The extent of somatic mutation and clonal selection in the human bladder remains unknown. We sequenced 2097 bladder microbiopsies from 20 individuals using targeted (
= 1914 microbiopsies), ...whole-exome (
= 655), and whole-genome (
= 88) sequencing. We found widespread positive selection in 17 genes. Chromatin remodeling genes were frequently mutated, whereas mutations were absent in several major bladder cancer genes. There was extensive interindividual variation in selection, with different driver genes dominating the clonal landscape across individuals. Mutational signatures were heterogeneous across clones and individuals, which suggests differential exposure to mutagens in the urine. Evidence of APOBEC mutagenesis was found in 22% of the microbiopsies. Sequencing multiple microbiopsies from five patients with bladder cancer enabled comparisons with cancer-free individuals and across histological features. This study reveals a rich landscape of mutational processes and selection in normal urothelium with large heterogeneity across clones and individuals.
To better understand how the COVID-19 pandemic has affected surgical trainees' and early-career surgeons' professional and personal experiences, a survey of the membership of the American College of ...Surgeons (ACS) Resident and Associate Society (RAS) and Young Fellows Association (YFA) was performed.
An anonymous online survey was disseminated to members of RAS and YFA. Descriptive analyses were performed and factors associated with depression and burnout were examined with univariate and multivariable stepwise logistic regression.
Of the RAS/YFA membership of 21,385, there were 1,160 respondents. The majority of respondents (96%) reported the COVID-19 pandemic having a negative impact on their clinical experience, with 84% of residents reporting a > 50% reduction in operative volume and inability to meet minimum case requirements. Respondents also reported negative impacts on personal wellness. Nearly one-third reported inadequate access to personal protective equipment, and depression and burnout were pervasive (≥21% of respondents reported yes to every screening symptom). On multivariable analysis, female sex (odds ratio OR 1.54 for depression, OR 1.47 for burnout) and lack of wellness resources (OR 1.55 for depression, OR 1.44 for burnout) predicted depression and burnout. Access to adequate personal protective equipment was protective against burnout (OR 0.52).
These data demonstrate a significant impact of the COVID-19 pandemic on the lives of residents and early-career surgeons. Actionable items from these data include mitigation of burnout and depression through increasing personal protective equipment access and provision of wellness programs, with a particular focus on high-risk groups.
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Assessing the scope and severity of threats is necessary for evaluating impacts on populations to inform conservation planning. Quantitative threat assessment often requires monitoring programs that ...provide reliable data over relevant spatial and temporal scales, yet such programs can be difficult to justify until there is an apparent stressor. Leveraging efforts of wildlife management agencies to record winter counts of hibernating bats, we collated data for 5 species from over 200 sites across 27 U.S. states and 2 Canadian provinces from 1995 to 2018 to determine the impact of white‐nose syndrome (WNS), a deadly disease of hibernating bats. We estimated declines of winter counts of bat colonies at sites where the invasive fungus that causes WNS (Pseudogymnoascus destructans) had been detected to assess the threat impact of WNS. Three species undergoing species status assessment by the U.S. Fish and Wildlife Service (Myotis septentrionalis, Myotis lucifugus, and Perimyotis subflavus) declined by more than 90%, which warrants classifying the severity of the WNS threat as extreme based on criteria used by NatureServe. The scope of the WNS threat as defined by NatureServe criteria was large (36% of Myotis lucifugus range) to pervasive (79% of Myotis septentrionalis range) for these species. Declines for 2 other species (Myotis sodalis and Eptesicus fuscus) were less severe but still qualified as moderate to serious based on NatureServe criteria. Data‐sharing across jurisdictions provided a comprehensive evaluation of scope and severity of the threat of WNS and indicated regional differences that can inform response efforts at international, national, and state or provincial jurisdictions. We assessed the threat impact of an emerging infectious disease by uniting monitoring efforts across jurisdictional boundaries and demonstrated the importance of coordinated monitoring programs, such as the North American Bat Monitoring Program (NABat), for data‐driven conservation assessments and planning.
Alcance y Severidad del Síndrome de Nariz Blanca en los Murciélagos Hibernando en América del Norte
Resumen
La evaluación del alcance y la severidad de las amenazas es necesaria para los análisis de impacto sobre las poblaciones que se usan para orientar a la planeación de la conservación. La evaluación cuantitativa de amenazas con frecuencia requiere de programas de monitoreo que proporcionen datos confiables en escalas espaciales y temporales, aunque dichos programas pueden ser difíciles de justificar hasta que exista un estresante aparente. Gracias a una movilización de esfuerzos de las agencias de manejo de fauna para registrar los conteos invernales de murciélagos hibernadores, recopilamos datos para cinco especies en más de 200 sitios a lo largos de 27 estados de EUA y dos provincias canadienses entre 1995 y 2018 para determinar el impacto del síndrome de nariz blanca (SNB), una enfermedad mortal de los murciélagos hibernadores. Estimamos declinaciones en los conteos invernales de las colonias de murciélagos en sitios en donde el hongo invasivo que ocasiona el SNB (Pseudogymnoascus destructans) había sido detectado para evaluar el impacto de amenaza del SNB. Tres especies que se encuentran bajo valoración por parte del Servicio de Pesca y Vida Silvestre de los EUA (Myotis septentrionalis, Myotis lucifugus y Perimyotis subflavus) tuvieron una declinación de más del 90%, lo que justifica la clasificación de la severidad de la amenaza del SNB como extrema con base en el criterio usado por NatureServe. El alcance de la amenaza del SNB definido por el criterio de NatureServe fue desde amplio (36% de la distribución de Myotis lucifugus) hasta dominante (79% de la distribución de Myotis septentrionalis) para estas especies. Las declinaciones de otras dos especies (Myotis sodalis y Eptesicus fuscus) fueron menos severas, pero de igual manera quedaron clasificadas desde moderada hasta seria con base en los criterios de NatureServe. El intercambio de datos entre las jurisdicciones proporcionó una evaluación completa del alcance y la severidad de la amenaza del SNB e indicó las diferencias regionales que pueden guiar a los esfuerzos de respuesta realizados en las jurisdicciones internacionales, nacionales, estatales o provinciales. Evaluamos el impacto de amenaza de una enfermedad infecciosa emergente mediante la combinación de los esfuerzos de monitoreo que sobrepasan fronteras jurisdiccionales y demostramos la importancia que tienen para la planeación y la evaluación basadas en datos de la conservación los programas de monitoreo coordinados, como el Programa de Monitoreo de los Murciélagos Norteamericanos (NABat).
Article impact statement: Data sharing and coordinated monitoring are needed to assess species’ response to threats to inform conservation planning at relevant scales.
The Saturn-mass exoplanet WASP-39b has been the subject of extensive efforts to determine its atmospheric properties using transmission spectroscopy
. However, these efforts have been hampered by ...modelling degeneracies between composition and cloud properties that are caused by limited data quality
. Here we present the transmission spectrum of WASP-39b obtained using the Single-Object Slitless Spectroscopy (SOSS) mode of the Near Infrared Imager and Slitless Spectrograph (NIRISS) instrument on the JWST. This spectrum spans 0.6-2.8 μm in wavelength and shows several water-absorption bands, the potassium resonance doublet and signatures of clouds. The precision and broad wavelength coverage of NIRISS/SOSS allows us to break model degeneracies between cloud properties and the atmospheric composition of WASP-39b, favouring a heavy-element enhancement ('metallicity') of about 10-30 times the solar value, a sub-solar carbon-to-oxygen (C/O) ratio and a solar-to-super-solar potassium-to-oxygen (K/O) ratio. The observations are also best explained by wavelength-dependent, non-grey clouds with inhomogeneous coverageof the planet's terminator.
Trypanosoma brucei drug transporters include the TbAT1/P2 aminopurine transporter and the high-affinity pentamidine transporter (HAPT1), but the genetic identity of HAPT1 is unknown. We recently ...reported that loss of T. brucei aquaglyceroporin 2 (TbAQP2) caused melarsoprol/pentamidine cross-resistance (MPXR) in these parasites and the current study aims to delineate the mechanism by which this occurs.
The TbAQP2 loci of isogenic pairs of drug-susceptible and MPXR strains of T. brucei subspecies were sequenced. Drug susceptibility profiles of trypanosome strains were correlated with expression of mutated TbAQP2 alleles. Pentamidine transport was studied in T. brucei subspecies expressing TbAQP2 variants.
All MPXR strains examined contained TbAQP2 deletions or rearrangements, regardless of whether the strains were originally adapted in vitro or in vivo to arsenicals or to pentamidine. The MPXR strains and AQP2 knockout strains had lost HAPT1 activity. Reintroduction of TbAQP2 in MPXR trypanosomes restored susceptibility to the drugs and reinstated HAPT1 activity, but did not change the activity of TbAT1/P2. Expression of TbAQP2 sensitized Leishmania mexicana promastigotes 40-fold to pentamidine and >1000-fold to melaminophenyl arsenicals and induced a high-affinity pentamidine transport activity indistinguishable from HAPT1 by Km and inhibitor profile. Grafting the TbAQP2 selectivity filter amino acid residues onto a chimeric allele of AQP2 and AQP3 partly restored susceptibility to pentamidine and an arsenical.
TbAQP2 mediates high-affinity uptake of pentamidine and melaminophenyl arsenicals in trypanosomes and TbAQP2 encodes the previously reported HAPT1 activity. This finding establishes TbAQP2 as an important drug transporter.
Plasmodium berghei and Plasmodium chabaudi are widely used model malaria species. Comparison of their genomes, integrated with proteomic and microarray data, with the genomes of Plasmodium falciparum ...and Plasmodium yoelii revealed a conserved core of 4500 Plasmodium genes in the central regions of the 14 chromosomes and highlighted genes evolving rapidly because of stage-specific selective pressures. Four strategies for gene expression are apparent during the parasites' life cycle: (i) housekeeping; (ii) host-related; (iii) strategy-specific related to invasion, asexual replication, and sexual development; and (iv) stage-specific. We observed posttranscriptional gene silencing through translational repression of messenger RNA during sexual development, and a 47-base 3' untranslated region motif is implicated in this process.
We report a simple, mild, and synthetically clean approach to accelerate the rate of enzymatic oxidation reactions by a factor of up to 100 when compared to conventional batch gas/liquid systems. ...Biocatalytic decomposition of H2O2 is used to produce a soluble source of O2 directly in reaction media, thereby enabling the concentration of aqueous O2 to be increased beyond equilibrium solubility under safe and practical conditions. To best exploit this method, a novel flow reactor was developed to maximize productivity (g product L−1 h−1). This scalable benchtop method provides a distinct advantage over conventional bio‐oxidation in that no pressurized gas or specialist equipment is employed. The method is general across different oxidase enzymes and compatible with a variety of functional groups. These results culminate in record space‐time yields for bio‐oxidation.
Go with the flow: Decomposition of H2O2 produces a soluble source of O2 for enzymatic oxidation reactions directly in the reaction media, thereby increasing the concentration of aqueous O2 beyond equilibrium solubility. A novel multipoint‐injection flow reactor was developed to maximize productivity. This method requires no pressurized gas or specialist equipment and improves the reaction rate by up to 100‐fold compared to conventional batch gas/liquid systems.
Susceptibility of tsetse flies (Glossina spp.) to trypanosomes of both humans and animals has been associated with the presence of the endosymbiont Sodalis glossinidius. However, intrinsic biological ...characteristics of the flies and environmental factors can influence the presence of both S. glossinidius and the parasites. It thus remains unclear whether it is the S. glossinidius or other attributes of the flies that explains the apparent association. The objective of this study was to test whether the presence of Trypanosoma vivax, T. congolense and T. brucei are related to the presence of S. glossinidius in tsetse flies when other factors are accounted for: geographic location, species of Glossina, sex or age of the host flies.
Flies (n = 1090) were trapped from four sites in the Shimba Hills and Nguruman regions in Kenya. Sex and species of tsetse (G. austeni, G. brevipalpis, G. longipennis and G. pallidipes) were determined based on external morphological characters and age was estimated by a wing fray score method. The presence of trypanosomes and S. glossinidius was detected using PCR targeting the internal transcribed spacer region 1 and the haemolysin gene, respectively. Sequencing was used to confirm species identification. Generalised Linear Models (GLMs) and Multiple Correspondence Analysis (MCA) were applied to investigate multivariable associations. The overall prevalence of trypanosomes was 42.1%, but GLMs revealed complex patterns of associations: the presence of S. glossinidius was associated with trypanosome presence but only in interactions with other factors and only in some species of trypanosomes. The strongest association was found for T. congolense, and no association was found for T. vivax. The MCA also suggested only a weak association between the presence of trypanosomes and S. glossinidius. Trypanosome-positive status showed strong associations with sex and age while S. glossinidius-positive status showed a strong association with geographic location and species of fly.
We suggest that previous conclusions about the presence of endosymbionts increasing probability of trypanosome presence in tsetse flies may have been confounded by other factors, such as community composition of the tsetse flies and the specific trypanosomes found in different regions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Motile cilia are essential components of the mucociliary escalator and are central to respiratory-tract host defenses. Abnormalities in these evolutionarily conserved organelles cause primary ciliary ...dyskinesia (PCD). Despite recent strides characterizing the ciliome and sensory ciliopathies through exploration of the phenotype-genotype associations in model organisms, the genetic bases of most cases of PCD remain elusive. We identified nine related subjects with PCD from geographically dispersed Amish communities and performed exome sequencing of two affected individuals and their unaffected parents. A single autosomal-recessive nonsynonymous missense mutation was identified in HEATR2, an uncharacterized gene that belongs to a family not previously associated with ciliary assembly or function. Airway epithelial cells isolated from PCD-affected individuals had markedly reduced HEATR2 levels, absent dynein arms, and loss of ciliary beating. MicroRNA-mediated silencing of the orthologous gene in Chlamydomonas reinhardtii resulted in absent outer dynein arms, reduced flagellar beat frequency, and decreased cell velocity. These findings were recapitulated by small hairpin RNA-mediated knockdown of HEATR2 in airway epithelial cells from unaffected donors. Moreover, immunohistochemistry studies in human airway epithelial cells showed that HEATR2 was localized to the cytoplasm and not in cilia, which suggests a role in either dynein arm transport or assembly. The identification of HEATR2 contributes to the growing number of genes associated with PCD identified in both individuals and model organisms and shows that exome sequencing in family studies facilitates the discovery of novel disease-causing gene mutations.
Combined Janus kinase 1 (JAK1) and JAK2 inhibition therapy effectively reduces splenomegaly and symptom burden related to myelofibrosis but is associated with dose-dependent anemia and ...thrombocytopenia. In this open-label phase II study, we evaluated the efficacy and safety of three dose levels of INCB039110, a potent and selective oral JAK1 inhibitor, in patients with intermediate- or high-risk myelofibrosis and a platelet count ≥50×10
/L. Of 10, 45, and 32 patients enrolled in the 100 mg twice-daily, 200 mg twice-daily, and 600 mg once-daily cohorts, respectively, 50.0%, 64.4%, and 68.8% completed week 24. A ≥50% reduction in total symptom score was achieved by 35.7% and 28.6% of patients in the 200 mg twice-daily cohort and 32.3% and 35.5% in the 600 mg once-daily cohort at week 12 (primary end point) and 24, respectively. By contrast, two patients (20%) in the 100 mg twice-daily cohort had ≥50% total symptom score reduction at weeks 12 and 24. For the 200 mg twice-daily and 600 mg once-daily cohorts, the median spleen volume reductions at week 12 were 14.2% and 17.4%, respectively. Furthermore, 21/39 (53.8%) patients who required red blood cell transfusions during the 12 weeks preceding treatment initiation achieved a ≥50% reduction in the number of red blood cell units transfused during study weeks 1-24. Only one patient discontinued for grade 3 thrombocytopenia. Non-hematologic adverse events were largely grade 1 or 2; the most common was fatigue. Treatment with INCB039110 resulted in clinically meaningful symptom relief, modest spleen volume reduction, and limited myelosuppression.
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