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Carotid artery stenosis prevalence increases with age, and carotid endarterectomy (CEA) is a possible treatment option. However, nonagenarians are at high risk of experiencing postoperative complications and are often not considered surgical candidates. We aimed to identify risk factors associated with postoperative myocardial infarction (MI), stroke, and death within 30 days for nonagenarians undergoing CEA and to analyze the predictive ability of modified frailty indices (mFI) in predicting adverse outcomes for this population. This was a retrospective cohort study of patients aged 90 + years who underwent CEA from 2015 to 2019 utilizing the validated multi-institutional National Surgical Quality Improvement Program (NSQIP) vascular targeted registry. Multivariable logistic regression was used to analyze and identify factors associated with incidence of MI, stroke, and death within 30 days of surgery. The utility of 2-factor mFI consisting of functional dependence and dyspnea in predicting these complications was separately tested with univariable logistic regression. Of 191 patients meeting study criteria, 2.1 % had strokes, 3.7 % MIs, and 3.7 % died. Preoperative aspirin use (OR 0.09, 95 % CI:0.01–0.8, p = .02) was associated with lower odds of stroke. Functional status (OR 14.1, 95 % CI:1.4–151.0, p = .02) and dyspnea (OR 22.6, 95 % CI:2.1–309.3, p < .01) were associated with higher odds of MI, while statin use (OR 0.07, 95 % CI:0.007–0.5, p = .01) was associated with lower odds. Death was less frequent in elective cases (OR 0.1, 95 % CI:0.005–0.6, p = .04). The 2-factor mFI was not predictive of stroke but did predict MI and death and outperformed an existing 5-factor mFI. The risk profile of CEA can be acceptable in highly select nonagenarians. Functionally independent, non-dyspneic nonagenarians with preoperative aspirin and statin use who are scheduled electively have the lowest risk for a 30-day complication following CEA. Functional dependence and dyspnea are reasonable surrogate measures of frailty and may indicate a high complication risk for nonagenarians being considered for CEA. •The complication rate of CEA can meet acceptable thresholds in select nonagenarians.•Functional dependence and self-reported dyspnea correlated with higher odds of MI.•Elective surgery and aspirin/statin use correlated with fewer complications.•The 2-factor mFI outperformed the 5-factor mFI in predicting complications.

Soil is an important reservoir of antibiotic resistance genes (ARGs) and understanding how corresponding environmental changes influence their emergence, evolution, and spread is crucial. The soil-dwelling bacterial genus Listeria , including L. monocytogenes , the causative agent of listeriosis, serves as a key model for establishing this understanding. Here, we characterize ARGs in 594 genomes representing 19 Listeria species that we previously isolated from soils in natural environments across the United States. Among the five putatively functional ARGs identified, lin , which confers resistance to lincomycin, is the most prevalent, followed by mprF, sul, fosX , and norB . ARGs are predominantly found in Listeria sensu stricto species, with those more closely related to L. monocytogenes tending to harbor more ARGs. Notably, phylogenetic and recombination analyses provide evidence of recent horizontal gene transfer (HGT) in all five ARGs within and/or across species, likely mediated by transformation rather than conjugation and transduction. In addition, the richness and genetic divergence of ARGs are associated with environmental conditions, particularly soil properties (e.g., aluminum and magnesium) and surrounding land use patterns (e.g., forest coverage). Collectively, our data suggest that recent HGT and environmental selection play a vital role in the acquisition and diversification of bacterial ARGs in natural environments. It remains elusive how environmental antibiotic resistance evolves and spreads. Goh et al. analyzed a nationwide genomic dataset of soil-dwelling Listeria and find evidence of horizontal gene transfer mediated by transformation and environmental selection acting on antibiotic resistance evolution in soil environments.

The degradation of excess subunits of protein complexes is a major quality-control problem for the cell. How such “orphans” are recognized and tagged for degradation is poorly understood. Two papers identify a protein quality-control pathway that acts on some of the most abundant protein complexes in the human body: hemoglobin and ribosomes (see the Perspective by Hampton and Dargemont). Yanagitani et al. show that the central player in this process is an unusual enzyme (UBE2O) that recognizes substrates and tags them for destruction. Other quality-contr ol pathways tend to use separate factors for target selection (often a chaperone), ubiquitin donation (an E2), and ubiquitin conjugati on (an E3). Encoding all three activities in a single factor whose function can be reconstituted in a purified system provides a tractable route to detailed mechanistic and structural dissection. Nguyen et al. show the importance of the UBE2O pathway in the differentiation of red blood cells. Science , this issue p. 472 , p. eaan0218 ; see also p. 450 During terminal differentiation, a specialized state is achieved through the targeted elimination of preexisting proteins. During terminal differentiation, the global protein complement is remodeled, as epitomized by erythrocytes, whose cytosol is ~98% globin. The erythroid proteome undergoes a rapid transition at the reticulocyte stage; however, the mechanisms driving programmed elimination of preexisting cytosolic proteins are unclear. We found that a mutation in the murine Ube2o gene, which encodes a ubiquitin-conjugating enzyme induced during erythropoiesis, results in anemia. Proteomic analysis suggested that UBE2O is a broad-spectrum ubiquitinating enzyme that remodels the erythroid proteome. In particular, ribosome elimination, a hallmark of reticulocyte differentiation, was defective in Ube2o −/− mutants. UBE2O recognized ribosomal proteins and other substrates directly, targeting them to proteasomes for degradation. Thus, in reticulocytes, the induction of ubiquitinating factors may drive the transition from a complex to a simple proteome.

Classically, G-protein-coupled receptors (GPCRs) are thought to activate G protein from the plasma membrane and are subsequently desensitized by β-arrestin (β-arr). However, some GPCRs continue to signal through G protein from internalized compartments, mediated by a GPCR–G protein–β-arr ‘megaplex’. Nevertheless, the molecular architecture of the megaplex remains unknown. Here, we present its cryo-electron microscopy structure, which shows simultaneous engagement of human G protein and bovine β-arr to the core and phosphorylated tail, respectively, of a single active human chimeric β2-adrenergic receptor with the C-terminal tail of the arginine vasopressin type 2 receptor (β2V2R). All three components adopt their canonical active conformations, suggesting that a single megaplex GPCR is capable of simultaneously activating G protein and β-arr. Our findings provide a structural basis for GPCR-mediated sustained internalized G protein signaling.

For over 15 years, canine genetics research relied on a reference assembly from a Boxer breed dog named Tasha (i.e., canFam3.1). Recent advances in long-read sequencing and genome assembly have led to the development of numerous high-quality assemblies from diverse canines. These assemblies represent notable improvements in completeness, contiguity, and the representation of gene promoters and gene models. Although genome graph and pan-genome approaches have promise, most genetic analyses in canines rely upon the mapping of Illumina sequencing reads to a single reference. The Dog10K consortium, and others, have generated deep catalogs of genetic variation through an alignment of Illumina sequencing reads to a reference genome obtained from a German Shepherd Dog named Mischka (i.e., canFam4, UU_Cfam_GSD_1.0). However, alignment to a breed-derived genome may introduce bias in genotype calling across samples. Since the use of an outgroup reference genome may remove this effect, we have reprocessed 1929 samples analyzed by the Dog10K consortium using a Greenland wolf (mCanLor1.2) as the reference. We efficiently performed remapping and variant calling using a GPU-implementation of common analysis tools. The resulting call set removes the variability in genetic differences seen across samples and breed relationships revealed by principal component analysis are not affected by the choice of reference genome. Using this sequence data, we inferred the history of population sizes and found that village dog populations experienced a 9–13 fold reduction in historic effective population size relative to wolves.

β-Arrestins (βarrs) interact with G protein-coupled receptors (GPCRs) to desensitize G protein signaling, to initiate signaling on their own, and to mediate receptor endocytosis. Prior structural studies have revealed two unique conformations of GPCR–βarr complexes: the “tail” conformation, with βarr primarily coupled to the phosphorylated GPCR C-terminal tail, and the “core” conformation, where, in addition to the phosphorylated C-terminal tail, βarr is further engaged with the receptor transmembrane core. However, the relationship of these distinct conformations to the various functions of βarrs is unknown. Here, we created a mutant form of βarr lacking the “finger-loop” region, which is unable to form the core conformation but retains the ability to form the tail conformation. We find that the tail conformation preserves the ability to mediate receptor internalization and βarr signaling but not desensitization of G protein signaling. Thus, the two GPCR–βarr conformations can carry out distinct functions.

The main objective of this pilot study was to identify circulatory microRNAs in aqueous or plasma that were reflecting changes in vitreous of diabetic retinopathy patients. Aqueous, vitreous and plasma samples were collected from a total of 27 patients undergoing vitreoretinal surgery: 11 controls (macular pucker or macular hole patients) and 16 with diabetes mellitus(DM): DM-Type I with proliferative diabetic retinopathy(PDR) (DMI-PDR), DM Type II with PDR(DMII-PDR) and DM Type II with nonproliferative DR(DMII-NPDR). MicroRNAs were isolated using Qiagen microRNeasy kit, quantified on BioAnalyzer, and profiled on Affymetrix GeneChip miRNA 3.0 microarrays. Data were analyzed using Expression Console, Transcriptome Analysis Console, and Ingenuity Pathway Analysis. The comparison analysis of circulatory microRNAs showed that out of a total of 847 human microRNA probes on the microarrays, common microRNAs present both in aqueous and vitreous were identified, and a large number of unique microRNA, dependent on the DM type and severity of retinopathy. Most of the dysregulated microRNAs in aqueous and vitreous of DM patients were upregulated, while in plasma, they were downregulated. Dysregulation of miRNAs in aqueous did not appear to be a good representative of the miRNA abundance in vitreous, or plasma, although a few potential candidates for common biomarkers stood out: let-7b, miR-320b, miR-762 and miR-4488. Additionally, each of the DR subtypes showed miRNAs that were uniquely dysregulated in each fluid (i.e. aqueous: for DMII-NPDR was miR-455-3p; for DMII-PDR was miR-296, and for DMI-PDR it was miR-3202). Pathway analysis identified TGF-beta and VEGF pathways affected. The comparative profiling of circulatory miRNAs showed that a small number of them displayed differential presence in diabetic retinopathy vs. controls. A pattern is emerging of unique molecular microRNA signatures in bodily fluids of DR subtypes, offering promise for the use of ocular fluids and plasma for diagnostic and therapeutic purposes.

As healthcare providers receive fixed amounts of reimbursement for given services under DRG (Diagnosis-Related Groups) payment, DRG codes are valuable for cost monitoring and resource allocation. However, coding is typically performed retrospectively post-discharge. We seek to predict DRGs and DRG-based case mix index (CMI) at early inpatient admission using routine clinical text to estimate hospital cost in an acute setting. We examined a deep learning-based natural language processing (NLP) model to automatically predict per-episode DRGs and corresponding cost-reflecting weights on two cohorts (paid under Medicare Severity (MS) DRG or All Patient Refined (APR) DRG), without human coding efforts. It achieved macro-averaged area under the receiver operating characteristic curve (AUC) scores of 0·871 (SD 0·011) on MS-DRG and 0·884 (0·003) on APR-DRG in fivefold cross-validation experiments on the first day of ICU admission. When extended to simulated patient populations to estimate average cost-reflecting weights, the model increased its accuracy over time and obtained absolute CMI error of 2·40 (1·07%) and 12·79% (2·31%), respectively on the first day. As the model could adapt to variations in admission time, cohort size, and requires no extra manual coding efforts, it shows potential to help estimating costs for active patients to support better operational decision-making in hospitals.