Benzocyclobutenes (BCBs) are of growing interest in materials and medicinal chemistry, although general routes for their provision remain underexplored. A modular, divergent, and stereoselective Cu- ...and Pd-catalyzed assembly/cyclization sequence allows the synthesis of densely functionalized BCBs, from readily accessible imine, allene, and diboron precursors. Preliminary results have identified enantioselective conditions for our protocol and highlighted, for example, its applicability to the synthesis of BCB-containing peptides. By simple variation of experimental conditions or substrate modification, our strategy was expanded to deliver indoline and quinoline derivatives, suitable for further manipulations.
Skin injuries across the body continue to disrupt everyday life for millions of patients and result in prolonged hospital stays, infection, and death. Advances in wound healing devices have improved ...clinical practice but have mainly focused on treating macroscale healing versus underlying microscale pathophysiology. Consensus is lacking on optimal treatment strategies using a spectrum of wound healing products, which has motivated the design of new therapies. We summarize advances in the development of novel drug, biologic products, and biomaterial therapies for wound healing for marketed therapies and those in clinical trials. We also share perspectives for successful and accelerated translation of novel integrated therapies for wound healing.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and fourth-leading cause of cancer death. While drug discovery to improve disease survival was historically poor, there is now ...evidence of significant potential for immune checkpoint inhibitors (ICPIs) in treatment of the disease, and indeed such drug approvals are beginning to emerge.
HCC typically arises in the context of cirrhosis and chronic liver disease (CLD), and HCC exhibits significant biological heterogeneity, in part reflecting the broad range of etiologies of CLD. Different classes and combinations of ICPI-based therapy exist, but not all patients will respond and predictive biomarkers are not yet available to guide clinician decision-making, unlike some other cancer types. In this review, we discuss the emerging biomarkers for ICPI sensitivity in HCC, including tumor genomic features, perturbation of the gut microbiome, and systemic inflammatory markers.
Additional profiling studies are required to appreciate existing trends with clinical outcome and to further drive clinical studies in disease stratification by response. This will only be possible within collaborative and international efforts, especially regarding biopsy collection. A close collaboration between basic scientists and clinicians will be the key to shape the next future of HCC biomarker research.
Above-ground biomass and structure of 260 African tropical forests Lewis, Simon L.; Sonké, Bonaventure; Sunderland, Terry ...
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
09/2013, Letnik:
368, Številka:
1625
Journal Article
Recenzirano
Odprti dostop
We report above-ground biomass (AGB), basal area, stem density and wood mass density estimates from 260 sample plots (mean size: 1.2 ha) in intact closed-canopy tropical forests across 12 African ...countries. Mean AGB is 395.7 Mg dry mass ha−1 (95% CI: 14.3), substantially higher than Amazonian values, with the Congo Basin and contiguous forest region attaining AGB values (429 Mg ha−1) similar to those of Bornean forests, and significantly greater than East or West African forests. AGB therefore appears generally higher in palaeo- compared with neotropical forests. However, mean stem density is low (426 ± 11 stems ha−1 greater than or equal to 100 mm diameter) compared with both Amazonian and Bornean forests (cf. approx. 600) and is the signature structural feature of African tropical forests. While spatial autocorrelation complicates analyses, AGB shows a positive relationship with rainfall in the driest nine months of the year, and an opposite association with the wettest three months of the year; a negative relationship with temperature; positive relationship with clay-rich soils; and negative relationships with C : N ratio (suggesting a positive soil phosphorus–AGB relationship), and soil fertility computed as the sum of base cations. The results indicate that AGB is mediated by both climate and soils, and suggest that the AGB of African closed-canopy tropical forests may be particularly sensitive to future precipitation and temperature changes.
Testing of asymptomatic patients for severe acute respiratory coronavirus virus 2 (SARS-CoV-2) (ie, "asymptomatic screening) to attempt to reduce the risk of nosocomial transmission has been ...extensive and resource intensive, and such testing is of unclear benefit when added to other layers of infection prevention mitigation controls. In addition, the logistic challenges and costs related to screening program implementation, data noting the lack of substantial aerosol generation with elective controlled intubation, extubation, and other procedures, and the adverse patient and facility consequences of asymptomatic screening call into question the utility of this infection prevention intervention. Consequently, the Society for Healthcare Epidemiology of America (SHEA) recommends against routine universal use of asymptomatic screening for SARS-CoV-2 in healthcare facilities. Specifically, preprocedure asymptomatic screening is unlikely to provide incremental benefit in preventing SARS-CoV-2 transmission in the procedural and perioperative environment when other infection prevention strategies are in place, and it should not be considered a requirement for all patients. Admission screening may be beneficial during times of increased virus transmission in some settings where other layers of controls are limited (eg, behavioral health, congregate care, or shared patient rooms), but widespread routine use of admission asymptomatic screening is not recommended over strengthening other infection prevention controls. In this commentary, we outline the challenges surrounding the use of asymptomatic screening, including logistics and costs of implementing a screening program, and adverse patient and facility consequences. We review data pertaining to the lack of substantial aerosol generation during elective controlled intubation, extubation, and other procedures, and we provide guidance for when asymptomatic screening for SARS-CoV-2 may be considered in a limited scope.
The establishment of polarity is a critical process in pathogenic fungi, mediating infection-related morphogenesis and host tissue invasion. Here, we report the identification of TPC1 (Transcription ...factor for Polarity Control 1), which regulates invasive polarized growth in the rice blast fungus Magnaporthe oryzae. TPC1 encodes a putative transcription factor of the fungal Zn(II)2Cys6 family, exclusive to filamentous fungi. Tpc1-deficient mutants show severe defects in conidiogenesis, infection-associated autophagy, glycogen and lipid metabolism, and plant tissue colonisation. By tracking actin-binding proteins, septin-5 and autophagosome components, we show that Tpc1 regulates cytoskeletal dynamics and infection-associated autophagy during appressorium-mediated plant penetration. We found that Tpc1 interacts with Mst12 and modulates its DNA-binding activity, while Tpc1 nuclear localisation also depends on the MAP kinase Pmk1, consistent with the involvement of Tpc1 in this signalling pathway, which is critical for appressorium development. Importantly, Tpc1 directly regulates NOXD expression, the p22phox subunit of the fungal NADPH oxidase complex via an interaction with Mst12. Tpc1 therefore controls spatial and temporal regulation of cortical F-actin through regulation of the NADPH oxidase complex during appressorium re-polarisation. Consequently, Tpc1 is a core developmental regulator in filamentous fungi, linking the regulated synthesis of reactive oxygen species and the Pmk1 pathway, with polarity control during host invasion.
The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence ...has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI.
We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022.
We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per μL (the median for the cohort) was 45% (95% CI 38–52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63–87), increasing to 89% (80–94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05–3·08) but not after 30 days (1·25, 0·84–2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16–8·84).
In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients.
This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A.
Two bottlenecks impeding the genetic analysis of complex traits in rodents are access to mapping populations able to deliver gene-level mapping resolution and the need for population-specific ...genotyping arrays and haplotype reference panels. Here we combine low-coverage (0.15×) sequencing with a new method to impute the ancestral haplotype space in 1,887 commercially available outbred mice. We mapped 156 unique quantitative trait loci for 92 phenotypes at a 5% false discovery rate. Gene-level mapping resolution was achieved at about one-fifth of the loci, implicating Unc13c and Pgc1a at loci for the quality of sleep, Adarb2 for home cage activity, Rtkn2 for intensity of reaction to startle, Bmp2 for wound healing, Il15 and Id2 for several T cell measures and Prkca for bone mineral content. These findings have implications for diverse areas of mammalian biology and demonstrate how genome-wide association studies can be extended via low-coverage sequencing to species with highly recombinant outbred populations.
Abstract
Background
As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination coverage increases in the United States, there is a need to understand the real-world effectiveness ...against severe coronavirus disease 2019 (COVID-19) and among people at increased risk for poor outcomes.
Methods
In a multicenter case-control analysis of US adults hospitalized March 11–May 5, 2021, we evaluated vaccine effectiveness to prevent COVID-19 hospitalizations by comparing odds of prior vaccination with a messenger RNA (mRNA) vaccine (Pfizer-BioNTech or Moderna) between cases hospitalized with COVID-19 and hospital-based controls who tested negative for SARS-CoV-2.
Results
Among 1212 participants, including 593 cases and 619 controls, median age was 58 years, 22.8% were Black, 13.9% were Hispanic, and 21.0% had immunosuppression. SARS-CoV-2 lineage B0.1.1.7 (Alpha) was the most common variant (67.9% of viruses with lineage determined). Full vaccination (receipt of 2 vaccine doses ≥14 days before illness onset) had been received by 8.2% of cases and 36.4% of controls. Overall vaccine effectiveness was 87.1% (95% confidence interval CI, 80.7–91.3). Vaccine effectiveness was similar for Pfizer-BioNTech and Moderna vaccines, and highest in adults aged 18–49 years (97.4%; 95% CI, 79.3–9.7). Among 45 patients with vaccine-breakthrough COVID hospitalizations, 44 (97.8%) were ≥50 years old and 20 (44.4%) had immunosuppression. Vaccine effectiveness was lower among patients with immunosuppression (62.9%; 95% CI,20.8–82.6) than without immunosuppression (91.3%; 95% CI, 85.6–94.8).
Conclusion
During March–May 2021, SARS-CoV-2 mRNA vaccines were highly effective for preventing COVID-19 hospitalizations among US adults. SARS-CoV-2 vaccination was beneficial for patients with immunosuppression, but effectiveness was lower in the immunosuppressed population.
From March to May 2021, full vaccination using authorized mRNA products was associated with 87.1% (95% CI, 80.7–91.3) protection against COVID-19 hospitalization among US adults. Vaccine effectiveness was lower in adults with versus without immunosuppression (62.9% versus 91.3%).
Libraries of protein-encoding sequences can be generated by identification of open reading frames (ORFs) from a genome of choice that are then assembled into collections of plasmids termed ORFeome ...libraries. These represent powerful resources to facilitate functional genomic characterization of genes and their encoded products. Here, we report the generation of an ORFeome for Zymoseptoria tritici, which causes the most serious disease of wheat in temperate regions of the world. We screened the genome of strain IP0323 for high confidence gene models, identifying 4075 candidates from 10,933 predicted genes. These were amplified from genomic DNA, cloned into the Gateway® Entry Vector pDONR207, and sequenced, providing a total of 3022 quality-controlled plasmids. The ORFeome includes genes predicted to encode effectors (n = 410) and secondary metabolite biosynthetic proteins (n = 171), in addition to genes residing at dispensable chromosomes (n= 122), or those that are preferentially expressed during plant infection (n = 527). The ORFeome plasmid library is compatible with our previously developed suite of Gateway® Destination vectors, which have various combinations of promoters, selection markers, and epitope tags. The Z. tritici ORFeome constitutes a powerful resource for functional genomics, and offers unparalleled opportunities to understand the biology of Z. tritici.
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