The Comprehensive Antibiotic Resistance Database (CARD; card.mcmaster.ca) combines the Antibiotic Resistance Ontology (ARO) with curated AMR gene (ARG) sequences and resistance-conferring mutations to provide an informatics framework for annotation and interpretation of resistomes. As of version 3.2.4, CARD encompasses 6627 ontology terms, 5010 reference sequences, 1933 mutations, 3004 publications, and 5057 AMR detection models that can be used by the accompanying Resistance Gene Identifier (RGI) software to annotate genomic or metagenomic sequences. Focused curation enhancements since 2020 include expanded β-lactamase curation, incorporation of likelihood-based AMR mutations for Mycobacterium tuberculosis, addition of disinfectants and antiseptics plus their associated ARGs, and systematic curation of resistance-modifying agents. This expanded curation includes 180 new AMR gene families, 15 new drug classes, 1 new resistance mechanism, and two new ontological relationships: evolutionary_variant_of and is_small_molecule_inhibitor. In silico prediction of resistomes and prevalence statistics of ARGs has been expanded to 377 pathogens, 21,079 chromosomes, 2,662 genomic islands, 41,828 plasmids and 155,606 whole-genome shotgun assemblies, resulting in collation of 322,710 unique ARG allele sequences. New features include the CARD:Live collection of community submitted isolate resistome data and the introduction of standardized 15 character CARD Short Names for ARGs to support machine learning efforts.

Summary NPGPx is a member of the glutathione peroxidase (GPx) family; however, it lacks GPx enzymatic activity due to the absence of a critical selenocysteine residue, rendering its function an enigma. We report that NPGPx is a novel stress sensor that transmits oxidative stress signals by transferring the disulfide bond between its Cys57 and Cys86 residues to downstream effectors. Oxidized NPGPx binds and oxidizes the chaperone glucose-regulated protein (GRP)78 in the endoplasmic reticulum through covalent bonding between Cys86 of NPGPx and Cys41/Cys420 of GRP78, and facilitates the refolding of misfolded proteins by GRP78 to alleviate stress. NPGPx-deficient cells display impaired GRP78 chaperone activity, accumulate misfolded proteins, and suffer oxidative stress. Complete loss of NPGPx in animals causes systemic oxidative stress, increases carcinogenesis, and shortens lifespan. These results, for the first time, suggest that NPGPx is essential for mediating the oxidative stress response by modulating GRP78 chaperone activity to maintain physiological homeostasis.

Abstract. We investigate the roles of climate forcings and chaos (unforced variability) in climate change via ensembles of climate simulations in which we add forcings one by one. The experiments suggest that most interannual climate variability in the period 1979-1996 at middle and high latitudes is chaotic. But observed SST anomalies, which themselves are partly forced and partly chaotic, account for much of the climate variability at low latitudes and a small portion of the variability at high latitudes. Both a natural radiative forcing (volcanic aerosols) and an anthropogenic forcing (ozone depletion) leave clear signatures in the simulated climate change that are identified in observations. Pinatubo aerosols warm the stratosphere and cool the surface globally, causing a tendency for regional surface cooling. Ozone depletion cools the lower stratosphere, troposphere and surface, steepening the temperature lapse rate in the troposphere. Solar irradiance effects are small, but our model is inadequate to fully explore this forcing.

BRCA1 exerts transcriptional repression through interaction with CtIP in the C-terminal BRCT domain and ZBRK1 in the central domain. A dozen genes, including angiopoietin-1 (ANG1), a secreted angiogenic factor, are corepressed by BRCA1 and CtIP based on microarray analysis of mammary epithelial cells in 3D culture. BRCA1, CtIP, and ZBRK1 form a complex that coordinately represses ANG1 expression via a ZBRK1 recognition site in the ANG1 promoter. Impairment of this complex upregulates ANG1, which stabilizes endothelial cells that form a capillary-like network structure. Consistently, Brca1-deficient mouse mammary tumors exhibit accelerated growth, pronounced vascularization, and overexpressed ANG1. These results suggest that, besides its role in maintaining genomic stability, BRCA1 directly regulates the expression of angiogenic factors to modulate the tumor microenvironment.

Cumulative evidence indicates that breast cancer-associated gene 1 (BRCA1) participates in DNA damage repair and cell-cycle checkpoint control, serving as a tumor susceptibility gene to maintain the global genomic stability. However, whether BRCA1 has a direct role in cell proliferation and differentiation, two key biological functions in tumorigenesis, remains unclear. Here we demonstrate BRCA1 mediates differentiation of mammary epithelial cell (MEC) for acinus formation by using the in vitro 3D culture system. Reduction of BRCA1 in MEC by RNA interference impairs the acinus formation but enhances proliferation. Such aberrations can be rescued by expression of wild-type BRCA1 as well as a mutant at the RAD50-binding domain but not at the C-terminal BRCT domain, suggesting that the C-terminal BRCT domain has a critical role in these processes. Consistently, depletion of BRCA1 up-regulates the gene expression for proliferation but down-regulates that for differentiation. Moreover, application of the medium conditioned by differentiating normal MEC can reverse the phenotypes of differentiation-defective breast cancer cells bearing reduced BRCA1 functions. Our observation implies BRCA1 is involved in secretion of certain paracrine͞autocrine factors that induce MEC differentiation in response to extracellular matrix signals, providing, in part, an explanation for the etiological basis of either sporadic or familial breast cancer due to the loss or reduction of BRCA1.breast cancer ͉ tumor suppressor ͉ 3D culture ͉ matrix gel M utations in the breast cancer susceptibility gene breast cancer-associated gene 1 (BRCA1) account for up to half of hereditary breast cancer cases (1, 2) and almost all hereditary breast and ovarian cancer cases (3). Also, decreased BRCA1 expression is often found during sporadic breast cancer progression (4). Despite that a tissue-specific role of BRCA1 in breast and ovary is speculated (3), the cumulated evidence primarily converges on its universal functions, DNA damage repair, cell-cycle checkpoint control, and transcriptional regulation, to maintain genomic stability (3).The BRCA1 protein encompasses distinctive modules to interact with various proteins of diverse functions (5, 6). The N terminus possesses a RING finger domain, which dimerizes with BARD1 to exhibit ubiquitin ligase activity (5). The central region possesses two nuclear localization signals (5) and interacts with the DNA damage repair complex RAD50͞MRE11͞NBS1, transcription repressor ZBRK1, and BRCA2 (3, 6, 7). The C terminus possesses two tandem repeats of the BRCT motif, which is commonly found in DNA repair proteins (5) and interacts with CtIP, HDAC, and BACH1 (6,8,9). Loss of BRCA1 function leads to genomic instability, which diverges into two consequences (10). One is to trigger cell cycle arrest and apoptosis through activation of p53 (10). Alternatively, BRCA1 deficiency perturbs the chromosomal integrity (11) and increases the mutation rate of other genes (10). Breast tumors from the BRCA1 germ-line mutation carrie...