Miracle-dz/UniFAR-FTUs huggingface dataset:
Metabolic reprogramming of fibro/adipogenic progenitors facilitates muscle regeneration

High-fat diet ameliorates muscle dystrophic phenotype by promoting the FAP-dependent myogenesis of satellite cells. In Duchenne muscular dystrophy (DMD), the absence of the dystrophin protein causes a variety of poorly understood secondary effects. Notably, muscle fibers of dystrophic individuals are characterized by mitochondrial dysfunctions, as revealed by a reduced ATP production rate and by defective oxidative phosphorylation. Here, we show that in a mouse model of DMD (mdx), fibro/adipogenic progenitors (FAPs) are characterized by a dysfunctional mitochondrial metabolism which correlates with increased adipogenic potential. Using high-sensitivity mass spectrometry–based proteomics, we report that a short-term high-fat diet (HFD) reprograms dystrophic FAP metabolism in vivo. By combining our proteomic dataset with a literature-derived signaling network, we revealed that HFD modulates the β-catenin–follistatin axis. These changes are accompanied by significant amelioration of the histological phenotype in dystrophic mice. Transplantation of purified FAPs from HFD-fed mice into the muscles of dystrophic recipients demonstrates that modulation of FAP metabolism can be functional to ameliorate the dystrophic phenotype. Our study supports metabolic reprogramming of muscle interstitial progenitor cells as a novel approach to alleviate some of the adverse outcomes of DMD.
Experiences of GP trainees in undertaking telephone consultations: a mixed-methods study

Background Primary care telephone consultations are increasingly used for patient triage, reviews, and providing clinical information. They are also a key postgraduate training component yet little is known about GP trainees’ preparation for, or experiences and perceptions of, them. Aim To understand the experiences, perceptions, and training of GP trainees in conducting telephone consultations. Design & setting A mixed-methods study was undertaken of North Central and East London (NCEL) GP trainees. Method A cross-sectional electronic survey of trainees was performed with subsequent semi-structured interviews. Survey data were analysed using descriptive statistics, and qualitative data using thematic analysis. Results The survey response was 16% (n = 100/618), and 10 participated in semi-structured interviews. Trainees felt least confident with complicated telephone consulting, and there was a strong positive correlation between the percentage reporting having received training and their confidence (R 2 = 0.71, P<0.0001). Positive experiences included managing workload and convenience. Negative experiences included complex encounters, communication barriers, and absence of examination. Trainees reported that training for telephone consultations needed strengthening, and that recently introduced audio-clinical observation tools (COTs) were useful. Positive correlations were found between the length of out-of-hours (OOH) but not in-hours training and the level of supervision or feedback received for telephone consultations. Conclusion This project sheds light on GP trainees’ current experiences of telephone consultations and the need to enhance future training. The findings will inform a wider debate among stakeholders and postgraduate learners regarding training for telephone consultations, and potentially for other remote technologies.
Identification of abnormally expressed genes and their roles in invasion and migration of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death in the world, mainly attributable to its high migration tendency. Most patients with HCC miss the benefit of radical resection or liver transplantation because of distant metastasis of the tumor. Therefore, identification of diagnostic and therapeutic targets by analyzing abnormally expressed genes associated with tumor invasion and migration in HCC could be useful. In this study, we carried out a meta-analysis of three gene expression profile data sets (GSE45050, GSE84598 and GSE89377), including 112 liver cancer and 77 normal tissue samples, to identify candidate genes and pathways. The three gene expression omnibus (GEO) data sets had 155 differentially expressed genes (DEGs) in common, including 25 up-regulated and 129 down-regulated genes. Protein-protein interaction (PPI) networks were generated in the STRING database and explored further in Cytoscape to identify network hubs. Moreover, the statistically significant (p < 0.05) functions and signaling pathways enriched by the shared DEGs were identified. The Kaplan-Meier curve was applied to analyze univariate survival outcomes of the hub genes, which suggested AURKA and CDC20 as independent prognostic factors in HCC. Additionally, we found that AURKA and CDC20 were markedly upregulated in HCC cell lines. Quantitative PCR, western blot, and Immunohistochemistry (IHC) was performed to determine mRNA and protein expression of AURKA and CDC20 in 20 normal liver tissues and 66 HCC tissues from patients with HCC who underwent complete surgical resection in stage 1 to 4. Results showed that expression of AURKA and CDC20 were significantly higher in HCC tissues than normal tissues and were increased from HCC stage 1 to 4. Importantly, through loss of function, we showed that AURKA and CDC20 both significantly promote HCC migration and invasion. In summary, we identified the key candidate DEGs and dysregulated pathways in HCC through bioinformatic analysis and experimental validation. These candidate DEGs and pathways enhance our understanding of the potential pathogenesis of HCC and may hold promise as markers for the diagnosis, treatment, and prognosis of HCC.
Helicobacter pylori seropositivity is associated with antinuclear antibodies in US adults, NHANES 1999–2000

Abstract Infectious diseases, such as Helicobacter pylori, which produce systemic inflammation may be one key factor in the onset of autoimmunity. The association between H. pylori and antinuclear antibodies (ANA), a marker of autoimmunity, has been understudied. Data from the 1999–2000 National Health and Nutrition Examination Survey were used to evaluate the cross-sectional association between H. pylori seroprevalence and ANA positivity in US adults aged ≥20 years. ANA was measured in a 1:80 dilution of sera by indirect immunofluorescence using HEp-2 cells (positive ⩾3). H. pylori immunoglobulin G enzyme-linked immunosorbent assays were used to categorise individuals as seropositive or seronegative. H. pylori seropositivity and ANA positivity were common in the adult US population, with estimated prevalences of 33.3% and 9.9%, respectively. Both were associated with increasing age. H. pylori seropositivity was associated with higher odds of ANA (prevalence odds ratio = 1.89, 95% confidence interval = 1.08–3.33), adjusted for age, sex, race/ethnicity, educational attainment and body mass index. H. pylori infection may be one key factor in the loss of self-tolerance, contributing to immune dysfunction.
Male fertility in Mus musculus requires the activity of TRYX5 in sperm migration into the oviduct

Nowadays, abnormal loss of serine proteases appears very frequently in male patients with unexplained sterility. In fact, many testis‐specific serine proteases, the largest family among the four protease families implicated in murine spermatogenesis, are indispensable for reproduction. In the present study, we demonstrate that the previously uncharacterized testis‐specific serine protease TRYX5 (1700074P13Rik) is required for male fertility in mice. Tryx5−/− male mice are sterile, yet they have normal spermatogenesis and normal sperm parameters. In vivo fertilization experiments showed that the fertilization rate of Tryx5−/− sperm was almost zero. Sperm counting and analysis of paraffin sections of oviducts revealed that Tryx5−/− sperm were unable to migrate into the oviduct, which is likely the cause of the observed infertility of the Tryx5−/− male mice. Importantly, we also found that there was almost no mature ADAM3 present in Tryx5−/− sperm and almost no ADAM3 precursor in Tryx5−/− elongated spermatids of S13‐16 stage, even though testes of Tryx5−/− and wild type mice had the same amount of the total precursor ADAM3. Collectively, our results demonstrate that Tryx5 is essential for male fertility in mice and suggest that TRYX5 functions in the stability or localization of ADAM3 precursor in elongated spermatids S13‐16 stage, thereby regulating the ability of sperm to migrate from the uterus into the ampulla of the oviduct, the site of fertilization.
Community-acquired pneumonia in chronic obstructive pulmonary disease.

PURPOSE OF REVIEW The aim of this study was to discuss the literature on community-acquired pneumonia (CAP) in patients with chronic obstructive pulmonary disease (COPD). RECENT FINDINGS Well designed studies show that COPD is the strongest risk factor for development of CAP. Lung microbiome, abnormal lung immunity and pathogen virulence are important components of the pathogenesis of CAP in COPD. The cause of CAP in patients with COPD is similar to that of non-COPD patients. However, patients with COPD are at an increased risk of infection by Gram-negative bacilli, including Pseudomonas aeruginosa. Empiric treatment regimens for CAP in COPD should contemplate the most common pathogens, and consideration should be given for the coverage of Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus depending on the severity of CAP, severity of COPD or prior isolation of these pathogens. COPD has not been consistently shown to be an independent risk factor for worse short-term outcomes in patients with CAP. In a long-term study, COPD is associated with worse outcomes in these patients. SUMMARY Research focused on lung microbiome and abnormal lug immunity in patients with COPD should be prioritized. Further clinical research should try to consolidate the role of additional treatment approaches such as immunomodulating medications in COPD patients with CAP.
A Comparison of Osteoblast and Osteoclast In Vitro Co-Culture Models and Their Translation for Preclinical Drug Testing Applications

As the population of western societies on average ages, the number of people affected by bone remodeling-associated diseases such as osteoporosis continues to increase. The development of new therapeutics is hampered by the high failure rates of drug candidates during clinical testing, which is in part due to the poor predictive character of animal models during preclinical drug testing. Co-culture models of osteoblasts and osteoclasts offer an alternative to animal testing and are considered to have the potential to improve drug development processes in the future. However, a robust, scalable, and reproducible 3D model combining osteoblasts and osteoclasts for preclinical drug testing purposes has not been developed to date. Here we review various types of osteoblast–osteoclast co-culture models and outline the remaining obstacles that must be overcome for their successful translation.
Clinical Impact of Somatic Variants in Homologous Recombination Repair-Related Genes in Ovarian High-Grade Serous Carcinoma

Purpose In this study, we investigated the frequencies of mutations in DNA damage repair genes including BRCA1, BRCA2, homologous recombination genes and TP53 gene in ovarian high-grade serous carcinoma, alongside those of germline and somatic BRCA mutations, with the aim of improving the identification of patients suitable for treatment with poly(ADP-ribose) polymerase inhibitors. Materials and Methods Tissue samples from 77 Korean patients with ovarian high-grade serous carcinoma were subjected to next-generation sequencing. Pathogenic alterations of 38 DNA damage repair genes and TP53 gene and their relationships with patient survival were examined. Additionally, we analyzed BRCA germline variants in blood samples from 47 of the patients for comparison. Results BRCA1, BRCA2, and TP53 mutations were detected in 28.6%, 5.2%, and 80.5% of the 77 patients, respectively. Alterations in RAD50, ATR, MSH6, MSH2, and FANCA were also identified. At least one mutation in a DNA damage repair gene was detected in 40.3% of patients (31/77). Germline and somatic BRCA mutations were found in 20 of 47 patients (42.6%), and four patients had only somatic mutations without germline mutations (8.5%, 4/47). Patients with DNA damage repair gene alterations with or without TP53 mutation, exhibited better disease-free survival than those with TP53 mutation alone. Conclusion DNA damage repair genes were mutated in 40.3% of patients with high-grade serous carcinoma, with somatic BRCA mutations in the absence of germline mutation in 8.5%. Somatic variant examination, along with germline testing of DNA damage repair genes, has potential to detect additional candidates for PARP inhibitor treatment.
Enzymatic Modification of Native Chitin and Conversion to Specialty Chemical Products

Chitin is one of the most abundant biomolecules on earth, occurring in crustacean shells and cell walls of fungi. While the polysaccharide is threatening to pollute coastal ecosystems in the form of accumulating shell-waste, it has the potential to be converted into highly profitable derivatives with applications in medicine, biotechnology, and wastewater treatment, among others. Traditionally this is still mostly done by the employment of aggressive chemicals, yielding low quality while producing toxic by-products. In the last decades, the enzymatic conversion of chitin has been on the rise, albeit still not on the same level of cost-effectiveness compared to the traditional methods due to its multi-step character. Another severe drawback of the biotechnological approach is the highly ordered structure of chitin, which renders it nigh impossible for most glycosidic hydrolases to act upon. So far, only the Auxiliary Activity 10 family (AA10), including lytic polysaccharide monooxygenases (LPMOs), is known to hydrolyse native recalcitrant chitin, which spares the expensive first step of chemical or mechanical pre-treatment to enlarge the substrate surface. The main advantages of enzymatic conversion of chitin over conventional chemical methods are the biocompability and, more strikingly, the higher product specificity, product quality, and yield of the process. Products with a higher Mw due to no unspecific depolymerisation besides an exactly defined degree and pattern of acetylation can be yielded. This provides a new toolset of thousands of new chitin and chitosan derivatives, as the physio-chemical properties can be modified according to the desired application. This review aims to provide an overview of the biotechnological tools currently at hand, as well as challenges and crucial steps to achieve the long-term goal of enzymatic conversion of native chitin into specialty chemical products.
MicroRNA-299-5p inhibits cell metastasis in breast cancer by directly targeting serine/threonine kinase 39

Numerous studies have demonstrated that microRNAs (miRNAs) play a key role in human carcinogenesis and metastasis. For example, miR-299-5p has previously been revealed to be dysregulated in several human cancers. However, the biological function of miR-299-5p in breast cancer remains unclear. The present study demonstrated that miR-299-5p was downregulated in breast cancer tissues and cell lines. The restoration of miR-299-5p expression suppressed cell migration and invasion, whereas inhibition of miR-299-5p promoted cell migration and invasion. In addition, in vivo studies demonstrated that miR-299-5p overexpression was able to inhibit tumour metastasis in nude mice. Mechanistically, through bioinformatics analysis and a dual-luciferase assay, it was confirmed that miR-299-5p directly targets serine/threonine kinase 39 (STK39). Silencing STK39 inhibited cell metastasis and suppressed epithelial-mesenchymal transition markers and matrix metalloproteinase expression, whereas restoration of STK39 expression was able to reverse miR-299-5p-inhibited cell migration and invasion. Collectively, the results of the present study demonstrated that miR-299-5p supresses breast cancer cell migration and invasion by targeting STK39. These findings may provide novel insights into miR-299-5p and its potential diagnostic and therapeutic benefits in breast cancer.
Comprehensive analysis of the dermatophyte Trichophyton rubrum transcriptional profile reveals dynamic metabolic modulation.

The environmental challenges imposed onto fungal pathogens require a dynamic metabolic modulation, which relies on activation or repression of critical factors and is essential for the establishment and perpetuation of host infection. Wherefore, to overcome the different host microenvironments, pathogens not only depend on virulence factors but also on metabolic flexibility, which ensures their dynamic response to stress conditions in the host. Here, we evaluate Trichophyton rubrum interaction with keratin from a metabolic perspective. We present information about gene modulation of the dermatophyte during early infection stage after shifting from glucose- to keratin-containing culture media, in relation to its use of glucose as the carbon source. Analyzing T. rubrum transcriptome using high-throughput RNA-sequencing technology, we identified the modulation of essential genes related to nitrogen, fatty acid, ergosterol, and carbohydrate metabolisms, among a myriad of other genes necessary for the growth of T. rubrum in keratinized tissues. Our results provide reliable and critical strategies for adaptation to keratin and confirm that the urea-degrading activity associated with the reduction in disulfide bonds and proteolytic activity facilitated keratin degradation. The global modulation orchestrates the responses that support virulence and the proper adaptation to keratin compared to glucose as the carbon source. The gene expression profiling of the host-pathogen interaction highlights candidate genes involved in fungal adaptation and survival and elucidates the machinery required for the establishment of the initial stages of infection.
Behavioral Action of Deltamethrin and Cypermethrin in Pyrethroid-Resistant Aedes aegypti (Diptera: Culicidae): Implications for Control Strategies in Thailand

Abstract Contact irritant (locomotor excitation) and noncontact spatial repellent avoidance behavior to deltamethrin and cypermethrin at dosages 0.025, 0.05, and 0.1 g/m2 impregnated on papers were evaluated in the laboratory against deltamethrin- and cypermethrin-resistant field populations of female Aedes aegypti (L.) from Rayong and Chanthaburi Provinces,Thailand. Pyrethroid-resistant populations were compared with a susceptible laboratory strain (NIH-Thai) using an ‘excito-repellency’ (ER) test system. Both NIH-Thai and field mosquitoes had stronger contact irritancy responses compared to the relatively weak noncontact repellency effects. Contact assays with deltamethrin and cypermethrin at 0.1 g/m2 showed high escape rates for Rayong (80.1 and 83.4%, respectively) and Chanthaburi (84.6 and 73.1%, respectively) mosquitoes. Cypermethrin produced significantly different (P < 0.05) percent escape responses in contact tests between NIH-Thai and field mosquitoes. Only deltamethrin contact at 0.05 g/m2 produced a significant escape response (P < 0.001) between NIH-Thai and Rayong mosquitoes.These results suggest that there may not be an overall significant effect of background pyrethroid resistance on escape response, and the differences by comparisons may reflect inherent individual variation when using the ER bioassay system.The results show that pyrethroid resistance in Ae. aegypti does not appear to influence or reduce contact avoidance responses with the compounds tested. In particular, deltamethrin at 0.1 g/m2 was an effective contact irritant and toxic compound against pyrethroid-resistant populations of Ae. aegypti.Therefore, 0.1 g/m2 deltamethrin could be considered for residual applications of either fixed surfaces or materials (e.g., curtains) as a supplemental control measure against adult dengue vectors.
The effects of a dance intervention on somatic symptoms and emotional distress in adolescent girls: A randomized controlled trial

Objective To investigate whether a dance intervention for adolescent girls reduces stress-related symptoms. Methods This was a randomized controlled trial of an after-school intervention. Participants were 112 girls aged 13 to 18 years with stress-related somatic symptoms and emotional distress. The intervention comprised twice-weekly dance sessions for 8 months with a focus on enjoyment and socialization. A questionnaire was administered at baseline and after 8, 12 and 20 months. Participants rated the frequency with which they had experienced somatic symptoms and emotional distress during the previous 3 months. Results After the intervention, there was a significantly greater reduction in somatic symptoms and emotional distress in the dance intervention group than in the control group. The difference in the mean score change on a 5-point scale was 0.26 (95% confidence interval [CI]: 0.04 to 0.47) for somatic symptoms and 0.30 (95% CI: 0.04 to 0.58) for emotional distress. Conclusion Dance interventions may reduce somatic symptoms and emotional distress in adolescent girls, and may constitute a nonpharmacological complement to school health services. However, continued participation is needed for long-term sustainable results. Additional randomized studies are required to further evaluate the effect of this type of intervention in different settings. This study was registered with ClinicalTrials.gov. Study name: ‘Influencing Adolescent Girls With Creative Dance Twice Weekly’. URL: http: //clinicaltrials.gov/ct2/show/study/NCT01523561. Trial registration number: NCT01523561.
Cheating in arbuscular mycorrhizal mutualism: a network and phylogenetic analysis of mycoheterotrophy.

While mutualistic interactions are widespread and essential in ecosystem functioning, the emergence of uncooperative cheaters threatens their stability, unless there are some physiological or ecological mechanisms limiting interactions with cheaters. In this framework, we investigated the patterns of specialization and phylogenetic distribution of mycoheterotrophic cheaters versus non-cheating autotrophic plants and their respective fungi in a global arbuscular mycorrhizal network with >25,000 interactions. We show that mycoheterotrophy repeatedly evolved among vascular plants, suggesting low phylogenetic constraints for plants. However, mycoheterotrophic plants are significantly more specialized than autotrophic plants, and they tend to be associated with specialized and closely related fungi. These results raise new hypotheses about the mechanisms (e.g. sanctions, or habitat filtering) that actually limit the interaction of mycoheterotrophic plants and their associated fungi with the rest of the autotrophic plants. Beyond mycorrhizal symbiosis, this unprecedented comparison of mycoheterotrophic versus autotrophic plants provides a network and phylogenetic framework to assess the presence of constraints upon cheating emergences in mutualisms.