Age-Dependent Decline in Mouse Lung Regeneration with Loss of Lung Fibroblast Clonogenicity and Increased Myofibroblastic Differentiation

While aging leads to a reduction in the capacity for regeneration after pneumonectomy (PNX) in most mammals, this biological phenomenon has not been characterized over the lifetime of mice. We measured the age-specific (3, 9, 24 month) effects of PNX on physiology, morphometry, cell proliferation and apoptosis, global gene expression, and lung fibroblast phenotype and clonogenicity in female C57BL6 mice. The data show that only 3 month old mice were fully capable of restoring lung volumes by day 7 and total alveolar surface area by 21 days. By 9 months, the rate of regeneration was slower (with incomplete regeneration by 21 days), and by 24 months there was no regrowth 21 days post-PNX. The early decline in regeneration rate was not associated with changes in alveolar epithelial cell type II (AECII) proliferation or apoptosis rate. However, significant apoptosis and lack of cell proliferation was evident after PNX in both total cells and AECII cells in 24 mo mice. Analysis of gene expression at several time points (1, 3 and 7 days) post-PNX in 9 versus 3 month mice was consistent with a myofibroblast signature (increased Tnc, Lox1, Col3A1, Eln and Tnfrsf12a) and more alpha smooth muscle actin (αSMA) positive myofibroblasts were present after PNX in 9 month than 3 month mice. Isolated lung fibroblasts showed a significant age-dependent loss of clonogenicity. Moreover, lung fibroblasts isolated from 9 and 17 month mice exhibited higher αSMA, Col3A1, Fn1 and S100A expression, and lower expression of the survival gene Mdk consistent with terminal differentiation. These data show that concomitant loss of clonogenicity and progressive myofibroblastic differentiation contributes to the age-dependent decline in the rate of lung regeneration

Efficacy and Safety of Viltolarsen in Boys With Duchenne Muscular Dystrophy: Results From the Phase 2, Open-Label, 4-Year Extension Study

Background: Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations, resulting in absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, significantly increased dystrophin levels in patients with DMD. Presented here are completed study results of \u3e 4 years of functional outcomes in viltolarsen-treated patients compared to a historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study [CINRG DNHS]). Objective: To evaluate the efficacy and safety of viltolarsen for an additional 192 weeks in boys with DMD. Methods: This phase 2, open-label, 192-week long-term extension (LTE) study (NCT03167255) evaluated the efficacy and safety of viltolarsen in participants aged 4 to \u3c 10 years at baseline with DMD amenable to exon 53 skipping. All 16 participants from the initial 24-week study enrolled into this LTE. Timed function tests were compared to the CINRG DNHS group. All participants received glucocorticoid treatment. The primary efficacy outcome was time to stand from supine (TTSTAND). Secondary efficacy outcomes included additional timed function tests. Safety was continuously assessed. Results: For the primary efficacy outcome (TTSTAND), viltolarsen-treated patients showed stabilization of motor function over the first two years and significant slowing of disease progression over the following two years compared with the CINRG DNHS control group which declined. Viltolarsen was well tolerated, with most reported treatment-emergent adverse events being mild or moderate. No participants discontinued drug during the study. Conclusions: Based on the results of this 4-year LTE, viltolarsen can be an important treatment strategy for DMD patients amenable to exon 53 skipping

Excess Post-Exercise Oxygen Consumption (Epoc) Following Multiple Effort Sprint and Moderate Aerobic Exercise

The purpose of this study was to investigate the effects of 30-second all-out sprint interval exercise (SIE) vs. moderate aerobic exercise (MA) on excess post-exercise oxygen consumption (EPOC). Six recreationally-trained males (age=23.3 +/- 1.4 yrs, weight=81.8 +/- 9.9 kg, height=180.8 +/- 6.3 cm) completed a sprint interval exercise session consisting of three repeated 30-second Wingate cycling tests separated by four minutes (duration similar to 11minutes) as well as a moderate aerobic exercise session consisting of 30-minute cycling at 60% heart rate reserve (HRR) in a random counterbalanced design. Baseline oxygen consumption (VO2) was determined by an average VO2 from the final five minutes of a 30-minute supine rest period prior to each trial. Following each protocol, VO2 was measured for 30 minutes or until baseline measures were reached. EPOC was determined by subtracting baseline VO2 from post-exercise VO2 measurements. Energy expenditure (kJ) was determined by multiplying kJ per liter of oxygen by the average VO2 during recovery. EPOC values were significantly higher in SIE (7.5 +/- 1.3 L) than MA (1.8 +/- 0.7 L). SIE produced a higher recovery caloric expenditure (156.9 kJ) compared to MA (41.0 kJ) and remained significantly elevated (p=.024) over resting levels during the entire recovery period (30 minutes) compared to MA (6 minutes, p=.003). The energy required to recover from three repeated maximal effort 30-second Wingate cycling tests was greater than 30 minutes of moderate aerobic exercise. Future studies should examine the chronic effects of maximal effort sprint training protocol on cardiovascular fitness and body composition

Orbitally forced ice sheet fluctuations during the Marinoan Snowball Earth glaciation

Two global glaciations occurred during the Neoproterozoic. Snowball Earth theory posits that these were terminated after millions of years of frigidity when initial warming from rising atmospheric CO2 concentrations was amplified by the reduction of ice cover and hence a reduction in planetary albedo. This scenario implies that most of the geological record of ice cover was deposited in a brief period of melt-back. However, deposits in low palaeo-latitudes show evidence of glacial–interglacial cycles. Here we analyse the sedimentology and oxygen and sulphur isotopic signatures of Marinoan Snowball glaciation deposits from Svalbard, in the Norwegian High Arctic. The deposits preserve a record of oscillations in glacier extent and hydrologic conditions under uniformly high atmospheric CO2 concentrations. We use simulations from a coupled three-dimensional ice sheet and atmospheric general circulation model to show that such oscillations can be explained by orbital forcing in the late stages of a Snowball glaciation. The simulations suggest that while atmospheric CO2 concentrations were rising, but not yet at the threshold required for complete melt-back, the ice sheets would have been sensitive to orbital forcing. We conclude that a similar dynamic can potentially explain the complex successions observed at other localities

Vaccine effectiveness against COVID-19 among symptomatic persons aged ≥12 years with reported contact with COVID-19 cases, February-September 2021

BACKGROUND: Individuals in contact with persons with COVID-19 are at high risk of developing COVID-19; protection offered by COVID-19 vaccines in the context of known exposure is poorly understood. METHODS: Symptomatic outpatients aged ≥12 years reporting acute onset of COVID-19-like illness and tested for SARS-CoV-2 between February 1 and September 30, 2021 were enrolled. Participants were stratified by self-report of having known contact with a COVID-19 case in the 14 days prior to illness onset. Vaccine effectiveness was evaluated using the test-negative study design and multivariable logistic regression. RESULTS: Among 2229 participants, 283/451 (63%) of those reporting contact and 331/1778 (19%) without known contact tested SARS-CoV-2-positive. Adjusted vaccine effectiveness was 71% (95% confidence interval [CI], 49%-83%) among fully vaccinated participants reporting a known contact versus 80% (95% CI, 72%-86%) among those with no known contact (p-value for interaction = 0.2). CONCLUSIONS: This study contributes to growing evidence of the benefits of vaccinations in preventing COVID-19 and support vaccination recommendations and the importance of efforts to increase vaccination coverage

Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy.

Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases

Different paths to the modern state in Europe: the interaction between domestic political economy and interstate competition

Theoretical work on state formation and capacity has focused mostly on early modern Europe and on the experience of western European states during this period. While a number of European states monopolized domestic tax collection and achieved gains in state capacity during the early modern era, for others revenues stagnated or even declined, and these variations motivated alternative hypotheses for determinants of fiscal and state capacity. In this study we test the basic hypotheses in the existing literature making use of the large date set we have compiled for all of the leading states across the continent. We find strong empirical support for two prevailing threads in the literature, arguing respectively that interstate wars and changes in economic structure towards an urbanized economy had positive fiscal impact. Regarding the main point of contention in the theoretical literature, whether it was representative or authoritarian political regimes that facilitated the gains in fiscal capacity, we do not find conclusive evidence that one performed better than the other. Instead, the empirical evidence we have gathered lends supports to the hypothesis that when under pressure of war, the fiscal performance of representative regimes was better in the more urbanized-commercial economies and the fiscal performance of authoritarian regimes was better in rural-agrarian economie

Collective cancer invasion forms an integrin-dependent radioresistant niche

Contains fulltext : 219833.pdf (Publisher’s version ) (Open Access)Cancer fatalities result from metastatic dissemination and therapy resistance, both processes that depend on signals from the tumor microenvironment. To identify how invasion and resistance programs cooperate, we used intravital microscopy of orthotopic sarcoma and melanoma xenografts. We demonstrate that these tumors invade collectively and that, specifically, cells within the invasion zone acquire increased resistance to radiotherapy, rapidly normalize DNA damage, and preferentially survive. Using a candidate-based approach to identify effectors of invasion-associated resistance, we targeted beta1 and alphaVbeta3/beta5 integrins, essential extracellular matrix receptors in mesenchymal tumors, which mediate cancer progression and resistance. Combining radiotherapy with beta1 or alphaV integrin monotargeting in invading tumors led to relapse and metastasis in 40-60% of the cohort, in line with recently failed clinical trials individually targeting integrins. However, when combined, anti-beta1/alphaV integrin dual targeting achieved relapse-free radiosensitization and prevented metastatic escape. Collectively, invading cancer cells thus withstand radiotherapy and DNA damage by beta1/alphaVbeta3/beta5 integrin cross-talk, but efficient radiosensitization can be achieved by multiple integrin targeting

Collective cancer invasion forms an integrin-dependent radioresistant niche

Cancer fatalities result from metastatic dissemination and therapy resistance, both processes that depend on signals from the tumor microenvironment. To identify how invasion and resistance programs cooperate, we used intravital microscopy of orthotopic sarcoma and melanoma xenografts. We demonstrate that these tumors invade collectively and that, specifically, cells within the invasion zone acquire increased resistance to radiotherapy, rapidly normalize DNA damage, and preferentially survive. Using a candidate-based approach to identify effectors of invasion-associated resistance, we targeted beta 1 and alpha V beta 3/beta 5 integrins, essential extracellular matrix receptors in mesenchymal tumors, which mediate cancer progression and resistance. Combining radiotherapy with beta 1 or alpha V integrin monotargeting in invading tumors led to relapse and metastasis in 40-60% of the cohort, in line with recently failed clinical trials individually targeting integrins. However, when combined, anti-beta 1/alpha V integrin dual targeting achieved relapse-free radiosensitization and prevented metastatic escape. Collectively, invading cancer cells thus withstand radiotherapy and DNA damage by beta 1/alpha V beta 3/beta 5 integrin cross-talk, but efficient radiosensitization can be achieved by multiple integrin targeting

Reliability of the Woodway Curve (TM) Non-Motorized Treadmill for Assessing Anaerobic Performance

A curved treadmill offers a practical method of assessing anaerobic power by enabling unrestricted running motion and greater sport specificity. The purpose of this research was to determine reliability of a curved treadmill (cTM) sprint test and to compare performance measures to the traditional Wingate anaerobic power test (WAnT) performed on a cycle ergometer. Thirty-two recreationally active men and women (22.4 +/- 2.8 yrs; 1.73 +/- 0.08 m; 74.2 +/- 13.2 kg) performed four familiarization trials on cTM, followed by two randomly assigned experimental trials consisting of one 30-second maximum effort on either cTM or WAnT. Each trial was separated by at least 48 hours. Repeated measures analysis of variance (ANOVA), interclass correlations (ICC), standard error of measurement (SEM), and minimal differences (MD) were used to determine reliability of familiarization trials on cTM, and Pearson product moment correlations were calculated to compare cTM and WAnT. ANOVA results showed significant differences (p \u3c 0.05) during the four familiarization trials. Post hoc analysis showed significant differences (p \u3c 0.05) between the first two trials. Familiarization trials 3 and 4 showed a high reliability for each performance variable (distance: ICC2,1 = 0.969, %SEM = 2.645, p = 0.157; mean velocity: ICC2,1 = 0.969, %SEM = 2.622, p = 0.173; peak velocity: ICC2,1 = 0.966, %SEM = 3.142, p = 0.033; mean power: ICC2,1 = 0.940, %SEM = 4.140, p = 0.093; and peak power: ICC2,1 = 0.887, %SEM = 11.244, p = 0.669). Participants elicited an average peak power of 1050.4 +/- 338.5 Watts on cTM and 1031.4 +/- 349.8 Watts on WAnT. Pearson product moment coefficients indicated high correlations between peak power, mean power, and peak velocity (r = 0.75, p \u3c 0.001; r = 0.84, p \u3c 0.001; and r = 0.76, p \u3c 0.001, respectively) derived from cTM and WAnT. In conclusion, results suggest that after two familiarization trials, cTM is a reliable sprint test for recreationally active men and women. In addition, there are strong relationships between cTM and WAnT in assessing anaerobic performance