Activity-based probes and chemical proteomics uncover the biological impact of targeting HMGCS1 in the mevalonate pathway.

Mevalonate is a precursor for essential metabolites, such as isoprenoids and sterols. Its synthesis starts with HMGCS1 producing HMG-CoA, which is then converted to mevalonate by HMGCR, a target of statins. Cancer cells often upregulate enzymes in the mevalonate pathway (MVP) to meet their metabolic demands, leading to the development of inhibitors targeting several enzymes in this pathway.

Enkephalin-producing regulatory T cells in the skin restrain local inflammation through control of nociception.

The skin integrates diverse signals discerned by sensory neurons and immune cells to elicit adaptive responses to a range of stresses. Considering interactions between nervous and immune systems, we examined whether regulatory T (T) cells, which suppress systemic and local inflammation, can modulate activation of peripheral neurons. Acute T cell "loss of function" increased neuronal activation to noxious stimuli independently of their immunosuppressive function.

Organelle bridges and nanodomain partitioning govern targeting of membrane-embedded proteins to lipid droplets.

Numerous metabolic enzymes translocate from the ER membrane bilayer to the lipid droplet (LD) monolayer, where they perform essential functions. Mislocalization of certain LD-targeted membrane proteins, including HSD17B13 and PNPLA3, is implicated in metabolic dysfunction-associated steatotic liver disease (MASLD). However, the mechanisms governing the trafficking and accumulation of ER proteins on LDs remain poorly understood.

Benefits of Maternal Choline Supplementation on Aged Basal Forebrain Cholinergic Neurons (BFCNs) in a Mouse Model of Down Syndrome and Alzheimer's Disease.

Down syndrome (DS), stemming from the triplication of human chromosome 21, results in intellectual disability, with early mid-life onset of Alzheimer's disease (AD) pathology. Early interventions to reduce cognitive impairments and neuropathology are lacking. One modality, maternal choline supplementation (MCS), has shown beneficial effects on behavior and gene expression in neurodevelopmental and neurodegenerative disorders, including trisomic mice.

A mouse organoid platform for modeling cerebral cortex development and cis-regulatory evolution in vitro.

Natural selection has shaped the gene regulatory networks that orchestrate cortical development, leading to structural and functional variation across mammals, but the molecular and cellular mechanisms underpinning these changes have only begun to be characterized. Here, we develop a reproducible protocol for cerebral cortex organoid generation from mouse epiblast stem cells (EpiSCs), which recapitulates the timing and cellular differentiation programs of the embryonic cortex. We generated cortical organoids from F1 hybrid EpiSCs derived from crosses between laboratory mice (C57BL/6J) and four wild-derived inbred strains spanning ∼1 M years of evolutionary divergence to comprehensively map cis-acting transcriptional regulatory variation across developing cortical cell types, using single-cell RNA sequencing (scRNA-seq).

Transcription factors SP5 and SP8 drive primary cilia formation in mammalian embryos.

Although specific transcription factors (TFs) are known to regulate cell fate decisions, the degree to which they can stimulate formation of specific cell organelles is less clear. We used a multiomics comparison of the transcriptomes of ciliated and unciliated embryonic cells to identify TFs up-regulated in ciliated cells. We also used conditional genetics in mouse embryos and stem cells and found that the TFs SP5 and SP8 regulate cilia formation and gene expression.

CD371-Targeted CAR T cells Secreting Interleukin-18 Exhibit Robust Expansion and Clear Refractory Acute Myeloid Leukemia.

Success of chimeric antigen receptor (CAR) T-cell therapy in lymphoid malignancies has not yet been recapitulated in acute myeloid leukemia (AML). We developed CAR T-cells targeting CD371 with a mutated CD28 costimulatory domain to limit T-cell exhaustion, and constitutive interleukin-18 secretion to enhance immune function (CD371/SAVVY/IL-18 CAR). We initiated a phase I trial (NCT06017258), successfully manufactured and administered CD371/SAVVY/IL-18 CAR T-cells in 5 patients with relapsed/refractory AML and observed expansion following a single infusion of 3x104 or 3x105 CAR T-cells/kg; three patients refractory to ≥5 lines of therapy and post-allogeneic transplant exhibited AML clearance and no evidence of graft-versus-host disease.

Multicenter basket trial for Central Nervous System tumors identifies activity of the CDK4/6 inhibitor abemaciclib in recurrent meningioma.

Background: Central nervous system (CNS) tumors are associated with considerable morbidity and high mortality. Cyclin-dependent kinases (CDKs) regulate cell division in cancer, and CDK4/6 inhibitors are used for the treatment of breast cancer, representing an attractive therapy for different tumor types.

Methods: Here, we report mature results of a multicenter basket trial exploring the CDK4/6 inhibitor abemaciclib in patients with recurrent CNS tumors, including patients with glioma, primary CNS lymphoma, meningioma, and ependymoma.

Enhancer remodeling by OTX2 directs specification and patterning of mammalian definitive endoderm.

The molecular mechanisms that drive essential patterning events in the mammalian embryo remain poorly understood. Analysis of transcription factor expression kinetics at peri-gastrulation stages of development suggest Otx2 as a candidate regulator of the definitive endoderm, the precursor of all gut-derived organs. Accordingly, timed OTX2 depletion in gastruloids or during directed differentiation results in abnormal definitive endoderm specification in mouse and human, characterized by altered expression of components and transcriptional targets of the canonical WNT signaling pathway, perturbed adhesion and migration programs, and de-repression of regulators of other lineages.

Mechanism for oil-phase separation by the lipid droplet assembly complex.

Cells store metabolic energy as triglyceride (TG) oils in lipid droplets (LDs). LDs form from the endoplasmic reticulum. How the lipid droplet assembly complex (LDAC), composed of seipin and LDAF1, catalyzes the organized formation of an oil phase in a membrane bilayer before spontaneous phase separation is triggered is unknown.

The grand biological universe: A comprehensive geometric construction of genome space.

Analyzing the geometric relationships among genomic sequences from a mathematical perspective and revealing the laws hidden within these relationships is a crucial challenge in bioinformatics. The natural vector method constructs a genome space by extracting statistical moments of -mers to illuminate the relationships among genomes. This approach highlights a fundamental law in biology known as the convex hull principle, which states that natural vectors corresponding to different types of biological sequences form distinct, non-overlapping convex hulls.

Germline landscape of high grade serous ovarian cancer across age groups: Is age just a number?

Objective: To characterize age-related variations in germline pathogenic variants (gPVs) in patients with high-grade serous ovarian cancer (HGSOC).

Methods: Patients with HGSOC who underwent clinical tumor-normal sequencing of ≥76 genes from 1/1/2015-11/15/2022, were included. Clinical variables including age at diagnosis were collected.

Epigenetic targeting of PGBD5-dependent DNA damage in SMARCB1-deficient sarcomas.

Despite the potential of targeted epigenetic therapies, most cancers do not respond to current epigenetic drugs. The Polycomb repressive complex EZH2 inhibitor tazemetostat was recently approved for the treatment of SMARCB1-deficient epithelioid sarcomas, based on the functional antagonism between PRC2 and SMARCB1. Through the analysis of tazemetostat-treated patient tumors, we recently defined key principles of their response and resistance to EZH2 epigenetic therapy.

An increase in reactive oxygen species underlies neonatal cerebellum repair.

The neonatal mouse cerebellum shows remarkable regenerative potential upon injury at birth, wherein a subset of Nestin-expressing progenitors (NEPs) undergoes adaptive reprogramming to replenish granule cell progenitors that die. Here, we investigate how the microenvironment of the injured cerebellum changes upon injury and contributes to the regenerative potential of normally gliogenic-NEPs and their adaptive reprogramming. Single-cell transcriptomic and bulk chromatin accessibility analyses of the NEPs from injured neonatal cerebella compared to controls show a temporary increase in cellular processes involved in responding to reactive oxygen species (ROS), a known damage-associated molecular pattern.

Activation of -Formyldipeptide-Masked Prodrugs by Human Peptide Deformylase.

Targeted enzyme-prodrug systems deliver an exogenous enzyme to a disease site to generate active drug locally, thus increasing therapeutic efficacy and decreasing systemic toxicity. The majority of such systems have used bacterial enzymes, which are subject to immune recognition and inactivation or clearance . To address this problem, we report herein the development of a new enzyme-prodrug system that uses a human enzyme, peptide deformylase (PDF), which can be supplied exogenously while the endogenous enzyme is restricted to the mitochondria.

A Simultaneous Inhibition of ID1 and ID3 Protects Against Pulmonary Fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which novel therapeutic approaches are desperately needed. Inhibitor of DNA binding (ID) proteins are regulated by Transforming Growth Factor-b. However, the regulation and the effects of ID proteins in IPF remain poorly understood.

Human iPSC derived alveolar macrophages reveal macrophage subtype specific functions of itaconate in host defense.

(Mtb) must survive within multiple macrophage populations during infection, including alveolar macrophages (AM) and recruited inflammatory macrophages. In mice, itaconate, produced in macrophages by ACOD1 mediated decarboxylation of aconitate, has direct antimicrobial activity, modulates inflammatory cytokines, and is required for resistance to (Mtb) infection. The role of itaconate in human macrophages is less clear and whether itaconate mediates distinct effects in macrophage subtypes is unknown.

Epigenetic evolution and clinicopathological implications of distinct DNA methylation profiles in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with poor prognosis. We investigated intratumoral deoxyribonucleic acid methylation heterogeneity by analyzing 44 tumor samples and 5 normal samples from 6 cases of PDAC by using high-resolution methylation arrays. Two distinct methylation profiles were identified: T1, which is similar to normal pancreatic tissue and is associated with well-differentiated histology, and T2, which is significantly different from normal tissue and is linked to poorly differentiated morphology and squamous features.

PTEN restrains SHH medulloblastma growth through cell autonomous and nonautonomous mechanisms.

A third of patients with the pediatric cerebellar tumor Medulloblastoma (MB) have mutations that activate Sonic hedgehog (SHH) signaling (SHH-MB subgroup). The contribution of secondary mutations to tumor severity, however is not clear. mutations are enriched in the SHH-1 subtype that has the lowest survival rate.

The derived transposase 5 (PGBD5) can interact with human -like elements.

PGBD5 is encoded by a gene domesticated at the chordate origin from a DNA transposon of the family. During its evolution, PGBD5's sequence has been under strong purifying selection among vertebrate genomes. This suggests PGBD5 functions in the development and physiology of chordates, as recently demonstrated in mouse and human brain development, where it was implicated in double strand DNA breaks on neurons.

An IFN/STAT1/CYBB Axis Defines Protective Plasmacytoid DC to Neutrophil Crosstalk in Aspergillus fumigatus - Infected mice.

Aspergillus fumigatus is the most common cause of invasive aspergillosis (IA), a devastating infection in immunocompromised patients. Plasmacytoid dendritic cells (pDCs) regulate host defense against IA by enhancing neutrophil antifungal properties in the lung. Here, we define the pDC activation trajectory during A.

Evaluation of Anti-HPV18 Antibody Titers Preceding an Incident Cervical HPV18/45 Infection.

The Human Papillomavirus (HPV) vaccine generates high antibody titers against targeted HPV types. This study investigated vaccine-induced anti-HPV18 immunoglobulin (IgG) antibody titers and subsequent HPV18/45 infections. We performed a nested matched case-control study leveraging a prospective longitudinal cohort of adolescent and young adult women (AYW) vaccinated with the quadrivalent HPV vaccine (4vHPV) attending the Mount Sinai Adolescent Health Center (MSAHC) in Manhattan, NY.

Dietary lipids induce PPARd and BCL6 to repress macrophage IL-23 induction after intestinal injury and LPS exposure.

Unresolved tissue damage is a common feature of Inflammatory Bowel Disease (IBD) that facilitates disease progression. Here, we showed that high animal fat diets (HFD), an environmental risk factor associated with IBD pathogenesis, suppress intestinal macrophage production of critical tissue repair responses after damage. This includes reduced IL-23 production, which drives downstream production of IL-22, which is needed for barrier repair.

A resource of RNA-binding protein motifs across eukaryotes reveals evolutionary dynamics and gene-regulatory function.

RNA-binding proteins (RBPs) are key regulators of gene expression; however, their RNA-binding specificities, that is, motifs, have not been comprehensively determined. Here we introduce Eukaryotic Protein-RNA Interactions (EuPRI), a freely available resource of RNA motifs for 34,746 RBPs from 690 eukaryotes. EuPRI includes in vitro binding data for 504 RBPs, including newly collected RNAcompete data for 174 RBPs, along with thousands of predicted motifs.