Messenger RNA encodes cellular function and phenotype. In the context of human cancer, it defines the identities of malignant cells and the diversity of tumor tissue. We studied 72,501 single-cell ...transcriptomes of human renal tumors and normal tissue from fetal, pediatric, and adult kidneys. We matched childhood Wilms tumor with specific fetal cell types, thus providing evidence for the hypothesis that Wilms tumor cells are aberrant fetal cells. In adult renal cell carcinoma, we identified a canonical cancer transcriptome that matched a little-known subtype of proximal convoluted tubular cell. Analyses of the tumor composition defined cancer-associated normal cells and delineated a complex vascular endothelial growth factor (VEGF) signaling circuit. Our findings reveal the precise cellular identities and compositions of human kidney tumors.
A bout of resistance exercise did not elicit the same T-cell responses as a bout of walking on a treadmill, and the response was also not the same for people who participate in regular exercise ...compared with those who do not. Although there were several similarities, these potential differences underscore the importance of careful selection of exercise protocol based on the population studied and the desired T-cell response to exercise outcome.
T cells often undergo age-related changes, which may be offset by regular exercise training. However, the majority of literature is derived from cardiorespiratory exercise studies. The purpose of this study was to examine the effects of acute cardiorespiratory exercise and acute resistance exercise on the T-cell response among physically active (PA) older adults compared with physically inactive (PI) older adults. Twenty-four healthy older adults PA n = 12; PI n = 12; means ± SD; age (years) PA 62 ± 5, PI 64 ± 5; body mass index (BMI; kg/m
2
) PA 23.9 ± 3.0, PI 25.6 ± 3.5 completed one bout each of matched intensity cardiorespiratory exercise and resistance exercise in a randomized order. Blood samples drawn preexercise, postexercise, and 1 h postexercise (recovery) were analyzed by flow cytometry for T cells and T-cell subsets. Resistance exercise mobilized more T-cell subsets in PI (10 of the measured types, including total T cells; CD45RA
+
CD62L
+
, CD45RA
−
CD62L
+
, CD45RA
−
CD62L
−
, and CD45RA
+
CD62L
−
T cells), whereas cardiorespiratory exercise mobilized more subsets in PA (CD45RA
+
CD62L
−
and CD57
+
CD45RA
+
CD62L
−
CD4
+
T cells). Both cardiorespiratory exercise and resistance exercise elicited a significant ( P < 0.05) mobilization of highly differentiated (CD45RA
+
CD62L
−
; CD57
+
CD45RA
+
CD62L
−
) CD8
+
T cells into the circulation postexercise in both PA and PI groups. Furthermore, cardiorespiratory exercise resulted in a decrease in the number of circulating Th17 cells postexercise, whereas resistance exercise increased Th17 cell mobilization compared with the cardiorespiratory exercise response. There are differences between cardiorespiratory exercise and resistance exercise on the immune responses of T cells, particularly in PI individuals. This research study was registered at clinicaltrials.gov NCT03794050.
NEW & NOTEWORTHY A bout of resistance exercise did not elicit the same T-cell responses as a bout of walking on a treadmill, and the response was also not the same for people who participate in regular exercise compared with those who do not. Although there were several similarities, these potential differences underscore the importance of careful selection of exercise protocol based on the population studied and the desired T-cell response to exercise outcome.
We present the first frequency-dependent analyses of the geographic smoothing of wind power’s variability, analyzing the interconnected measured output of 20 wind plants in Texas. Reductions in ...variability occur at frequencies corresponding to times shorter than ∼24
h and are quantified by measuring the departure from a Kolmogorov spectrum. At a frequency of 2.8×10
−4
Hz (corresponding to 1
h), an 87% reduction of the variability of a single wind plant is obtained by interconnecting 4 wind plants. Interconnecting the remaining 16 wind plants produces only an additional 8% reduction. We use step change analyses and correlation coefficients to compare our results with previous studies, finding that wind power ramps up faster than it ramps down for each of the step change intervals analyzed and that correlation between the power output of wind plants 200
km away is half that of co-located wind plants. To examine variability at very low frequencies, we estimate yearly wind energy production in the Great Plains region of the United States from automated wind observations at airports covering 36 years. The estimated wind power has significant inter-annual variability and the severity of wind drought years is estimated to be about half that observed nationally for hydroelectric power.
Immune dysregulation associated with mercury has been suggested, although data in the general population are lacking. Chronic exposure to low levels of methylmercury (organic) and inorganic mercury ...is common, such as through fish consumption and dental amalgams.
We examined associations between mercury biomarkers and antinuclear antibody (ANA) positivity and titer strength.
Among females 16-49 years of age (n = 1,352) from the National Health and Nutrition Examination Survey (NHANES) 1999-2004, we examined cross-sectional associations between mercury and ANAs (indirect immunofluorescence; cutoff ≥ 1:80). Three biomarkers of mercury exposure were used: hair (available 1999-2000) and total blood (1999-2004) predominantly represented methylmercury, and urine (1999-2002) represented inorganic mercury. Survey statistics were used. Multivariable modeling adjusted for several covariates, including age and omega-3 fatty acids.
Sixteen percent of females were ANA positive; 96% of ANA positives had a nuclear speckled staining pattern. Geometric mean (geometric SD) mercury concentrations were 0.22 (0.03) ppm in hair, 0.92 (0.05) μg/L blood, and 0.62 (0.04) μg/L urine. Hair and blood, but not urinary, mercury were associated with ANA positivity (sample sizes 452, 1,352, and 804, respectively), after adjusting for confounders: for hair, odds ratio (OR) = 4.10 (95% CI: 1.66, 10.13); for blood, OR = 2.32 (95% CI: 1.07, 5.03) comparing highest versus lowest quantiles. Magnitudes of association were strongest for high-titer (≥ 1:1,280) ANA: hair, OR = 11.41 (95% CI: 1.60, 81.23); blood, OR = 5.93 (95% CI: 1.57, 22.47).
Methylmercury, at low levels generally considered safe, was associated with subclinical autoimmunity among reproductive-age females. Autoantibodies may predate clinical disease by years; thus, methylmercury exposure may be relevant to future autoimmune disease risk.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Cycling induced by functional electrical stimulation (FES) coupled with motorized assistance is a promising rehabilitative strategy. A switching controller that activates lower limb muscles alongside ...an electric motor based on the crank angle is developed to facilitate cycling. Due to the periodic nature of cadence tracking in cycling, a repetitive learning controller (RLC) is developed to track a desired cadence trajectory with a known period. The RLC is developed for an uncertain, nonlinear cycle-rider system with autonomous state-dependent switching. Electrical stimulation switches across multiple lower limb muscle groups based on the torque effectiveness throughout the crank cycle. The electric motor provides assistance when the muscle groups yield low torque production. A Lyapunov-based stability analysis that invokes a recently developed LaSalle-Yoshizawa corollary for nonsmooth systems is used to guarantee asymptotic tracking. The developed controller was tested during FES-cycling experiments in five able-bodied individuals and three participants with neurological conditions. The added value of the RLC in cadence tracking is illustrated by comparing the results of two trials with and without the learning feedforward term. The results indicate that the RLC yields a lower mean root-mean-squared cadence tracking error.
Background:
Knee laxity in the setting of anterior cruciate ligament (ACL) injury is often assessed through physical examination using the Lachman, pivot shift, and anterior drawer tests. The degree ...of laxity noted on these examinations may influence treatment decisions and prognosis.
Hypothesis:
Increased preoperative knee laxity is associated with increased risk of revision ACL reconstruction, increased risk of contralateral ACL reconstruction, and poorer patient-reported outcomes at 6 years postoperatively.
Study Design:
Cohort study; Level of evidence, 2.
Methods:
2333 patients who underwent primary isolated ACL reconstruction without additional ligament injury were identified. Patients reported by the operating surgeons to have an International Knee Documentation Committee (IKDC) grade D Lachman, anterior drawer, or pivot shift examination were classified as having a high-grade laxity. Multiple logistic regression models were used to evaluate whether having high-grade preoperative laxity was predictive of increased odds of undergoing subsequent revision or contralateral ACL reconstruction within 6 years of the index procedure, controlling for patient age, sex, body mass index, Marx activity level, sport, graft type, medial meniscal treatment, and lateral meniscal treatment. Multiple linear regression modeling was used to evaluate whether having high-grade preoperative laxity was predictive of poorer IKDC or Knee injury and Osteoarthritis Outcome Score Knee-Related Quality of Life (KOOS-QOL) scores at 6 years postoperatively, after controlling for baseline score, patient age, ethnicity, sex, body mass index, marital status, smoking status, sport participation, competition level, Marx activity rating score, graft type, and articular cartilage and meniscal status.
Results:
In total, 743 of 2325 patients (32.0%) were noted to have high-grade laxity on at least 1 physical examination test. High-grade Lachman was noted in 334 patients (14.4%), high-grade pivot shift was noted in 617 patients (26.5%), and high-grade anterior drawer was noted in 233 patients (10.0%). Six-year revision and contralateral ACL reconstruction data were available for 2129 patients (91.6%). High-grade prereconstruction Lachman was associated with significantly increased odds of ACL graft revision (odds ratio OR, 1.76; 95% CI, 1.10-2.80, P = .02) and contralateral ACL reconstruction (OR, 1.68; 95% CI, 1.09-2.69; P = .019). High-grade prereconstruction pivot shift was associated with significantly increased odds of ACL graft revision (OR, 1.75; 95% CI, 1.19-2.54, P = .002) but not with significantly increased odds of contralateral ACL reconstruction (OR, 1.30; 95% CI, 0.89-1.87; P = .16). High-grade prereconstruction laxity was associated with statistically significantly lower 6-year IKDC (β = −2.26, P = .003), KOOS-QOL (β = −2.67, P = .015), and Marx activity scores (β = −0.54, P = .020), but these differences did not approach clinically relevant differences in patient-reported outcomes.
Conclusion:
High-grade preoperative knee laxity is predictive of increased odds of revision ACL reconstruction and contralateral ACL reconstruction 6 years after ACL reconstruction. Poorer patient-reported outcome scores in the high-grade laxity group were also noted, but the difference did not reach a level of clinical relevance.
The story of hyaluronan in articular cartilage, pericellular hyaluronan in particular, essentially is also the story of aggrecan. Without properly tethered aggrecan, the load bearing function of ...cartilage is compromised. The anchorage of aggrecan to the cell surface only occurs due to the binding of aggrecan to hyaluronan—with hyaluronan tethered either to a hyaluronan synthase or by multivalent binding to CD44. In this review, details of hyaluronan synthesis are discussed including how HAS2 production of hyaluronan is necessary for normal chondrocyte development and matrix assembly, how an abundance or deficit of pericellular hyaluronan alters chondrocyte metabolism, and whether hyaluronan size matters or changes with aging or disease. The biomechanical role and matrix assembly function of hyaluronan in addition to the functions of hyaluronidases are discussed. The turnover of hyaluronan is considered including mechanisms by which its turnover, at least in part, is mediated by endocytosis by chondrocytes and regulated by aggrecan degradation. Differences between turnover and clearance of newly synthesized hyaluronan and aggrecan versus the half-life of hyaluronan remaining within the inter-territorial matrix of cartilage are discussed. The release of neutral pH-acting hyaluronidase activity remains one unanswered question concerning the loss of cartilage hyaluronan in osteoarthritis. Signaling events driven by changes in hyaluronan-chondrocyte interactions may involve a chaperone function of CD44 with other receptors/cofactors as well as the changes in hyaluronan production functioning as a metabolic rheostat.
•Hyaluronan is synthesized in cartilage by hyaluronan synthase-2 (HAS2).•Hyaluronan and aggrecan contribute to cell-cell spacing in cartilage.•Hyaluronan functions to anchor aggrecan to the surface of chondrocytes.•Hyaluronan turnover involves chondrocyte-mediated endocytosis.•Turnover of hyaluronan may differ in the pericellular and inter-territorial matrices and during disease or steady state.
The extravillous trophoblast cell lineage is a key feature of placentation and successful pregnancy. Knowledge of transcriptional regulation driving extravillous trophoblast cell development is ...limited. Here, we map the transcriptome and epigenome landscape as well as chromatin interactions of human trophoblast stem cells and their transition into extravillous trophoblast cells. We show that integrating chromatin accessibility, long-range chromatin interactions, transcriptomic, and transcription factor binding motif enrichment enables identification of transcription factors and regulatory mechanisms critical for extravillous trophoblast cell development. We elucidate functional roles for TFAP2C, SNAI1, and EPAS1 in the regulation of extravillous trophoblast cell development. EPAS1 is identified as an upstream regulator of key extravillous trophoblast cell transcription factors, including ASCL2 and SNAI1 and together with its target genes, is linked to pregnancy loss and birth weight. Collectively, we reveal activation of a dynamic regulatory network and provide a framework for understanding extravillous trophoblast cell specification in trophoblast cell lineage development and human placentation.
Historically marginalized populations bear a disparate burden of preventable diseases.1,2 Health outcomes result from the interaction of multiple domains over an individual's life course (i.e., ...sociocultural environment, health care and government systems, built environment) and at multiple levels of influence (e.g., individual, interpersonal, community). Where we are born, live, work, and play are directly related to our health, risk, safety, prosperity, and life expectancy. Differences in these drivers of health lead to unequal access to community-based programs, directly contributing to health disparities.The Rapid Acceleration of Diagnostics Underserved Populations (RADx-UP) program is a consortium of research projects throughout the United States funded by the National Institutes of Health. RADx-UP seeks to measure and understand factors that have led to the disproportionate burden of the COVID-19 pandemic on historically marginalized and vulnerable populations so that interventions can be designed and implemented to reduce health disparities. As part of this program, RADx-UP built a data dashboard to support research dissemination. Generally, public health dashboards are data display platforms used for health surveillance and data reporting. As noted by Dasgupta and Kapadia,3 data dashboard priorities and dissemination products are typically decided by individuals and organizations that are external to the communities that the data represent. However, the wisdom and expertise of community organizations, community members, and stakeholders are needed to fully address health inequalities and improve population health. Community partners bring deep knowledge of the lived experiences, values, and historical legacies of their communities.Building alliances between community partners and academic researchers can enable local communities to use and adapt data, knowledge, tools, and expertise in the design, implementation, evaluation, and dissemination of public health interventions. Furthermore, this collaboration fosters healthy communities that can close health equity gaps caused by education level, immigration status, language, income, place, race/ethnicity, gender identity, or sexual orientation inequalities. Incorporating community partners' lived experience through community-academic partnership is necessary to address health disparities.Data dashboards serve as vital visualization tools supporting community partner engagement in research and dissemination. Dashboards enable community partners to explore results, postulate new questions, and disseminate findings based on data visualization capabilities. Providing community members access to intuitive, welldescribed, accurate, and informative data visualization contributes to true bidirectional communication. Community partners must be central participants in research dissemination, given longstanding barriers to information access; lack of access contributes to mistrust and the spread of misinformation and impedes cultural competence.4 We describe the components of the RADx-UP Data Dashboard, the infrastructures established to support community partner dashboard use, and challenges and recommended steps for enabling data dashboards to bridge the information gap between researchers and communities.
Summary Objective To test whether a brief mindfulness meditation training intervention buffers self-reported psychological and neuroendocrine responses to the Trier Social Stress Test (TSST) in young ...adult volunteers. A second objective evaluates whether pre-existing levels of dispositional mindfulness moderate the effects of brief mindfulness meditation training on stress reactivity. Methods Sixty-six ( N = 66) participants were randomly assigned to either a brief 3-day (25-min per day) mindfulness meditation training or an analytic cognitive training control program. All participants completed a standardized laboratory social-evaluative stress challenge task (the TSST) following the third mindfulness meditation or cognitive training session. Measures of psychological (stress perceptions) and biological (salivary cortisol, blood pressure) stress reactivity were collected during the social evaluative stress-challenge session. Results Brief mindfulness meditation training reduced self-reported psychological stress reactivity but increased salivary cortisol reactivity to the TSST, relative to the cognitive training comparison program. Participants who were low in pre-existing levels of dispositional mindfulness and then received mindfulness meditation training had the greatest cortisol reactivity to the TSST. No significant main or interactive effects were observed for systolic or diastolic blood pressure reactivity to the TSST. Conclusions The present study provides an initial indication that brief mindfulness meditation training buffers self-reported psychological stress reactivity, but also increases cortisol reactivity to social evaluative stress. This pattern may indicate that initially brief mindfulness meditation training fosters greater active coping efforts, resulting in reduced psychological stress appraisals and greater cortisol reactivity during social evaluative stressors.
PDF
