Systematic identification of signaling pathways required for the fitness of cancer cells will facilitate the development of new cancer therapies. We used gene essentiality measurements in 1,086 ...cancer cell lines to identify selective coessentiality modules and found that a ubiquitin ligase complex composed of UBA6, BIRC6, KCMF1, and UBR4 is required for the survival of a subset of epithelial tumors that exhibit a high degree of aneuploidy. Suppressing BIRC6 in cell lines that are dependent on this complex led to a substantial reduction in cell fitness in vitro and potent tumor regression in vivo. Mechanistically, BIRC6 suppression resulted in selective activation of the integrated stress response (ISR) by stabilization of the heme-regulated inhibitor, a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. These observations uncover a novel ubiquitination cascade that regulates ISR and highlight the potential of ISR activation as a new therapeutic strategy.
We describe the identification of a heretofore unrecognized ubiquitin ligase complex that prevents the aberrant activation of the ISR in a subset of cancer cells. This provides a novel insight on the regulation of ISR and exposes a therapeutic opportunity to selectively eliminate these cancer cells. See related commentary Leli and Koumenis, p. 535. This article is highlighted in the In This Issue feature, p. 517.
There is a continuing drive in microfluidics to transfer microchip systems from the more expensive glass microchips to cheaper polymer microchips. Here, we investigate using polyelectrolyte ...multilayers (PEM) as a coating system for PMMA microchips to improve their functionality. The multilayer system was prepared by layer‐to‐layer deposition of poly(diallyldimethylammonium) chloride and polystyrene sulfonate. Practical aspects of coating PMMA microchips were explored. The multilayer buildup process was monitored using EOF measurements, and the stability of the PEM was investigated. The performance of the PEM‐PMMA microchip was compared with those of a standard glass microchip and a PEM‐glass microchip in terms of EOF and separating two fluorescent dyes. Several key findings in the development of the multilayer coating procedure for PMMA chips are also presented. It was found that, with careful preparation, a PEM‐PMMA microchip can be prepared that has properties comparable – and in some cases superior – to those of a standard glass microchip.
There is a continuing drive in microfluidics to transfer microchip systems from the more expensive glass microchips to cheaper polymer microchips. Here, we investigate using polyelectrolyte ...multilayers (PEM) as a coating system for poly (methylmethacrylate) (PMMA) microchips to improve their functionality. The multilayer system was prepared by layer-on-layer depositon of poly (diallydimethylammonium) chloride (PDAD) and polystyrene sulfonate (PSS). Practical aspects of coating PMMA microchips were explored. The multilayer buildup process was monitored using EOF measurements, and the stability of the PEM was investigated. The performance of the PEM-PMMA microchip was compared to those of a standard glass microchip and a PEM-glass microchip in terms of electroosmotic flow and separating two fluorescent dyes. Several key findings in the development of the multilayer coating procedure for PMMA chips are also presented. It was found that, with careful preparation, a PEM-PMMA microchip can be prepared that has properties comparable - and in some cases superior - to those of a standard glass microchip.
Abstract Compared to intact limbs, running-specific prostheses have high resonance non-biologic materials and lack active tissues to damp high frequencies. These differences may lead to ground ...reaction forces (GRFs) with high frequency content. If so, ubiquitously applying low-pass filters to prosthetic and intact limb GRFs may attenuate veridical high frequency content and mask important and ecologically valid data from prostheses. To explore differences in frequency content between prosthetic and intact limbs we divided signal power from transtibial unilateral amputees and controls running at 2.5, 3.0, and 3.5 m/s into Low (<10 Hz), High (10-25 Hz), and Non-biologic (>25 Hz) frequency bandwidths. Faster speeds tended to reduce the proportion of signal power in the Low bandwidth while increasing it in the High and Non-biologic bandwidths. Further, prostheses had lower proportions of signal power at the High frequency bandwidth but greater proportions at the Non-biologic bandwidth. To evaluate whether these differences in frequency content interact with filter cut-offs and alter results, we filtered GRFs with cut-offs from 1-100 Hz and calculated vertical impact peak (VIP). Changing cut-off had inconsistent effects on VIP across speeds and limbs: Faster speeds had significantly larger changes in VIP per change in cut-off while, compared to controls, prosthetic limbs had significantly smaller changes in VIP per change in cut-off. These findings reveal differences in GRF frequency content between prosthetic and intact limbs and suggest that a cut-off frequency that is appropriate for one limb or speed may be inappropriate for another.
Abstract Objectives (1) To test the validity of a trifilar pendulum in estimating moments of inertia (MOIs) for running-specific prostheses (RSPs), (2) to measure inertial properties (mass, center of ...mass CM position, and MOIs) for 4 RSPs, (3) to verify the influence of the stiffness on the inertial properties of RSPs, and (4) to develop a predictive equation to estimate RSP CM positions. Design An aluminum block with known MOIs was used for verifying the accuracy of the trifilar pendulum MOI measurements. MOI errors were investigated by systematically misaligning the block and pendulum principal axes across a range of 1 to 10cm. Mass, CM position, and MOI were tested across 4 RSP designs with 3 stiffness categories each. Setting University biomechanics laboratory. Specimens Four different RSP designs and 3 stiffness categories per design were examined. Interventions Not applicable. Main Outcome Measures MOI errors from known values and principal axis misalignments between RSPs and pendulum; mass, CM positions, and RSP principal axis MOIs; and predictive equation CM position errors. Results The trifilar pendulum estimated MOIs within −6.21×10−5 kg/m2 (≤1% error) for a block with known MOIs. Misalignments of 1 to 5cm between the RSPs' and pendulum's CM yielded errors from .00002 to .00113 kg/m2 (0.3%−59.2%). Each RSP's inertial properties are presented. MOIs about any axis varied <.004kg/m2 across stiffness categories; MOIs differed up to .013kg/m2 between different designs. The predictive CM equation erred between .010 and .028m when using average input values across an RSP design. Conclusions Trifilar pendulums can accurately measure RSP MOI. The RSP inertial properties differed slightly across stiffness categories within each design, but differed more substantially across different RSP designs. Using a predictive equation to estimate RSP CM positions can provide adequate data, but directly measuring CM positions is preferable.
Rhinovirus (RV) is a common cause of respiratory illness in all people, including those experiencing homelessness. RV epidemiology in homeless shelters is unknown.
We analyzed data from a ...cross-sectional homeless shelter study in King County, Washington, October 2019-May 2021. Shelter residents or guardians aged ≥3 months reporting acute respiratory illness completed questionnaires and submitted nasal swabs. After 1 April 2020, enrollment expanded to residents and staff regardless of symptoms. Samples were tested by multiplex RT-PCR for respiratory viruses. A subset of RV-positive samples was sequenced.
There were 1066 RV-positive samples with RV present every month of the study period. RV was the most common virus before and during the coronavirus disease 2019 (COVID-19) pandemic (43% and 77% of virus-positive samples, respectively). Participants from family shelters had the highest prevalence of RV. Among 131 sequenced samples, 33 RV serotypes were identified with each serotype detected for ≤4 months.
RV infections persisted through community mitigation measures and were most prevalent in shelters housing families. Sequencing showed a diversity of circulating RV serotypes, each detected over short periods of time. Community-based surveillance in congregate settings is important to characterize respiratory viral infections during and after the COVID-19 pandemic.
NCT04141917.
Emphysema is an important feature of chronic obstructive pulmonary disease (COPD). Genetic factors likely affect emphysema pathogenesis, but this question has predominantly been studied in those of ...European ancestry. In this study, we sought to determine genetic components of emphysema severity and characterize the potential function of the associated loci in Korean population. We performed a genome-wide association study (GWAS) on quantitative emphysema in subjects with or without COPD from two Korean COPD cohorts. We investigated the functional consequences of the loci using epigenetic annotation and gene expression data. We also compared our GWAS results with an epigenome-wide association study and previous differential gene expression analysis. In total, 548 subjects (476 86.9% male) including 514 COPD patients were evaluated. We identified one genome-wide significant SNP (P < 5.0 × 10
), rs117084279, near PIBF1. We identified an additional 57 SNPs (P < 5.0 × 10
) associated with emphysema in all subjects, and 106 SNPs (P < 5.0 × 10
) in COPD patients. Of these candidate SNPs, 2 (rs12459249, rs11667314) near CYP2A6 were expression quantitative trait loci in lung tissue and a SNP (rs11214944) near NNMT was an expression quantitative trait locus in whole blood. Of note, rs11214944 was in linkage disequilibrium with variants in enhancer histone marks in lung tissue. Several genes near additional SNPs were identified in our previous EWAS study with nominal level of significance. We identified a novel SNP associated with quantitative emphysema on CT. Including the novel SNP, several candidate SNPs in our study may provide clues to the genetic etiology of emphysema in Asian populations. Further research and validation of the loci will help determine the genetic factors for the development of emphysema.
Highlights • Vertical loading rates using running-specific prostheses were examined. • Eight amputee runners performed overground running at a range of running speeds. • Loading rates in intact limbs ...were greater than prosthetic limbs and control subjects. • Amputee runners may be exposed to a greater risk of injury than able-bodied runners.
To determine the epidemiology of human parainfluenza virus in homeless shelters during the COVID-19 pandemic, we analyzed data and sequences from respiratory specimens collected in 23 shelters in ...Washington, USA, during 2019-2021. Two clusters in children were genetically similar by shelter of origin. Shelter-specific interventions are needed to reduce these infections.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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