It is expected that serum protein biomarkers in Duchenne muscular dystrophy (DMD) will reflect disease pathogenesis, progression and aid future therapy developments. Here, we describe use of ...quantitative in vivo stable isotope labeling in mammals to accurately compare serum proteomes of wild-type and dystrophin-deficient mdx mice. Biomarkers identified in serum from two independent dystrophin-deficient mouse models (mdx-Δ52 and mdx-23) were concordant with those identified in sera samples of DMD patients. Of the 355 mouse sera proteins, 23 were significantly elevated and 4 significantly lower in mdx relative to wild-type mice (P-value < 0.001). Elevated proteins were mostly of muscle origin: including myofibrillar proteins (titin, myosin light chain 1/3, myomesin 3 and filamin-C), glycolytic enzymes (aldolase, phosphoglycerate mutase 2, beta enolase and glycogen phosphorylase), transport proteins (fatty acid-binding protein, myoglobin and somatic cytochrome-C) and others (creatine kinase M, malate dehydrogenase cytosolic, fibrinogen and parvalbumin). Decreased proteins, mostly of extracellular origin, included adiponectin, lumican, plasminogen and leukemia inhibitory factor receptor. Analysis of sera from 1 week to 7 months old mdx mice revealed age-dependent changes in the level of these biomarkers with most biomarkers acutely elevated at 3 weeks of age. Serum analysis of DMD patients, with ages ranging from 4 to 15 years old, confirmed elevation of 20 of the murine biomarkers in DMD, with similar age-related changes. This study provides a panel of biomarkers that reflect muscle activity and pathogenesis and should prove valuable tool to complement natural history studies and to monitor treatment efficacy in future clinical trials.
Duchenne muscular dystrophy (DMD) is a fatal X-linked degenerative muscle disease caused by the absence of the microtubule-associated protein dystrophin, which results in a disorganized and denser ...microtubule cytoskeleton. In addition, mechanotransduction-dependent activation of calcium (Ca(2+)) and reactive oxygen species (ROS) signaling underpins muscle degeneration in DMD. We show that in muscle from adult mdx mice, a model of DMD, a brief physiologic stretch elicited microtubule-dependent activation of NADPH (reduced-form nicotinamide adenine dinucleotide phosphate) oxidase-dependent production of ROS, termed X-ROS. Further, X-ROS amplified Ca(2+) influx through stretch-activated channels in mdx muscle. Consistent with the importance of the microtubules to the dysfunction in mdx muscle, muscle cells with dense microtubule structure, such as those from adult mdx mice or from young wild-type mice treated with Taxol, showed increased X-ROS production and Ca(2+) influx, whereas cells with a less dense microtubule network, such as young mdx or adult mdx muscle treated with colchicine or nocodazole, showed little ROS production or Ca(2+) influx. In vivo treatments that disrupted the microtubule network or inhibited NADPH oxidase 2 reduced contraction-induced injury in adult mdx mice. Furthermore, transcriptome analysis identified increased expression of X-ROS-related genes in human DMD skeletal muscle. Together, these data show that microtubules are the proximate element responsible for the dysfunction in Ca(2+) and ROS signaling in DMD and could be effective therapeutic targets for intervention.
A Neoproterozoic Snowball Earth Hoffman, Paul F.; Kaufman, Alan J.; Halverson, Galen P. ...
Science (American Association for the Advancement of Science),
08/1998, Letnik:
281, Številka:
5381
Journal Article
Recenzirano
Negative carbon isotope anomalies in carbonate rocks bracketing Neoproterozoic glacial deposits in Namibia, combined with estimates of thermal subsidence history, suggest that biological productivity ...in the surface ocean collapsed for millions of years. This collapse can be explained by a global glaciation (that is, a snowball Earth), which ended abruptly when subaerial volcanic outgassing raised atmospheric carbon dioxide to about 350 times the modern level. The rapid termination would have resulted in a warming of the snowball Earth to extreme greenhouse conditions. The transfer of atmospheric carbon dioxide to the ocean would result in the rapid precipitation of calcium carbonate in warm surface waters, producing the cap carbonate rocks observed globally.
This study presents a novel approach for the detection of contrails in satellite imagery using a convolutional neural network (CNN). Contrails are important to monitor because their contribution to ...climate change is uncertain and complex. Contrails are found to have a net warming effect because the clouds prevent terrestrial (longwave) radiation from escaping the atmosphere. Globally, this warming effect is greater than the cooling effect the clouds have in the reduction of solar (shortwave) radiation reaching the surface during the daytime. The detection of contrails in satellite imagery is challenging due to their similarity to natural clouds. In this study, a certain type of CNN, U-Net, is used to perform image segmentation in satellite imagery to detect contrails. U-Net can accurately detect contrails with an overall probability of detection of 0.51, a false alarm ratio of 0.46 and a F1 score of 0.52. These results demonstrate the effectiveness of using a U-Net for the detection of contrails in satellite imagery and could be applied to large-scale monitoring of contrail formation to measure their impact on climate change.
Insulin is primarily considered for its glycemic effects in patients with diabetes. There are, however, non-glycemic adverse effects of insulin that may significantly impact patient health and ...interfere with glycemic control. Insulinogenic edema primarily occurs with rapid improvement in glycemic control either in patients with newly discovered diabetes or in patients with poorly-controlled diabetes. Insulin-induced sympathetic activation, vasodilation, changes in vascular permeability, and most importantly, sodium retention play significant etiologic roles in the development of edema. Clinically, it is usually self-limited, but significant complications can develop. Allergic reactions to all insulin preparations and various compounds used in insulin formulations with a wide range of severity have been reported. Frequently, changing the type of insulin or delivery method is sufficient, but more advanced treatments such as insulin desensitization and anti-IgE antibody treatment may be needed. Lipohypertrophy and lipoatrophy frequently develop with the overuse of injection sites. Lipohypertrophy can affect tissue insulin absorption and glycemic control.
In Radiation Therapy Oncology Group 9704, as previously published, patients with resected pancreatic adenocarcinoma received continuous infusion 5-FU and concurrent radiotherapy (5FU-RT). 5FU-RT ...treatment was preceded and followed by randomly assigned chemotherapy, either 5-FU or gemcitabine. This analysis explored whether failure to adhere to specified RT guidelines influenced survival and/or toxicity.
RT requirements were protocol specified. Adherence was scored as per protocol (PP) or less than per protocol (<PP). Scoring occurred after therapy but before trial analysis and without knowledge of individual patient treatment outcomes. Scoring was done for all tumor locations and for the subset of pancreatic head location.
RT was scored for 416 patients: 216 PP and 200 <PP. For all pancreatic sites (head, body/tail) median survival (MS) for PP vs. <PP was 1.74 vs. 1.46 years (log-rank p = 0.0077). In multivariate analysis, PP vs. <PP score correlated more strongly with MS than assigned treatment arm (p = 0.014, p = NS, respectively); for patients with pancreatic head tumors, both PP score and gemcitabine treatment correlated with improved MS (p = 0.016, p = 0.043, respectively). For all tumor locations, PP score was associated with decreased risk of failure (p = 0.016) and, for gemcitabine patients, a trend toward reduced Grade 4/5 nonhematologic toxicity (p = 0.065).
This is the first Phase III, multicenter, adjuvant protocol for pancreatic adenocarcinoma to evaluate the impact of adherence to specified RT protocol guidelines on protocol outcomes. Failure to adhere to specified RT guidelines was associated with reduced survival and, for patients receiving gemcitabine, trend toward increased nonhematologic toxicity.
Background
Imatinib inhibits the KIT and PDGFR tyrosine kinases, resulting in its notable antitumor activity in gastrointestinal stromal tumor (GIST). We previously reported the early results of a ...multi-institutional prospective trial (RTOG 0132) using neoadjuvant/adjuvant imatinib either in primary resectable GIST or as a planned preoperative cytoreduction agent for metastatic/recurrent GIST.
Methods.
Patients with primary GIST (≥5 cm, group A) or resectable metastatic/recurrent GIST (≥2 cm, group B) received neoadjuvant imatinib (600 mg/day) for approximately 2 months and maintenance postoperative imatinib for 2 years. We have now updated the clinical outcomes including progression-free survival, disease-specific survival, and overall survival at a median follow-up of 5.1 years, and we correlate these end points with duration of imatinib therapy.
Results
Sixty-three patients were originally entered (53 analyzable: 31 in group A and 22 in group B). Estimated 5-year progression-free survival and overall survival were 57% in group A, 30% in group B; and 77% in group A, 68% in group B, respectively. Median time to progression has not been reached for group A and was 4.4 years for group B. In group A, in 7 of 11 patients, disease progressed >2 years from registration; 6 of 7 patients with progression had stopped imatinib before progression. In group B, disease progressed in 10 of 13 patients >2 years from registration; 6 of 10 patients with progressing disease had stopped imatinib before progression. There was no significant increase in toxicity compared with our previous short-term analysis.
Conclusions
This long-term analysis suggests a high percentage of patients experienced disease progression after discontinuation of 2-year maintenance imatinib therapy after surgery. Consideration should be given to studying longer treatment durations in intermediate- to high-risk GIST patients.
Lumen establishment and maintenance are fundamental for tubular organs physiological functions. Most of the studies investigating the mechanisms regulating this process have been carried out in cell ...cultures or in smaller organisms, whereas little has been done in mammalian model systems in vivo. Here we used the salivary glands of live mice to examine the role of the small GTPase Cdc42 in the regulation of the homeostasis of the intercellular canaliculi, a specialized apical domain of the acinar cells, where protein and fluid secretion occur. Depletion of Cdc42 in adult mice induced a significant expansion of the apical canaliculi, whereas depletion at late embryonic stages resulted in a complete inhibition of their post-natal formation. In addition, intravital subcellular microscopy revealed that reduced levels of Cdc42 affected membrane trafficking from and towards the plasma membrane, highlighting a novel role for Cdc42 in membrane remodeling through the negative regulation of selected endocytic pathways. Movie S1 Movie S1 Movie S1. Volume rendering derived from a Z-stack phalloidin-stained acini. Cre-positive cells (green), Cre-negative cells (red), IC (yellow). Movie S2 Movie S2 Movie S2. Left: Time-lapse of 3 kDa Cascade Blue-dextran diffusion into the IC of adeno-Cre transfected Cdc42
visualized ISMic (5 sec/frame). Right: Maximal projection of a Z-stack acquired 180 sec after the injection of the dextran. Cre-positive cells (green), Cre-negative cells (red), Dextran (White). Movie S3 Movie S3 Movie S3. ISMic of representative Cre-positive cells where mGFP-labeled vesicles are tracked as described in Material and Methods. Arrows highlight the trajectories of selected vesicles. Basal membrane (BM), apical Plasma Membrane APM (II), lateral membrane (LM). Frame rate 2s per frame. Movie S4 Movie S4 Movie S4. ISMic of regulated exocytosis of secretory granules in mT/mG (Cdc42+) and Cdc42
(Cdc42 -/-) mice transfected with Adeno-Cre. Low magnification (Upper movies) and insets (lower movies) showing the integration of the secretory granules into the APM. Movie S5 Movie S5 Movie S5. Volume rendering derived from a Z-stack of phalloidin-stained acini in SMGs excised at postnatal day 5 (P5, left) and week 28 (Adult, right) from mTmG mouse (Cdc42+) and Cdc42
/AQP5-Cre mice (Cdc42-). Cre-positive cells (green), Cre-negative cells (red), IC (yellow). Movie S6 Movie S6 Movie S6. (related to Fig. S4) -Retrograde delivery of 3 kDa Cascade Blue-Dextran into the IC of Cdc42
/AQP5-Cre mice visualized by ISMic (2 sec/frame).
Sea ice leads, or fractures account for a small proportion of the Arctic Ocean surface area, but play a critical role in the energy and moisture exchanges between the ocean and atmosphere. As the sea ...ice area and volume in the Arctic has declined over the past few decades, changes in sea ice leads have not been studied as extensively. A recently developed approach uses artificial intelligence (AI) and satellite thermal infrared window data to build a twenty-year archive of sea ice lead detects with Moderate Resolution Imaging Spectroradiometer (MODIS) and later, an archive from Visible Infrared Imaging Radiometer Suite (VIIRS). The results are now available and show significant improvement over previously published methods. The AI method results have higher detection rates and a high level detection agreement between MODIS and VIIRS. Analysis over the winter season from 2002–2003 through to the 2021–2022 archive reveals lead detections have a small decreasing trend in lead area that can be attributed to increasing cloud cover in the Arctic. This work reveals that leads are becoming increasingly difficult to detect rather than less likely to occur. Although the trend is small and on the same order of magnitude as the uncertainty, leads are likely increasing at a rate of 3700 km2 per year with a range of uncertainty of 3500 km2 after the impact of cloud cover changes are removed.
The molecular mechanisms underlying the sex differences in human muscle morphology and function remain to be elucidated. The sex differences in the skeletal muscle transcriptome in both the resting ...state and following anabolic stimuli, such as resistance exercise (RE), might provide insight to the contributors of sexual dimorphism of muscle phenotypes. We used microarrays to profile the transcriptome of the biceps brachii of young men and women who underwent an acute unilateral RE session following 12 weeks of progressive training. Bilateral muscle biopsies were obtained either at an early (4 h post-exercise) or late recovery (24 h post-exercise) time point. Muscle transcription profiles were compared in the resting state between men (n = 6) and women (n = 8), and in response to acute RE in trained exercised vs. untrained non-exercised control muscle for each sex and time point separately (4 h post-exercise, n = 3 males, n = 4 females; 24 h post-exercise, n = 3 males, n = 4 females). A logistic regression-based method (LRpath), following Bayesian moderated t-statistic (IMBT), was used to test gene functional groups and biological pathways enriched with differentially expressed genes.
This investigation identified extensive sex differences present in the muscle transcriptome at baseline and following acute RE. In the resting state, female muscle had a greater transcript abundance of genes involved in fatty acid oxidation and gene transcription/translation processes. After strenuous RE at the same relative intensity, the time course of the transcriptional modulation was sex-dependent. Males experienced prolonged changes while females exhibited a rapid restoration. Most of the biological processes involved in the RE-induced transcriptional regulation were observed in both males and females, but sex specificity was suggested for several signaling pathways including activation of notch signaling and TGF-beta signaling in females. Sex differences in skeletal muscle transcriptional regulation might implicate a mechanism behind disproportional muscle growth in males as compared with female counterparts after RE training at the same relative intensity.
Sex differences exist in skeletal muscle gene transcription both at rest and following acute RE, suggesting that sex is a significant modifier of the transcriptional regulation in skeletal muscle. The findings from the present study provide insight into the molecular mechanisms for sex differences in muscle phenotypes and for muscle transcriptional regulation associated with training adaptations to resistance exercise.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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