A method for the regioselective arylboration of isoprene and its derivatives is presented. These reactions allow for the synthesis of useful building blocks from simple components. Through these ...studies, an unusual additive effect with DMAP has been uncovered that allows for altered reactivity and the formation of quaternary carbon centers. The utility of this method is demonstrated toward the formal synthesis of mesembrine.
Systemic sclerosis (SSc) is a rare connective tissue disease with a heterogeneous clinical course. Interstitial lung disease (ILD) is a common manifestation of SSc and a leading cause of death.
All ...patients newly diagnosed with SSc should receive a comprehensive clinical evaluation, including assessment of respiratory symptoms, a high-resolution computed tomography (HRCT) scan of the chest, and pulmonary function tests. ILD can develop in any patient with SSc, including those with pulmonary hypertension, but the risk is increased in those with diffuse (rather than limited) cutaneous SSc, those with anti-Scl-70/anti-topoisomerase I antibody, and in the absence of anti-centromere antibody. While it can occur at any time, the risk of developing ILD is greatest early in the course of SSc, so patients should be monitored closely in the first few years after diagnosis. An increased extent of lung fibrosis on HRCT and a low forced vital capacity (FVC) are predictors of early mortality. While not all patients will require treatment, current approaches to the treatment of progressive SSc-ILD focus on immunosuppressant therapies, including cyclophosphamide and mycophenolate mofetil. In patients with severe and/or rapidly progressive disease, both haematopoietic stem cell transplantation (HSCT) and lung transplantation have been successfully used. A number of medications, including the two drugs approved for the treatment of idiopathic pulmonary fibrosis (IPF), are under active investigation as potential new therapies for SSc-ILD.
Physicians managing patients with SSc should maintain a high level of suspicion and regularly monitor for ILD, particularly in the first few years after diagnosis.
VITT and Second Doses of Covid-19 Vaccine Lacy, Joanne; Pavord, Sue; Brown, Kevin E
New England journal of medicine/The New England journal of medicine,
01/2022, Volume:
386, Issue:
1
Journal Article
The ability to perturb genes in human cells is crucial for elucidating gene function and holds great potential for finding therapeutic targets for diseases such as cancer. To extend the catalog of ...human core and context-dependent fitness genes, we have developed a high-complexity second-generation genome-scale CRISPR-Cas9 gRNA library and applied it to fitness screens in five human cell lines. Using an improved Bayesian analytical approach, we consistently discover 5-fold more fitness genes than were previously observed. We present a list of 1,580 human core fitness genes and describe their general properties. Moreover, we demonstrate that context-dependent fitness genes accurately recapitulate pathway-specific genetic vulnerabilities induced by known oncogenes and reveal cell-type-specific dependencies for specific receptor tyrosine kinases, even in oncogenic KRAS backgrounds. Thus, rigorous identification of human cell line fitness genes using a high-complexity CRISPR-Cas9 library affords a high-resolution view of the genetic vulnerabilities of a cell.
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•Identification of 5-fold more fitness genes in human cells than previously observed•Core fitness genes are highly enriched for ancient protein complexes•Context-specific fitness genes illuminate biological differences between cell types•Distinct genetic signatures can be used to predict differential drug response
CRISPR knockout screens for essential genes reveal oncogenic drivers specific to different cancer cell lines as well as unexpected metabolic and signaling dependencies that may guide future therapeutic targeting.
A method for the catalytic enantioselective arylboration of alkenylarenes is disclosed. The reaction leads to the formation of 1,1‐diarylalkanes that also incorporate an additional pinacol boronic ...ester which can be easily transformed to a variety of groups. The products are formed with excellent diastereoselectivities and enantioselectivities.
Incorporate and transform: The title reaction yields 1,1‐diarylalkanes and simultaneously incorporates a pinacol boronic ester, which can be easily transformed to a variety of groups. Products are formed with excellent diastereoselectivities and enantioselectivities.
Protein-protein interaction (PPI) networks have been transferred between organisms using interologs, allowing model organisms to supplement the interactomes of higher eukaryotes. However, the ...conservation of various network components has not been fully explored. Unequal conservation of certain network components may limit the ability to fully expand the target interactomes using interologs.
In this study, we transfer high quality human interactions to lower eukaryotes, and examine the evolutionary conservation of individual network components. When human proteins are mapped to yeast, we find a strong positive correlation (r = 0.50, P = 3.9 x 10(-4)) between evolutionary conservation and the number of interacting proteins, which is also found when mapped to other model organisms. Examining overlapping PPI networks, Gene Ontology (GO) terms, and gene expression data, we are able to demonstrate that protein complexes are conserved preferentially, compared to transient interactions in the network. Despite the preferential conservation of complexes, and the fact that the human interactome comprises an abundance of transient interactions, we demonstrate how transferring human PPIs to yeast augments this well-studied protein interaction network, using the coatomer complex and replisome as examples.
Human proteins, like yeast proteins, show a correlation between the number of interacting partners and evolutionary conservation. The preferential conservation of proteins with higher degree leads to enrichment in protein complexes when interactions are transferred between organisms using interologs.
Nursing home residents have been disproportionately affected by coronavirus disease 2019 (COVID-19). Prevention recommendations emphasize frequent testing of health care personnel and residents, but ...additional strategies are needed.
To develop a reproducible index of nursing home crowding and determine whether crowding was associated with COVID-19 cases and mortality in the first months of the COVID-19 epidemic.
This population-based retrospective cohort study included more than 78 000 residents across more than 600 nursing homes in Ontario, Canada, and was conducted from March 29 to May 20, 2020.
The nursing home crowding index equaled the mean number of residents per bedroom and bathroom.
The cumulative incidence of COVID-19 cases confirmed by a validated nucleic acid amplification assay and mortality per 100 residents; the introduction of COVID-19 into a home (≥1 resident case) was a negative tracer.
Of 623 homes in Ontario, we obtained complete information on 618 homes (99%) housing 78 607 residents (women, 54 160 68.9%; age ≥85 years, 42 919 54.6%). A total of 5218 residents (6.6%) developed COVID-19 infection, and 1452 (1.8%) died of COVID-19 infection as of May 20, 2020. COVID-19 infection was distributed unevenly across nursing homes; 4496 infections (86%) occurred in 63 homes (10%). The crowding index ranged across homes from 1.3 (mainly single-occupancy rooms) to 4.0 (exclusively quadruple occupancy rooms); 308 homes (50%) had a high crowding index (≥2). Incidence in high crowding index homes was 9.7% vs 4.5% in low crowding index homes (P < .001), while COVID-19 mortality was 2.7% vs 1.3%, respectively (P < .001). The likelihood of COVID-19 introduction did not differ (high = 31.3% vs low = 30.2%; P = .79). After adjustment for regional, nursing home, and resident covariates, the crowding index remained associated with an increased incidence of infection (relative risk RR = 1.73, 95% CI, 1.10-2.72) and mortality (RR, 1.69; 95% CI, 0.99-2.87). A propensity score analysis yielded similar conclusions for infection (RR, 2.09; 95% CI, 1.30-3.38) and mortality (RR, 1.83; 95% CI, 1.09-3.08). Simulations suggested that converting all 4-bed rooms to 2-bed rooms would have averted 998 COVID-19 cases (19.1%) and 263 deaths (18.1%).
In this cohort of Canadian nursing homes, crowding was common and crowded homes were more likely to experience larger and deadlier COVID-19 outbreaks.
Cyclobutanes and cyclobutenes are important structural motifs found in numerous biologically significant molecules, and they are useful intermediates for chemical synthesis. Consequently, 2+2 ...cycloadditions to access cyclobutanes and cyclobutenes have been established to be particularly useful transformations. Within the last 10 years, an increase in the frequency of publications for catalytic enantioselective 2+2 cycloadditions has occurred. These reactions provide access to a wide array of enantiomerically enriched chemical diversity that was not previously attainable. Described in this review are the advances made in catalytic enantioselective 2+2 cycloadditions to access cyclobutanes and cyclobutenes.
Squared away: Cyclobutanes and cyclobutenes are important structural motifs found in numerous biologically significant molecules, and they are useful intermediates for chemical synthesis. Consequently, catalytic enantioselective 2+2 cycloadditions to access cyclobutanes and cyclobutenes have emerged as an attractive target for method development. The advances made in catalytic enantioselective 2+2 cycloadditions are described herein.
A method for the catalytic enantioselective diarylation of alkenes is presented. The method allowed for the synthesis of highly enantioenriched 2,3-dihydrobenzofurans and indolines containing ...molecules from readily available substrates. Furthermore, this method allowed for the enantioselective synthesis of quaternary carbons. Based on mechanism studies, the process likely functions by enantioselective insertion of an alkene into an Ar–CuBenzP* complex to generate a Csp3–Cu complex. Capture of this intermediate with an ArX led to formation of the desired product.
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