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The prohibitive cost of platinum for catalyzing the cathodic oxygen reduction reaction (ORR) has hampered the widespread use of polymer electrolyte fuel cells. We describe a family of non-precious metal catalysts that approach the performance of platinum-based systems at a cost sustainable for high-power fuel cell applications, possibly including automotive power. The approach uses polyaniline as a precursor to a carbon-nitrogen template for high-temperature synthesis of catalysts incorporating iron and cobalt. The most active materials in the group catalyze the ORR at potentials within ~60 millivolts of that delivered by state-of-the-art carbon-supported platinum, combining their high activity with remarkable performance stability for non-precious metal catalysts (700 hours at a fuel cell voltage of 0.4 volts) as well as excellent four-electron selectivity (hydrogen peroxide yield <1.0%).

Platinum and gold single crystal electrodes were decorated by noble metal islands (Ru, Os or Pt) by the spontaneous deposition procedure. These surfaces were characterized by scanning tunneling microscopy (STM) and electrochemical methods to develop fundamental structure-activity relationships relevant to direct methanol fuel cell research. The structures of the admetal deposits (Ru or Os) on Pt(111) and Au(111) were also compared to better understand the spontaneous deposition process. X-ray photoelectron spectroscopy (XPS) was used to provide supporting information for Pt(111)/Os. Repeating the spontaneous deposition process for low-index Pt(hkl)/Ru increases the Ru coverage and results in more active Pt(hkl)/Ru surfaces, with Pt(111)/Ru being the most active after 3--5 spontaneous depositions (ca. 30-40% Ru coverage). Pt(111)/Os is less active than Pt(111)/Ru at fuel cell relevant potentials, and a higher Os coverage (60-70%) is required for effective methanol electrooxidation. These differences are related to the greater oxygen-affinity of Ru under these conditions. Osmium deposition proceeds at a faster rate than ruthenium on both Pt(111) and Au(111) surfaces. The Au(111) surface exhibits preferential deposition of Ru or Os islands near steps in contrast to Pt(111), which shows homogeneous deposition across the surface. The structure of admetal deposits can be further manipulated by electrochemical treatments, as demonstrated for Pt(111)/Ru and Au(111)/Os. The size of the islands can be reduced and the island-island distance increased. For Pt(111)/Ru prepared by two spontaneous depositions, this resulted in a less active surface for methanol electrooxidation. Finally, ternary Au(111)/Ru/Pt and Pt(111)/Ru/Os surfaces were prepared as part of an ongoing study. The presence of the Au(111) substrate appears deactivating for the Pt-Ru deposit for both CO and methanol electrooxidation. The Pt(111)/Ru/Os surface compares favorably with optimized Pt(111)/Ru surfaces, and further optimization of Pt(111)/Ru/Os may result in increased activity.

These guidelines for the treatment of persons who have or are at risk for sexually transmitted infections (STIs) were updated by CDC after consultation with professionals knowledgeable in the field of STIs who met in Atlanta, Georgia, June 11–14, 2019. The information in this report updates the 2015 guidelines. These guidelines discuss 1) updated recommendations for treatment of Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis; 2) addition of metronidazole to the recommended treatment regimen for pelvic inflammatory disease; 3) alternative treatment options for bacterial vaginosis; 4) management of Mycoplasma genitalium; 5) human papillomavirus vaccine recommendations and counseling messages; 6) expanded risk factors for syphilis testing among pregnant women; 7) one-time testing for hepatitis C infection; 8) evaluation of men who have sex with men after sexual assault; and 9) two-step testing for serologic diagnosis of genital herpes simplex virus. Physicians and other health care providers can use these guidelines to assist in prevention and treatment of STIs.

Participants who had been fully vaccinated with current Covid-19 vaccines received homologous or heterologous boosters, and their immune response was measured on days 15 and 29. Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20, whereas heterologous boosters increased titers by a factor of 6 to 73.

Changes in DNA methylation are involved in development, disease, and the response to environmental conditions. However, not all regulatory elements are functionally methylation-dependent (MD). Here, we report a method, mSTARR-seq, that assesses the causal effects of DNA methylation on regulatory activity at hundreds of thousands of fragments (millions of CpG sites) simultaneously. Using mSTARR-seq, we identify thousands of MD regulatory elements in the human genome. MD activity is partially predictable using sequence and chromatin state information, and distinct transcription factors are associated with higher activity in unmethylated versus methylated DNA. Further, pioneer TFs linked to higher activity in the methylated state appear to drive demethylation of experimentally methylated sites. MD regulatory elements also predict methylation-gene expression relationships across individuals, where they are 1.6x enriched among sites with strong negative correlations. mSTARR-seq thus provides a map of MD regulatory activity in the human genome and facilitates interpretation of differential methylation studies.

Background. The worldwide prevalence of extended-spectrum β-lactamase (ESBL)—producing Enterobacteriaceae is increasing rapidly both in hospitals and in the community. A connection between ESBL-producing bacteria in food animals, retail meat, and humans has been suggested. We previously reported on the genetic composition of a collection of ESBL-producing Escherichia coli (ESBL-EC) from chicken meat and humans from a restricted geographic area. Now, we have extended the analysis with plasmid replicons, virulence factors, and highly discriminatory genomic profiling methods. Methods. One hundred forty-five ESBL-EC isolates from retail chicken meat, human rectal carriers, and blood cultures were analyzed using multilocus sequence typing, phylotyping, ESBL genes, plasmid replicons, virulence genes, amplified fragment length polymorphism (AFLP), and pulsed-field gel electrophoresis (PFGE). Results. Three source groups overlapped substantially when their genetic composition was compared. A combined analysis using all variables yielded the highest resolution (Wilks lambda [Λ]: 0.08). Still, a prediction model based on the combined data classified 40% of the human isolates as chicken meat isolates. AFLP and PFGE showed that the isolates from humans and chicken meat could not be segregated and identified 1 perfect match between humans and chicken meat. Conclusions. We found significant genetic similarities among ESBL-EC isolates from chicken meat and humans according to mobile resistance elements, virulence genes, and genomic backbone. Therefore, chicken meat is a likely contributor to the recent emergence of ESBL-EC in human infections in the study region. This raises serious food safety questions regarding the abundant presence of ESBL-EC in chicken meat.

Bacterial vaginosis, characterized in part by low levels of vaginal Lactobacillus species, has been associated with pro-inflammatory cytokines which could fuel uterine fibroid development. However, prior work on the associations between uterine fibroids and vaginal bacteria is sparse. Most studies have focused on assessment of individual taxa in a single sample. To address research gaps, we sought to compare short, longitudinal profiles of the vaginal microbiota in uterine fibroid cases versus controls with assessment for hormonal contraceptives (HCs), a possible confounder associated with both protection from fibroid development and increases in Lactobacillus -dominated vaginal microbiota. This is a secondary analysis of 83 reproductive-age cisgender women who presented for transvaginal ultrasound (TVUS) and self-collected mid-vaginal swabs daily for 1–2 weeks before TVUS (Range: 5–16 days, n = 697 samples). Sonography reports detailed uterine fibroid characteristics (N = 21 cases). Vaginal microbiota was assessed by 16S rRNA gene amplicon sequencing and longitudinal microbiota profiles were categorized by hierarchical clustering. We compared longitudinal profiles of the vaginal microbiota among fibroid cases and controls with exact logistic regression. Common indications for TVUS included pelvic mass (34%) and pelvic pain (39%). Fibroid cases tended to be older and report Black race. Cases less often reported HCs versus controls (32% vs. 58%). A larger proportion of cases had low- Lactobacillus longitudinal profiles (48%) than controls (34%). In unadjusted analysis, L . iners -dominated and low- Lactobacillus profiles had higher odds of fibroid case status compared to other Lactobacillus -dominated profiles, however these results were not statistically significant. No association between vaginal microbiota and fibroids was observed after adjusting for race, HC and menstruation. Results were consistent when number of fibroids were considered. There was not a statistically significant association between longitudinal profiles of vaginal microbiota and uterine fibroids after adjustment for common confounders; however, the study was limited by small sample size.

Cas12a is a next-generation gene editing tool that enables multiplexed gene targeting. Here, we present a mouse model that constitutively expresses enhanced Acidaminococcus sp. Cas12a ( enAsCas12a ) linked to an mCherry fluorescent reporter. We demonstrate efficient single and multiplexed gene editing in vitro, using primary and transformed cells from enAsCas12a mice. We further demonstrate successful in vivo gene editing, using normal and cancer-prone enAsCas12a stem cells to reconstitute the haematopoietic system of wild-type mice. We also present compact, genome-wide Cas12a knockout libraries, with four crRNAs per gene encoded across one (Scherzo) or two (Menuetto) vectors, and demonstrate the utility of these libraries across methodologies: in vitro enrichment and drop-out screening in lymphoma cells and immortalised fibroblasts, respectively, and in vivo screens to identify lymphoma-driving events. Finally, we demonstrate CRISPR multiplexing via simultaneous gene knockout (via Cas12a) and activation (via dCas9-SAM) using primary T cells and fibroblasts. Our enAsCas12a mouse and accompanying crRNA libraries enhance genome engineering capabilities and complement current CRISPR technologies. Cas12a represents the next generation of gene editing. Here, the authors present the generation and validation of a Cas12a transgenic mouse model. Additionally, the authors create whole-genome Cas12a knockout libraries, and demonstrate their utility across multiple in vitro and in vivo screens.

Despite advancements in targeting the immune checkpoints program cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) for cancer immunotherapy, a large number of patients and cancer types remain unresponsive. Current immunotherapies focus on modulating an antitumor immune response by directly or indirectly expanding antitumor CD8 T cells. A complementary strategy might involve inhibition of Tregs that otherwise suppress antitumor immune responses. Here, we sought to identify functional immune molecules preferentially expressed on tumor-infiltrating Tregs. Using genome-wide RNA-Seq analysis of purified Tregs sorted from multiple human cancer types, we identified a conserved Treg immune checkpoint signature. Using immunocompetent murine tumor models, we found that antibody-mediated depletion of 4-1BB-expressing cells (4-1BB is also known as TNFRSF9 or CD137) decreased tumor growth without negatively affecting CD8 T cell function. Furthermore, we found that the immune checkpoint 4-1BB had a high selectivity for human tumor Tregs and was associated with worse survival outcomes in patients with multiple tumor types. Thus, antibody-mediated depletion of 4-1BB-expressing Tregs represents a strategy with potential activity across cancer types.

Background The ectoparasitic mite Varroa destructor has emerged as the primary pest of domestic honey bees ( Apis mellifera ). Here we present an initial survey of the V. destructor genome carried out to advance our understanding of Varroa biology and to identify new avenues for mite control. This sequence survey provides immediate resources for molecular and population-genetic analyses of Varroa - Apis interactions and defines the challenges ahead for a comprehensive Varroa genome project. Results The genome size was estimated by flow cytometry to be 565 Mbp, larger than most sequenced insects but modest relative to some other Acari. Genomic DNA pooled from ~1,000 mites was sequenced to 4.3× coverage with 454 pyrosequencing. The 2.4 Gbp of sequencing reads were assembled into 184,094 contigs with an N50 of 2,262 bp, totaling 294 Mbp of sequence after filtering. Genic sequences with homology to other eukaryotic genomes were identified on 13,031 of these contigs, totaling 31.3 Mbp. Alignment of protein sequence blocks conserved among V. destructor and four other arthropod genomes indicated a higher level of sequence divergence within this mite lineage relative to the tick Ixodes scapularis . A number of microbes potentially associated with V. destructor were identified in the sequence survey, including ~300 Kbp of sequence deriving from one or more bacterial species of the Actinomycetales. The presence of this bacterium was confirmed in individual mites by PCR assay, but varied significantly by age and sex of mites. Fragments of a novel virus related to the Baculoviridae were also identified in the survey. The rate of single nucleotide polymorphisms (SNPs) in the pooled mites was estimated to be 6.2 × 10 -5 per bp, a low rate consistent with the historical demography and life history of the species. Conclusions This survey has provided general tools for the research community and novel directions for investigating the biology and control of Varroa mites. Ongoing development of Varroa genomic resources will be a boon for comparative genomics of under-represented arthropods, and will further enhance the honey bee and its associated pathogens as a model system for studying host-pathogen interactions.