of coronavirus disease (COVID-19) had been reported globally since December 2019 (1), severely burdening the healthcare system (2). The extremely fast transmission capability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has aroused concern about its various transmission routes.The main transmission routes for SARS-CoV-2 are respiratory droplets and close contact (3). Knowing the extent of environmental contamination of SARS-CoV-2 in COVID-19 wards is critical for improving safety practices for medical staff and answering questions about SARS-CoV-2 transmission among the public. However, whether SARS-CoV-2 can be transmitted by aerosols remains controversial, and the exposure risk for close contacts has not been systematically evaluated. Researchers have detected SARS-CoV-2 on surfaces of objects in a symptomatic patient's room and toilet area (4). However, that study was performed in a small sample from regions with few confirmed cases, which might not reflect real conditions in outbreak regions where hospitals are operating at full capacity. In this study, we tested surface and air samples from an intensive care unit (ICU) and a general COVID-19 ward (GW) at Huoshenshan Hospital in Wuhan, China (Figure 1). The StudyFrom February 19 through March 2, 2020, we collected swab samples from potentially contaminated objects in the ICU and GW as described previously (5). The ICU housed 15 patients with severe disease and the GW housed 24 patients with milder disease. We also sampled indoor air and the air outlets to detect aerosol exposure. Air samples were collected by using a SASS 2300 Wetted Wall Cyclone Sampler (Research International, Inc., https://www.resrchintl.com) at 300 L/min for of 30 min. We used sterile premoistened swabs to sample the floors, computer mice, trash cans, sickbed handrails, patient masks, personal protective equipment, and air outlets. We tested air and surface samples for the open reading frame (ORF) 1ab and nucleoprotein (N) genes of SARS-CoV-2 by quantitative real-time PCR. (Appendix, https://wwwnc.cdc.gov/EID/ article/26/7/20-0885-App1.pdf).Almost all positive results were concentrated in the contaminated areas (ICU 54/57, 94.7%; GW 9/9, 100%); the rate of positivity was much higher for the ICU (54/124, 43.5%) than for the GW (9/114, 7.9%) (Tables 1, 2). The rate of positivity was

Twenty percent of the familial form of amyotrophic lateral sclerosis (ALS) is caused by mutations in the Cu, Zn-superoxide dismutase gene (SOD1) through the gain of a toxic function. The nature of this toxic function of mutant SOD1 has remained largely unknown. Here we show that WT SOD1 not only hastens onset of the ALS phenotype but can also convert an unaffected phenotype to an ALS phenotype in mutant SOD1 transgenic mouse models. Further analyses of the single-and double-transgenic mice revealed that conversion of mutant SOD1 from a soluble form to an aggregated and detergent-insoluble form was associated with development of the ALS phenotype in transgenic mice. Conversion of WT SOD1 from a soluble form to an aggregated and insoluble form also correlates with exacerbation of the disease or conversion to a disease phenotype in double-transgenic mice. This conversion, observed in the mitochondrial fraction of the spinal cord, involved formation of insoluble SOD1 dimers and multimers that are crosslinked through intermolecular disulfide bonds via oxidation of cysteine residues in SOD1. Our data thus show a molecular mechanism by which SOD1, an important protein in cellular defense against free radicals, is converted to aggregated and apparently ALS-associated toxic dimers and multimers by redox processes. These findings provide evidence of direct links among oxidation, protein aggregation, mitochondrial damage, and SOD1-mediated ALS, with possible applications to the aging process and other late-onset neurodegenerative disorders. Importantly, rational therapy based on these observations can now be developed and tested.crosslinked ͉ disulfide bonds ͉ oxidation ͉ protein aggregation ͉ neurodegeneration A myotrophic lateral sclerosis (ALS) is a progressive paralytic disorder caused by degeneration of the motor neurons in brain and spinal cord (1). Most of the ALS cases are sporadic, with Ϸ5-10% being familial. The progressive paralysis in ALS usually affects respiratory function, leading to ventilatory failure and death; 50% of patients die within 3 years of onset of symptoms, and 90% die within 5 years. The juvenile form of ALS usually has a prolonged course of two to four decades. There is no known effective treatment for this fatal disease, although marginal delay in mortality has been noted with the drug riluzole (2).Familial ALS can be transmitted as either a dominant or a recessive trait. We and our collaborators have previously shown that mutations in the Cu, Zn-superoxide dismutase gene (SOD1) are associated with Ϸ20% of familial ALS cases (3, 4). The pathogenic mechanisms underlying this disease are still largely unknown. Most, but not all, transgenic mice overexpressing ALS-associated SOD1 mutants develop ALS-like disease (5), and transgenic mice overexpressing human WT SOD1 (hwtSOD1) or SOD1-deficient mice do not develop ALS-like disease (5, 6), suggesting that mutant SOD1 requires a threshold of expression to cause the disease through the gain of a toxic property.Thus far, Ͼ100 mutations, widely distrib...

Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, upfront resistance as well as relapse following initial response demonstrates the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax + azacitidine in patients with AML correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant. Mechanistically, resistant monocytic AML has a distinct transcriptomic profi le, loses expression of venetoclax target BCL2, and relies on MCL1 to mediate oxidative phosphorylation and survival. This differential sensitivity drives a selective process in patients which favors the outgrowth of monocytic subpopulations at relapse. Based on these fi ndings, we conclude that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation. We propose that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis. SIGNIFICANCE: Identifying characteristics of patients who respond poorly to venetoclax-based therapy and devising alternative therapeutic strategies for such patients are important topics in AML. We show that venetoclax resistance can arise due to intrinsic molecular/metabolic properties of monocytic AML cells and that such properties can potentially be targeted with alternative strategies.

In vitro generation of functional gametes is a promising approach for treating infertility, although faithful replication of meiosis has proven to be a substantial obstacle to deriving haploid gamete cells in culture. Here we report complete in vitro meiosis from embryonic stem cell (ESC)-derived primordial germ cells (PGCLCs). Co-culture of PGCLCs with neonatal testicular somatic cells and sequential exposure to morphogens and sex hormones reproduced key hallmarks of meiosis, including erasure of genetic imprinting, chromosomal synapsis and recombination, and correct nuclear DNA and chromosomal content in the resulting haploid cells. Intracytoplasmic injection of the resulting spermatid-like cells into oocytes produced viable and fertile offspring, showing that this robust stepwise approach can functionally recapitulate male gametogenesis in vitro. These findings provide a platform for investigating meiotic mechanisms and the potential generation of human haploid spermatids in vitro.