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Current techniques to assess chimerism after hematopoietic stem cell transplantation (HSCT) are limited in both sensitivity and precision. These drawbacks are problematic in the context of cellular therapies that frequently result in microchimerism (donor chimerism <1%). We have developed a highly sensitive droplet digital PCR (ddPCR) assay using commercially available regents with good performance throughout the range of clinically relevant chimerism measurements, including microchimerism. We tested the assay using spiked samples of known donor-recipient ratios and in clinical samples from HSCT recipients and patients enrolled on clinical trials of microtransplantation and third-party virus-specific T cells (VSTs). The levels of detection and quantification of the assay were .008% and .023%, with high levels of precision with samples of DNA content ranging from 1 to 300 ng DNA. From the panel of 29 insertion-deletion probes multiple informative markers were found for each of 43 HSCT donor-recipient pairs. In the case of third-party cellular therapies in which there were 3 DNA contributors (recipient, HSCT donor, and T-cell donor), a marker to detect the cellular product in a background of recipient and donor cells was available for 11 of 12 cases (92%). Chimerism by ddPCR was able to quantify chimerism in HSCT recipients and comparison against standard STR analysis in 8 HSCT patients demonstrated similar results, with the advantage of fast turnaround time. Persistence of donor microchimerism in patients undergoing microtransplantation for acute myeloid leukemia was detectable for up to 57 days in peripheral blood and bone marrow. The presence of microtransplant product DNA in bone marrow T cells after cell sorting was seen in the 1 patient tested. In patients receiving third-party VSTs for treatment of refractory viral infections, VST donor DNA was detected at low levels in 7 of 9 cases. ddPCR offers advantages over currently available methods for assessment of chimerism in standard HSCT and cellular therapies. [ABSTRACT FROM AUTHOR]

Under the Open Innovation paradigm, this paper analyzes emerging models of governance in platform-mediated networks subject to winner-takes-all competition regimes. Our research contends that modularity, an important attribute in technological systems, plays a relevant role in competition dynamics. The study is focused on the mobile networks industry, a highly dynamic and technology intensive sector, ideally suited to conduct research on competition under strong network effects. Based on a case study of an important firm in this sector, the paper finds that proprietary technological platforms require a large set of external contributors to ensure sustainable rates of development and innovation. Our results also suggest that, contrary to established theory, firms may opt for proprietary platforms rather than shared governance models and, nonetheless, they are able to successfully compete against the established ones. [ABSTRACT FROM AUTHOR]

Physical exercise is well-established as beneficial for health. With the 20th-century epidemiological transition, promoting healthy habits like exercise has become crucial for preventing chronic diseases. Stress can yield adaptive long-term benefits, potentially transmitted trans-generationally. Physical training exposes individuals to metabolic, thermal, mechanical, and oxidative stressors, activating cell signaling pathways that regulate gene expression and adaptive responses, thereby enhancing stress tolerance - a phenomenon known as hormesis. Muscle memory is the capacity of skeletal muscle to respond differently to environmental stimuli in an adaptive (positive) or maladaptive (negative) manner if the stimuli have been encountered previously. The Repeated Bout Effect encompasses our skeletal muscle capacity to activate an intrinsic protective mechanism that reacts to eccentric exercise-induced damage by activating an adaptive response that resists subsequent damage stimuli. Deciphering the molecular mechanism of this phenomenon would allow the incorporation of muscle memory in training programs for professional athletes, active individuals looking for the health benefits of exercise training, and patients with "exercise intolerance." Moreover, enhancing the adaptive response of muscle memory could promote healing in individuals who traditionally do not recover after immobilization. The improvement could be part of an exercise program but could also be targeted pharmacologically. This review explores Repeated Bout Effect mechanisms: neural adaptations, tendon and muscle fiber property changes, extracellular matrix remodeling, and improved inflammatory responses. [Display omitted] • The review explores the concept of muscle memory as the ability of skeletal muscle to adapt to repeated environmental stimuli. • The RBE, in which skeletal muscle activates protective mechanisms to resist damage from subsequent eccentric exercise, is discussed. • The role of hormesis enhancing stress tolerance through metabolic, thermal, mechanical, and oxidative stressors induced by physical training is noted. • Using muscle memory in training programs for athletes, individuals seeking health benefits, and patients with exercise intolerance is examined. • Enhancing muscle memory may aid recovery after immobilization if integrated into exercise programs or pharmacology. [ABSTRACT FROM AUTHOR]

Muscle atrophy is linked to reactive oxygen species (ROS) production during hindlimb-unloading due, at least in part, to the activation of xanthine oxidase (XO). The major aim of our study was to determine the mechanism by which ROS cause muscle atrophy and its possible prevention by allopurinol, a well-known inhibitor of XO widely used in clinical practice, and indomethacin, a nonsteroidal anti-inflammatory drug. We studied the activation of p38 MAP Kinase and NF-?B pathways, and the expression of two E3 ubiquitin ligases involved in proteolysis, the Muscle atrophy F-Box (MAFb) and Muscle RING Finger-1 (MuRF-1). Male Wistar rats (3 mold) conditioned by 14 days of hindlimb unloading (n=18), with or without the treatment, were compared with freely ambulating controls (n=18). After the experimental intervention, soleus muscles were removed, weighted and analyzed to determine oxidative stress and inflammatory parameters. We found that hindlimb unloading induced a significant increase in XO activity in plasma (39%, p=0.001) and in the protein expression of CuZnSOD and Catalase in skeletal muscle. Inhibitionof XO partially prevented protein carbonylation, both in plasma and in soleus muscle, in the unloaded animals. The most relevant new fact reported is that allopurinol prevents soleus muscle atrophy by ~20% after hindlimb unloading. Combining allopurinol and indomethacin we found a further prevention in the atrophy process. This is mediated by the inhibition of the p38 MAPK-MAFbx and NF-?B -MuRF-1 pathways. Our data point out the potential benefit of allopurinol and indomethacin administration for bedridden, astronauts, sarcopenic and cachexic patients. [ABSTRACT FROM AUTHOR]

Function declines throughout life although phenotypical manifestations in terms of frailty or disability are only seen in the later periods of our life. The causes underlying lifelong function decline are the aging process "per se", chronic diseases, and lifestyle factors. These three etiological causes result in the deterioration of several organs and systems which act synergistically to finally produce frailty and disability. Regardless of the causes, the skeletal muscle is the main organ affected by developing sarcopenia. In the first section of the manuscript, as an introduction, we review the quantitative and qualitative age-associated skeletal muscle changes leading to frailty and sarcopenia and their impact in the quality of life and independence in the elderly. The reversibility of frailty and sarcopenia are discussed in the second and third sections of the manuscript. The most effective intervention to delay and even reverse frailty is exercise training. We review the role of different training programs (resistance exercise, cardiorespiratory exercise, multicomponent exercise, and real-life interventions) not only as a preventive but also as a therapeutical strategy to promote healthy aging. We also devote a section in the text to the sexual dimorphic effects of exercise training interventions in aging. How to optimize the skeletal muscle anabolic response to exercise training with nutrition is also discussed in our manuscript. The concept of anabolic resistance and the evidence of the role of high-quality protein, essential amino acids, creatine, vitamin D, β-hydroxy-β-methylbutyrate, and Omega-3 fatty acids, is reviewed. In the last section of the manuscript, the main genetic interventions to promote robustness in preclinical models are discussed. We aim to highlight the molecular pathways that are involved in frailty and sarcopenia. The possibility to effectively target these signaling pathways in clinical practice to delay muscle aging is also discussed. [ABSTRACT FROM AUTHOR]

An archetypal anti-inflammatory compound against cytokine storm would inhibit it without suppressing the innate immune response. AG5, an anti-inflammatory compound, has been developed as synthetic derivative of andrographolide, which is highly absorbable and presents low toxicity. We found that the mechanism of action of AG5 is through the inhibition of caspase-1. Interestingly, we show with in vitro generated human monocyte derived dendritic cells that AG5 preserves innate immune response. AG5 minimizes inflammatory response in a mouse model of lipopolysaccharide (LPS)-induced lung injury and exhibits in vivo anti-inflammatory efficacy in the SARS-CoV-2-infected mouse model. AG5 opens up a new class of anti-inflammatories, since contrary to NSAIDs, AG5 is able to inhibit the cytokine storm, like dexamethasone, but, unlike corticosteroids, preserves adequately the innate immunity. This is critical at the early stages of any naïve infection, but particularly in SARS-CoV-2 infections. Furthermore, AG5 showed interesting antiviral activity against SARS-CoV-2 in humanized mice. [Display omitted] • AG5, a synthetic derivative of andrographolide, is a novel anti-inflammatory drug • AG5 minimizes inflammatory response by inhibition of caspase-1 route • AG5 inhibits cytokine storm and preserves adequately the innate immunity • AG5 shows antiviral activity against SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Frailty is associated with loss of functional reserve as well as with the prediction of adverse events in the old population. The traditional criteria of frailty are based on five physical determinations described in the Cardiovascular Health Study. We propose that biological and genetic markers of frailty should be used to increase the predictive capacity of the established clinical indeces. In recent times, research for biological markers of frailty has gained impetus. Finding a biological markers with diagnostic and prognostic capacity would be a major milestone to identify frailty risk, and also pre-frailty status. In the first section of the manuscript, we review the available biomarkers that help to monitor and prevent the evolution and the efficacy of interventions to delay the onset of frailty and to prevent its progression to incapacity. We also discuss the contribution of genetics to frailty. There are scientific bases that support that genetics influences frailty, although environmental factors probably will have the highest contribution. We review the known SNPs of the genes associated with frailty and classify them, taking into account the pathway in which they are involved. We also highlight the importance of longevity genes and their possible relation with frailty, citing centenarians who reach a very old age as an example of successful ageing. Finally, the reversibility of frailty is discussed. It can potentially be treated with nutritional or pharmacological interventions. However, physical exercise seems to be the most effective strategy to treat and prevent frailty. The last section of the manuscript is devoted to explaining the recommendations on the appropriate design of an exercise protocol to maximize its beneficial effects in a population of frail individuals. [ABSTRACT FROM AUTHOR]

Abstract: Coccidioidomycosis is a systemic disease caused by Coccidioides immitis and C posadasii spp, which are predominant in arid zones of the American continent, mainly in the Southwestern United States and the northern states of Mexico, as well as other regions with different environmental conditions. Some countries of Central and South America are also endemic zones. Most infected patients are asymptomatic. Disseminated disease develops in less than 5% of clinically affected individuals. Culture, biopsy, and DNA probes are used for fungus identification. Prognosis is related to low antibody detection and a positive intradermic skin reaction to coccidioidin. Immunodepressed patients and pregnant women require special attention in diagnosis, therapy, and prognosis. Amphotericin B in its different forms, itraconazole, and fluconazole, are the most frequently used treatments. Posaconazole and voriconazole are prescribed in some unresponsive cases. [Copyright &y& Elsevier]