Notes

Semi-supervised associative distinction utilizing ish colony marketing criteria.
MicroRNAs (miRNAs) are versatile regulators of gene expression with profound implications for human disease including atherosclerosis, but whether they can exert posttranslational functions to control cell adaptation and whether such noncanonical features harbor pathophysiological relevance is unknown. Here, we show that miR-126-5p sustains endothelial integrity in the context of high shear stress and autophagy. Bound to argonaute-2 (Ago2), miR-126-5p forms a complex with Mex3a, which occurs on the surface of autophagic vesicles and guides its transport into the nucleus. Mutational studies and biophysical measurements demonstrate that Mex3a binds to the central U- and G-rich regions of miR-126-5p with nanomolar affinity via its two K homology domains. In the nucleus, miR-126-5p dissociates from Ago2 and binds to caspase-3 in an aptamer-like fashion with its seed sequence, preventing dimerization of the caspase and inhibiting its activity to limit apoptosis. The antiapoptotic effect of miR-126-5p outside of the RNA-induced silencing complex is important for endothelial integrity under conditions of high shear stress promoting autophagy ablation of Mex3a or ATG5 in vivo attenuates nuclear import of miR-126-5p, aggravates endothelial apoptosis, and exacerbates atherosclerosis. STA-9090 In human plaques, we found reduced nuclear miR-126-5p and active caspase-3 in areas of disturbed flow. The direct inhibition of caspase-3 by nuclear miR-126-5p reveals a noncanonical mechanism by which miRNAs can modulate protein function.HIV-associated morbidity and mortality have markedly declined because of combinational antiretroviral therapy, but HIV readily mutates to develop drug resistance. Developing antivirals against previously undefined targets is essential to treat existing drug-resistant HIV strains. Some peptides derived from HIV-1 envelope glycoprotein (Env, gp120-gp41) have been shown to be effective in inhibiting HIV-1 infection. Therefore, we screened a peptide library from HIV-1 Env and identified a peptide from the cytoplasmic region, designated F9170, able to effectively inactivate HIV-1 virions and induce necrosis of HIV-1-infected cells, and reactivated latently infected cells. F9170 specifically targeted the conserved cytoplasmic tail of HIV-1 Env and effectively disrupted the integrity of the viral membrane. Short-term monoadministration of F9170 controlled viral loads to below the limit of detection in chronically SHIV-infected macaques. F9170 can enter the brain and lymph nodes, anatomic reservoirs for HIV latency. Therefore, F9170 shows promise as a drug candidate for HIV treatment.The coronavirus disease 2019 (COVID-19) pandemic has highlighted the need for different types of diagnostics, comparative validation of new tests, faster approval by federal agencies, and rapid production of test kits to meet global demands. In this Perspective, we discuss the utility and challenges of current diagnostics for COVID-19.Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous hematological malignancy. Although immunotherapy may be an attractive modality to exploit in patients with AML, the ability to predict the groups of patients and the types of cancer that will respond to immune targeting remains limited. This study dissected the complexity of the immune architecture of AML at high resolution and assessed its influence on therapeutic response. Using 442 primary bone marrow samples from three independent cohorts of children and adults with AML, we defined immune-infiltrated and immune-depleted disease classes and revealed critical differences in immune gene expression across age groups and molecular disease subtypes. Interferon (IFN)-γ-related mRNA profiles were predictive for both chemotherapy resistance and response of primary refractory/relapsed AML to flotetuzumab immunotherapy. Our compendium of microenvironmental gene and protein profiles provides insights into the immuno-biology of AML and could inform the delivery of personalized immunotherapies to IFN-γ-dominant AML subtypes.Seattle region hospitals have been impacted for several months by community spread of the coronavirus disease of 2019 (COVID-19).….Background The impact of diagnostic stewardship and testing algorithms on utilization and performance of the FilmArray® Meningitis/Encephalitis (ME) Panel has received limited investigation.Methods We performed a retrospective single-center cohort study assessing all individuals with suspected ME between February 2017 and April 2019 for whom the ME Panel was ordered. Testing was restricted to patients with cerebrospinal fluid (CSF) pleocytosis. Positive ME Panel results were confirmed before reporting through correlation with direct stain (Gram and Calcofluor white) and CSF Cryptococcal antigen or by repeat ME Panel testing. Outcomes included ME Panel test utilization rate, negative predictive value of non-pleocytic CSF samples, test yield and false-positivity rate, and time to appropriate de-escalation of acyclovir.Results Restricting testing to pleocytic CSF samples reduced ME Panel utilization by 42.7% (263 vs 459 tests performed) and increased test yield by 61.8% (18.6% vs 11.5% positivity rate; P less then 0.01) with application of criteria. The negative predictive value of normal CSF WBC for ME Panel targets was 100% (195/195) for non-viral targets and 98.0% (192/196) overall. All pathogens detected in non-pleocytic CSF samples were herpesviruses. Application of a selective testing algorithm based on repeat testing of non-viral targets avoided 75% (3/4) of false-positive results without generating false-negative results. Introduction of the ME panel reduced the duration of acyclovir treatment from an average of 66 hours (SD, 43) to 46 hours (SD, 36) (P = 0.03).Conclusions Implementation of the ME Panel with restriction criteria and a selective testing algorithm for non-viral targets optimizes its utilization, yield and accuracy.Objectives Enterobacter aerogenes was recently renamed Klebsiella aerogenes This study aimed to identify differences in clinical characteristics, outcomes, and bacterial genetics among patients with K. aerogenes versus Enterobacter species bloodstream infections (BSI).Methods We prospectively enrolled patients with K. aerogenes or Enterobacter cloacae complex (Ecc) BSI from 2002-2015. We performed whole genome sequencing (WGS) and pan-genome analysis on all bacteria.Results Overall, 150 patients with K. aerogenes (46/150 [31%]) or Ecc (104/150 [69%]) BSI were enrolled. The two groups had similar baseline characteristics. Neither total in-hospital mortality (13/46 [28%] versus 22/104 [21%]; p=0.3) nor attributable in-hospital mortality (9/46 [20%] versus 13/104 [12%]; p=0.3) differed between patients with K. aerogenes versus Ecc BSI, respectively. However, poor clinical outcome (death before discharge, recurrent BSI, and/or BSI complication) was higher for K. aerogenes than Ecc BSI (32/46 [70%] versus 42/104 [40%]; p=0.
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