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Abstract Background Exercise is widely considered to have beneficial impact on skeletal muscle aging. In addition, there are also several studies demonstrating a positive effect of exercise on muscular dystrophies. Oculopharyngeal muscular dystrophy (OPMD) is a late‐onset autosomal dominant inherited neuromuscular disorder caused by mutations in the PAPBN1 gene. These mutations consist in short (1‐8) and meiotically stable GCN trinucleotide repeat expansions in its coding region responsible for the formation of PAPBN1 intranuclear aggregates. This study aims to characterize the effects of two types of chronic exercise, resistance and endurance, on the OPMD skeletal muscle phenotype using a relevant murine model of OPMD. Methods In this study, we tested two protocols of exercise. In the first, based on endurance exercise, FvB (wild‐type) and A17 (OPMD) mice underwent a 6‐week‐long motorized treadmill protocol consisting in three sessions per week of running 20 cm/s for 20 min. In the second protocol, based on resistance exercise generated by chronic mechanical overload (OVL), surgical removal of gastrocnemius and soleus muscles was performed, inducing hypertrophy of the plantaris muscle. In both types of exercise, muscles of A17 and FvB mice were compared with those of respective sedentary mice. For all the groups, force measurement, muscle histology, and molecular analyses were conducted. Results Following the endurance exercise protocol, we did not observe any major changes in the muscle physiological parameters, but an increase in the number of PABPN1 intranuclear aggregates in both tibialis anterior (+24%, **P = 0.0026) and gastrocnemius (+18%, ****P

La implementación del teletrabajo se ha convertido en una estrategia clave para muchas organizaciones, particularmente en el sector de telecomunicaciones. Este artículo tiene como objetivo proponer una estrategia para introducir el teletrabajo en las empresas de telecomunicaciones en Santander, Colombia. El estudio sigue un diseño descriptivo y exploratorio con un enfoque mixto, cualitativo y cuantitativo. Se aplicaron cuestionarios estructurados con preguntas cerradas y escalas Likert a través de entrevistas presenciales y virtuales. El análisis cualitativo de los resultados, realizado con el software Atlas TI, permitió identificar patrones sobre la implementación del teletrabajo. Los hallazgos revelan que la propuesta es viable y efectiva, mejorando la eficiencia operativa, reduciendo costos y aumentando la satisfacción laboral. El teletrabajo, en el cual los empleados realizan sus tareas fuera de las instalaciones empresariales usando Tecnologías de la Información y Comunicaciones, ofrece mayor flexibilidad, reduce los desplazamientos y facilita la conciliación entre la vida personal y laboral. En conclusión, si se implementa correctamente, con una infraestructura tecnológica adecuada y políticas claras, esta modalidad laboral puede aumentar la productividad y disminuir los costos operativos, contribuyendo así a la adaptabilidad de las empresas frente a las demandas del entorno moderno.

Abstract Zebrafish is widely adopted as a grafting model for studying human development and diseases. Current zebrafish xenotransplantations are performed using embryo recipients, as the adaptive immune system, responsible for host versus graft rejection, only reaches maturity at juvenile stage. However, transplanted primary human hematopoietic stem/progenitor cells (HSC) rapidly disappear even in zebrafish embryos, suggesting that another barrier to transplantation exists before the onset of adaptive immunity. Here, using a labelled macrophage zebrafish line, we demonstrated that engraftment of human HSC induces a massive recruitment of macrophages which rapidly phagocyte transplanted cells. Macrophages depletion, by chemical or pharmacological treatments, significantly improved the uptake and survival of transplanted cells, demonstrating the crucial implication of these innate immune cells for the successful engraftment of human cells in zebrafish. Beyond identifying the reasons for human hematopoietic cell engraftment failure, this work images the fate of human cells in real time over several days in macrophage-depleted zebrafish embryos.

Truncation of the protein-protein interaction SH3 domain of the membrane remodeling Bridging Integrator 1 (BIN1, Amphiphysin 2) protein leads to centronuclear myopathy. Here, we assessed the impact of a set of naturally observed, previously uncharacterized BIN1 SH3 domain variants using conventional in vitro and cell-based assays monitoring the BIN1 interaction with dynamin 2 (DNM2) and identified potentially harmful ones that can be also tentatively connected to neuromuscular disorders. However, SH3 domains are typically promiscuous and it is expected that other, so far unknown partners of BIN1 exist besides DNM2, that also participate in the development of centronuclear myopathy. In order to shed light on these other relevant interaction partners and to get a holistic picture of the pathomechanism behind BIN1 SH3 domain variants, we used affinity interactomics. We identified hundreds of new BIN1 interaction partners proteome-wide, among which many appear to participate in cell division, suggesting a critical role of BIN1 in the regulation of mitosis. Finally, we show that the identified BIN1 mutations indeed cause proteome-wide affinity perturbation, signifying the importance of employing unbiased affinity interactomic approaches.

Recently, topical products advertising cannabinoid ingredients have gained popularity. Consumers are seeing an increase of commercial products containing ingredients from hemp oil to cannabidiol (CBD) due to health benefit claims. Cosmetic products containing cannabinoids are currently not regulated at the federal level. A laboratory experiment for undergraduate students in analytical and organic chemistry courses was developed utilizing high-performance liquid chromatography (HPLC) analysis to identify and quantify cannabinoid compounds present in commercially available topical products. Students used calibration curves of a cannabinoid standard to quantify cannabinoids present in the CBD products. By comparing relative retention times of the cannabinoids present in the standard, students were able to identify the cannabinoids present in their lotion sample. Responsibilities and assignments suit students ranging from introductory to advanced chemistry courses. Students are provided the opportunity to extract and experimentally calculate the amount of CBD and compare to the amounts advertised on product labels. Results showed that the average CBD amounts were higher than advertised for all lotions except CBDFx when analyzed using HPLC. This experiment can be modified to incorporate a variety of different topical water-based products including hair products, shampoo, and other cosmetics. Furthermore, an analysis of samples using gas chromatography mass spectrometry (GC-MS) was also developed to adapt to instrument availability.

Social insects often display extreme variation in body size and morphology within the same colony. In many species, adult morphology is socially regulated by workers during larval development. While larval nutrition may play a role in this regulation, it is often difficult to identify precisely what larvae receive from rearing workers, especially when larvae are fed through social regurgitation. Across insects, juvenile hormone is a major regulator of development. In the ant Camponotus floridanus, this hormone is present in the socially regurgitated fluid of workers. We investigated the role the social transfer of juvenile hormone in the social regulation of development. To do this, we administered an artificial regurgitate to larvae through a newly developed handfeeding method that was or was not supplemented with juvenile hormone. Orally administered juvenile hormone increased the nutritional needs of larvae, allowing them to reach a larger size at pupation. Instead of causing them to grow faster, the juvenile hormone treatment extended larval developmental time, allowing them to accumulate resources over a longer period. Handfeeding ant larvae with juvenile hormone resulted in larger adult workers after metamorphosis, suggesting a role for socially transferred juvenile hormone in the colony-level regulation of worker size over colony maturation.

Summary: To understand the function of multisubunit complexes, it is of key importance to uncover the precise mechanisms that guide their assembly. Nascent proteins can find and bind their interaction partners during their translation, leading to co-translational assembly. Here, we demonstrate that the core modules of ATAC (ADA-two-A-containing) and SAGA (Spt-Ada-Gcn5-acetyltransferase), two lysine acetyl transferase-containing transcription co-activator complexes, assemble co-translationally in the cytoplasm of mammalian cells. In addition, a SAGA complex containing all of its modules forms in the cytoplasm and acetylates non-histone proteins. In contrast, ATAC complex subunits cannot be detected in the cytoplasm of mammalian cells. However, an endogenous ATAC complex containing two functional modules forms and functions in the nucleus. Thus, the two related co-activators, ATAC and SAGA, assemble using co-translational pathways, but their subcellular localization, cytoplasmic abundance, and functions are distinct.

Background: The aim of the study is to identify the advantages, if any, of post-operative MRIs performed at 48 h compared to MRIs performed after 48 h in glioblastoma surgery. Materials and Methods: To assess the presence of a residual tumor, the T1-weighted Contrast Enhancement (CE), Apparent Diffusion Coefficient (ADC), and Cerebral Blood Volume (rCBV) in the proximity of the surgical cavity were considered. The rCBV ratio was calculated by comparing the rCBV with the contralateral normal white matter. After the blind image examinations by the two radiologists, the patients were divided into two groups according to time window after surgery: ≤48 h (group 1) and >48 h (group 2). Results: A total of 145 patients were enrolled; at the 6-month follow-up MRI, disease recurrence was 89.9% (125/139), with a mean patient survival of 8.5 months (SD 7.8). The mean ADC and rCBV ratio values presented statistical differences between the two groups (p < 0.05). Of these 40 patients in whom an ADC value was not obtained, the rCBV values could not be calculated in 52.5% (21/40) due to artifacts (p < 0.05). Conclusion: The study showed differences in CE, rCBV, and ADC values between the groups of patients undergoing MRIs before and after 48 h. An MRI performed within 48 h may increase the ability of detecting GBM by the perfusion technique with the calculation of the rCBV ratio.

Protein networks have been widely explored but most binding affinities remain unknown, limiting the quantitative interpretation of interactomes. Here the authors measure affinities of 65,000 interactions involving human PDZ domains and target sequence motifs relevant for viral infection and cancer.

On 27 February 2021, the Food and Drug Administration(FDA) authorized the administration of the adenovirus-based Ad26.COV2-S vaccine (J&J-Janssen) for the prevention of COVID-19, a viral pandemic that, to date, has killed more than 5.5 million people. Performed during the early phase of the COVID-19 4th wave, this retrospective observational study aims to report the computerized tomography (CT) findings and intensive care unit admission rates of Ad26.COV2-S-vaccinated vs. unvaccinated COVID-19 patients. From the 1st to the 23rd of December 2021, all confirmed COVID-19 patients that had been subjected to chest non-contrast CT scan analysis were enrolled in the study. These were divided into Ad26.COV2.S-vaccinated (group 1) and unvaccinated patients (group 2). The RSNA severity score was calculated for each patient and correlated to CT findings and type of admission to a healthcare setting after CT—i.e., home care, ordinary hospitalization, sub-intensive care, and intensive care. Descriptive and inference statistical analyses were performed by comparing the data from the two groups. Data from a total of 71 patients were collected: 10 patients in group 1 (4M, 6F, mean age 63.5 years, SD ± 4.2) and 61 patients in group 2 (32M, 29F, mean age 64.7 years, SD ± 3.7). Statistical analysis showed lower values of RSNA severity in group 1 compared to group 2 (mean value 14.1 vs. 15.7, p = 0.009, respectively). Furthermore, vaccinated patients were less frequently admitted to both sub-intensive and high-intensive care units than group 2, with an odds ratio of 0.45 [95%CI (0.01; 3.92)]. Ad26.COV2.S vaccination protects from severe COVID-19 based on CT severity scores. As a result, Ad26.COV2.S-vaccinated COVID-19 patients are more frequently admitted to home in comparison with unvaccinated patients.

Copy number variations (CNVs) of the human 16p11.2 locus are associated with several developmental/neurocognitive syndromes. Particularly, deletion and duplication of this genetic interval are found in patients with autism spectrum disorders, intellectual disability and other psychiatric traits. The high gene density associated with the region and the strong phenotypic variability of incomplete penetrance, make the study of the 16p11.2 syndromes extremely complex. To systematically study the effect of 16p11.2 CNVs and identify candidate genes and molecular mechanisms involved in the pathophysiology, mouse models were generated previously and showed learning and memory, and to some extent social deficits. To go further in understanding the social deficits caused by 16p11.2 syndromes, we engineered deletion and duplication of the homologous region to the human 16p11.2 genetic interval in two rat outbred strains, Sprague Dawley (SD) and Long Evans (LE). The 16p11.2 rat models displayed convergent defects in social behavior and in the novel object test in male carriers from both genetic backgrounds. Interestingly major pathways affecting MAPK1 and CUL3 were found altered in the rat 16p11.2 models with additional changes in males compared to females. Altogether, the consequences of the 16p11.2 genetic region dosage on social behavior are now found in three different species: humans, mice and rats. In addition, the rat models pointed to sexual dimorphism with lower severity of phenotypes in rat females compared to male mutants. This phenomenon is also observed in humans. We are convinced that the two rat models will be key to further investigating social behavior and understanding the brain mechanisms and specific brain regions that are key to controlling social behavior.

This perspective article is concerned with the question of how proteomics, which is a core technique of systems biology that is deeply embedded in the multi-omics field of modern bioresearch, can help us better understand the molecular pathogenesis of complex diseases. As an illustrative example of a monogenetic disorder that primarily affects the neuromuscular system but is characterized by a plethora of multi-system pathophysiological alterations, the muscle-wasting disease Duchenne muscular dystrophy was examined. Recent achievements in the field of dystrophinopathy research are described with special reference to the proteome-wide complexity of neuromuscular changes and body-wide alterations/adaptations. Based on a description of the current applications of top-down versus bottom-up proteomic approaches and their technical challenges, future systems biological approaches are outlined. The envisaged holistic and integromic bioanalysis would encompass the integration of diverse omics-type studies including inter- and intra-proteomics as the core disciplines for systematic protein evaluations, with sophisticated biomolecular analyses, including physiology, molecular biology, biochemistry and histochemistry. Integrated proteomic findings promise to be instrumental in improving our detailed knowledge of pathogenic mechanisms and multi-system dysfunction, widening the available biomarker signature of dystrophinopathy for improved diagnostic/prognostic procedures, and advancing the identification of novel therapeutic targets to treat Duchenne muscular dystrophy.

Electrospinning is an advanced manufacturing strategy used to create innovative medical devices from continuous nanoscale fibers that is endowed with tunable biological, chemical, and physical properties. Innovative medical patches manufactured entirely by electrospinning are discussed in this paper, using a specific plant-derived formulation “1 Primary Wound Dressing©” (1-PWD) as an active pharmaceutical ingredient (API). 1-PWD is composed of neem oil (Azadirachta indica A. Juss.) and the oily extracts of Hypericum perforatum (L.) flowers, according to the formulation patented by the ENEA of proven therapeutic efficacy as wound dressings. The goal of this work is to encapsulate this API and demonstrate that its slow release from an engineered electrospun patch can increase the therapeutic efficacy for wound healing. The prototyped patch is a three-layer core–shell membrane, with a core made of fibers from a 1-PWD-PEO blend, enveloped within two external layers made of medical-grade polycaprolactone (PCL), ensuring mechanical strength and integrity during manipulation. The system was characterized via electron microscopy (SEM) and chemical and contact angle tests. The encapsulation, release, and efficacy of the API were confirmed by FTIR and LC-HRMS and were validated via in vitro toxicology and scratch assays.

Androgen receptor (AR) signaling remains the key therapeutic target in the management of hormone‐naïve‐advanced prostate cancer (PCa) and castration‐resistant PCa (CRPC). Recently, landmark molecular features have been reported for CRPC, including the expression of constitutively active AR variants that lack the ligand‐binding domain. Besides their role in CRPC, AR variants lead to the expression of genes involved in tumor progression. However, little is known about the specificity of their mode of action compared with that of wild‐type AR (AR‐WT). We performed AR transcriptome analyses in an androgen‐dependent PCa cell line as well as cross‐analyses with publicly available RNA‐seq datasets and established that transcriptional repression capacity that was marked for AR‐WT was pathologically lost by AR variants. Functional enrichment analyses allowed us to associate AR‐WT repressive function to a panel of genes involved in cell adhesion and epithelial‐to‐mesenchymal transition. So, we postulate that a less documented AR‐WT normal function in prostate epithelial cells could be the repression of a panel of genes linked to cell plasticity and that this repressive function could be pathologically abrogated by AR variants in PCa.

Abstract Background Fibrosis is defined as an excessive accumulation of extracellular matrix (ECM) components. Many organs are subjected to fibrosis including the lung, liver, heart, skin, kidney, and muscle. Muscle fibrosis occurs in response to trauma, aging, or dystrophies and impairs muscle function. Fibrosis represents a hurdle for the treatment of human muscular dystrophies. While data on the mechanisms of fibrosis have mostly been investigated in mice, dystrophic mouse models often do not recapitulate fibrosis as observed in human patients. Consequently, the cellular and molecular mechanisms that lead to fibrosis in human muscle still need to be identified. Methods Combining mass cytometry, transcriptome profiling, in vitro co‐culture experiments, and in vivo transplantation in immunodeficient mice, we investigated the role and nature of nonmyogenic cells (fibroadipogenic progenitors, FAPs) from human fibrotic muscles of healthy individuals (FibMCT) and individuals with oculopharyngeal muscular dystrophy (OPMD; FibMOP), as compared with nonmyogenic cells from human nonfibrotic muscle (MCT). Results We found that the proliferation rate of FAPs from fibrotic muscle is 3–4 times higher than those of FAPs from nonfibrotic muscle (population doubling per day: MCT 0.2 ± 0.1, FibMCT 0.7 ± 0.1, and FibMOP 0.8 ± 0.3). When cocultured with muscle cells, FAPs from fibrotic muscle impair the fusion index unlike MCT FAPs (myoblasts alone 57.3 ± 11.1%, coculture with MCT 43.1 ± 8.9%, with FibMCT 31.7 ± 8.2%, and with FibMOP 36.06 ± 10.29%). We also observed an increased proliferation of FAPs from fibrotic muscles in these co‐cultures in differentiation conditions (FibMCT +17.4%, P

Summary: Inositol-requiring enzyme 1 (IRE1) is a major mediator of the unfolded protein response (UPR), which is activated upon endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues, a stress overcome by relying on IRE1 signaling as an adaptive mechanism. Herein, we report the discovery of structurally new IRE1 inhibitors identified through the structural exploration of its kinase domain. Characterization in in vitro and in cellular models showed that they inhibit IRE1 signaling and sensitize glioblastoma (GB) cells to the standard chemotherapeutic, temozolomide (TMZ). Finally, we demonstrate that one of these inhibitors, Z4P, permeates the blood–brain barrier (BBB), inhibits GB growth, and prevents relapse in vivo when administered together with TMZ. The hit compound disclosed herein satisfies an unmet need for targeted, non-toxic IRE1 inhibitors and our results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB.

Managers’ work and management issues are nowadays a major concern for ergonomist practitioners and researchers. In this paper, we highlight societal and corporate evolutions and the way that ergonomics has evolved as a result. We propose a reading of the evolution that has been affecting companies for the last forty years, and show how the tertiarization and financialization of the economy and of companies have led them to deploy more rigid forms of organization that accentuate the control and demands of customers. We go on to observe that this evolution has not been uniform consistent, because the 1990s were the cradle of attempts to add to the tasks of operators by delegating tasks from middle management, while at the same time highlighting the fact that managers’ jobs have been transformed, particularly by a move away from actual workof attempts to enrich the tasks of operators by delegating tasks to middle management, while pointing out that. But gradually, the work of managers was transformed, particularly by moving away from work (Gomez, 2013). We then make the observation that in response to these developments, ergonomists have looked at different levels of organizational determinants, in order to improve the sustainability of the effects and to continue the work already carried out on business development of the activity. Finally, we defend the utility of developing ergonomic approaches to managers’ work, both for its key role in organizational functioning, particularly regarding regulations, and for the role it plays in the development of the activity of other employees. Hence today, more than ever, their work becomes an essential object of study and above all a major target for organizational intervention. We will see that current and future societal transitions reinforce this position.