In this study,
APOL1
variants were associated with an increased risk of progression of chronic kidney disease in black patients, as compared with white patients, regardless of the cause of kidney ...disease or diabetes status.
In the United States, black patients have approximately twice the risk of end-stage renal disease observed among white patients, after accounting for differences in socioeconomic and clinical risk factors.
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This increased risk occurs despite a similar prevalence in earlier stages of chronic kidney disease
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in the two racial groups, which suggests that kidney function declines more rapidly after the onset of chronic kidney disease in black patients. However, there is little direct evidence in support of this hypothesis.
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The identification of factors that mediate differences in the progression of chronic kidney disease between black patients and white . . .
Mass extinction at the Cretaceous–Paleogene (K-Pg) boundary coincides with the Chicxulub bolide impact and also falls within the broader time frame of Deccan trap emplacement. Critically, though, ...empirical evidence as to how either of these factors could have driven observed extinction patterns and carbon cycle perturbations is still lacking. Here, using boron isotopes in foraminifera, we document a geologically rapid surface-ocean pH drop following the Chicxulub impact, supporting impact-induced ocean acidification as amechanism for ecological collapse in the marine realm. Subsequently, surface water pH rebounded sharply with the extinction of marine calcifiers and the associated imbalance in the global carbon cycle. Our reconstructed water-column pH gradients, combined with Earth system modeling, indicate that a partial ∼50% reduction in global marine primary productivity is sufficient to explain observed marine carbon isotope patterns at the K-Pg, due to the underlying action of the solubility pump. While primary productivity recovered within a few tens of thousands of years, inefficiency in carbon export to the deep sea lasted much longer. This phased recovery scenario reconciles competing hypotheses previously put forward to explain the K-Pg carbon isotope records, and explains both spatially variable patterns of change in marine productivity across the event and a lack of extinction at the deep sea floor. In sum, we provide insights into the drivers of the last mass extinction, the recovery of marine carbon cycling in a postextinction world, and the way in which marine life imprints its isotopic signal onto the geological record.
Purpose The guideline purpose is to provide the urologist with a framework for the early detection of prostate cancer in asymptomatic average risk men. Materials and Methods A systematic review was ...conducted and summarized evidence derived from over 300 studies that addressed the predefined outcomes of interest (prostate cancer incidence/mortality, quality of life, diagnostic accuracy and harms of testing). In addition to the quality of evidence, the panel considered values and preferences expressed in a clinical setting (patient-physician dyad) rather than having a public health perspective. Guideline statements were organized by age group in years (age <40; 40 to 54; 55 to 69; ≥70). Results Except prostate specific antigen-based prostate cancer screening, there was minimal evidence to assess the outcomes of interest for other tests. The quality of evidence for the benefits of screening was moderate, and evidence for harm was high for men age 55 to 69 years. For men outside this age range, evidence was lacking for benefit, but the harms of screening, including over diagnosis and overtreatment, remained. Modeled data suggested that a screening interval of two years or more may be preferred to reduce the harms of screening. Conclusions The Panel recommended shared decision-making for men age 55 to 69 years considering PSA-based screening, a target age group for whom benefits may outweigh harms. Outside this age range, PSA-based screening as a routine could not be recommended based on the available evidence. The entire guideline is available at www.AUAnet.org/education/guidelines/prostate-cancer-detection.cfm.
The second-generation antiandrogen enzalutamide was recently approved for patients with castration-resistant prostate cancer. Despite its success, the duration of response is often limited. For ...previous antiandrogens, one mechanism of resistance is mutation of the androgen receptor (AR). To prospectively identify AR mutations that might confer resistance to enzalutamide, we performed a reporter-based mutagenesis screen and identified a novel mutation, F876L, which converted enzalutamide into an AR agonist. Ectopic expression of AR F876L rescued the growth inhibition of enzalutamide treatment. Molecular dynamics simulations performed on antiandrogen-AR complexes suggested a mechanism by which the F876L substitution alleviates antagonism through repositioning of the coactivator recruiting helix 12. This model then provided the rationale for a focused chemical screen which, based on existing antiandrogen scaffolds, identified three novel compounds that effectively antagonized AR F876L (and AR WT) to suppress the growth of prostate cancer cells resistant to enzalutamide. DOI:http://dx.doi.org/10.7554/eLife.00499.001.
This study pools household travel and built environment data from 15 diverse US regions to produce travel models with more external validity than any to date. It uses a large number of consistently ...defined built environmental variables to predict five household travel outcomes – car trips, walk trips, bike trips, transit trips and vehicle miles travelled (VMT). It employs multilevel modelling to account for the dependence of households in the same region on shared regional characteristics and estimates 'hurdle' models to account for the excess number of zero values in the distributions of dependent variables such as household transit trips. It tests built environment variables for three different buffer widths around household locations to see which scale best explains travel behaviour. The resulting models are appropriate for post-processing outputs of conventional travel demand models, and for sketch planning applications in traffic impact analysis, climate action planning and health impact assessment.
The mitochondrial enzyme glutaminase (GLS) is frequently up-regulated during tumorigenesis and is being evaluated as a target for cancer therapy. GLS catalyzes the hydrolysis of glutamine to ...glutamate, which then supplies diverse metabolic pathways with carbon and/or nitrogen. Here, we report that SIRT5, a mitochondrial NAD⁺-dependent lysine deacylase, plays a key role in stabilizing GLS. In transformed cells, SIRT5 regulates glutamine metabolism by desuccinylating GLS and thereby protecting it from ubiquitin-mediated degradation. Moreover, we show that SIRT5 is up-regulated during cellular transformation and supports proliferation and tumorigenesis. Elevated SIRT5 expression in human breast tumors correlates with poor patient prognosis. These findings reveal a mechanism for increasing GLS expression in cancer cells and establish a role for SIRT5 in metabolic reprogramming and mammary tumorigenesis.
As a result of algae’s promise as a renewable energy feedstock, numerous studies have used Life Cycle Assessment (LCA) to quantify the environmental performance of algal biofuels, yet there is no ...consensus of results among them. Our work, motivated by the lack of comprehensive uncertainty analysis in previous studies, uses a Monte Carlo approach to estimate ranges of expected values of LCA metrics by incorporating parameter variability with empirically specified distribution functions. Results show that large uncertainties exist at virtually all steps of the biofuel production process. Although our findings agree with a number of earlier studies on matters such as the need for wet lipid extraction, nutrients recovered from waste streams, and high energy coproducts, the ranges of reported LCA metrics show that uncertainty analysis is crucial for developing technologies, such as algal biofuels. In addition, the ranges of energy return on (energy) invested (EROI) values resulting from our analysis help explain the high variability in EROI values from earlier studies. Reporting results from LCA models as ranges, and not single values, will more reliably inform industry and policy makers on expected energetic and environmental performance of biofuels produced from microalgae.
Coronavirus disease 2019 (COVID-19) is frequently associated with neurological deficits, but how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces these effects remains unclear. ...Here, we show that astrocytes are readily infected by SARS-CoV-2, but surprisingly, neuropilin-1, not angiotensin-converting enzyme 2 (ACE2), serves as the principal receptor mediating cell entry. Infection is further positively modulated by the two-pore segment channel 2 (TPC2) protein that regulates membrane trafficking and endocytosis. Astrocyte infection produces a pathological response closely resembling reactive astrogliosis characterized by elevated type I interferon (IFN) production, increased inflammation, and the decreased expression of transporters of water, ions, choline, and neurotransmitters. These combined events initiated within astrocytes produce a hostile microenvironment that promotes the dysfunction and death of uninfected bystander neurons.
SARS-CoV-2 infection primarily targets the lung but may also damage other organs, including the brain, heart, kidney, and intestine. Central nervous system (CNS) pathologies include loss of smell and taste, headache, delirium, acute psychosis, seizures, and stroke. Pathological loss of gray matter occurs in SARS-CoV-2 infection, but it is unclear whether this is due to direct viral infection, indirect effects associated with systemic inflammation, or both. Here, we used induced pluripotent stem cell (iPSC)-derived brain organoids and primary human astrocytes from the cerebral cortex to study direct SARS-CoV-2 infection. Our findings support a model where SARS-CoV-2 infection of astrocytes produces a panoply of changes in the expression of genes regulating innate immune signaling and inflammatory responses. The deregulation of these genes in astrocytes produces a microenvironment within the CNS that ultimately disrupts normal neuron function, promoting neuronal cell death and CNS deficits.
Weld overlays of Ni-based superalloys provide high-temperature corrosion, oxidation, and wear resistance for industrial applications. The objective of this study was to evaluate the microstructure of ...Ni–Cr-Mo superalloy Inconel 686 overlays fabricated using automatic gas metal arc welding (GMAW) with three different levels of voltage, travel speed, and wire feed speed. The variation of these parameters and their effects on the weld quality, dilution, and microsegregation were analyzed. The weld surface quality was assessed by visual examination. The weld dilution was measured by both geometric and chemical composition definitions. The maximum dilution was measured at 13.63%, induced by the highest weld heat input (5.97 kJ cm
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) and lowest wire feed speed (6 m min
−1
). The overlay dilution and the heat-affected zone (HAZ) size decreased by increasing the wire feed speed. However, increasing the wire feed speed and the heat input reduced the weld quality and even resulted in noncomplete joints. Microsegregation of elements was evaluated using energy-dispersive X-ray spectroscopy (EDS) analysis and it was found that microsegregation of Mo and Cr and the volume fraction of secondary phases in the interdendritic areas increased with increasing the weld heat input. According to the visual examination results and macro- and microscopic evaluation, the weld overlay parameters were found to be optimized for the mid-level heat inputs (4–5 kJ cm
−1
) and wire feed speeds between 6 and 8 m min
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.
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