, ability to manage patients independently, training, and competency. Well-defined policies and regulations can create an enabling environment for practice.

Fascin cross-links actin filaments (F-actin) into bundles that support tubular membrane protrusions including filopodia and stereocilia. Fascin dysregulation drives aberrant cell migration during metastasis, and fascin inhibitors are under development as cancer therapeutics. Here, we use cryo-EM, cryo-electron tomography coupled with custom denoising and computational modeling to probe human fascin-1's F-actin cross-linking mechanisms across spatial scales. Our fascin cross-bridge structure reveals an asymmetric F-actin binding conformation that is allosterically blocked by the inhibitor G2. Reconstructions of seven-filament hexagonal bundle elements, variability analysis and simulations show how structural plasticity enables fascin to bridge varied interfilament orientations, accommodating mismatches between F-actin's helical symmetry and bundle hexagonal packing. Tomography of many-filament bundles and modeling uncover geometric rules underlying emergent fascin binding patterns, as well as the accumulation of unfavorable cross-links that limit bundle size. Collectively, this work shows how fascin harnesses fine-tuned nanoscale structural dynamics to build and regulate micron-scale F-actin bundles.