Miracle-dz/UniFAR-FTUs huggingface dataset:
Progress on the role of extrachromosomal DNA in tumor pathogenesis and evolution

The amplification of oncogenes on extrachromosomal DNA (ecDNA) provides a new mechanism for cancer cells to adapt to the changes in the tumor microenvironment and accelerate tumor evolution. These extrachromosomal elements contain oncogenes, and their chromatin structures are more open than linear chromosomes and therefore have stronger oncogene transcriptional activity. ecDNA always contains enhancer elements, and genes on ecDNA can be reintegrated into the linear genome to regulate the selective expression of genes. ecDNA lacks centromeres, and the inheritance from the parent cell to the daughter cell is uneven. This non‐Mendelian genetic mechanism results in the increase of tumor heterogeneity with daughter cells that can gain a competitive advantage through a large number of copies of oncogenes. ecDNA promotes tumor invasiveness and provides a mechanism for drug resistance associated with poorer survival outcomes. Recent studies have demonstrated that the overall proportion of ecDNA in tumors is approximately 40%. In this review, we summarize the current knowledge of ecDNA in the field of tumorigenesis and development.
Is zebrafish heart regeneration “complete”? Lineage-restricted cardiomyocytes proliferate to pre-injury numbers but some fail to differentiate in fibrotic hearts

Adult zebrafish are frequently described to be able to “completely” regenerate the heart. Yet, the extent to which cardiomyocytes lost to injury are replaced is unknown, since only indirect or non-quantitative evidence for cardiomyocyte proliferation exists. We established stereological methods to quantify the number of cardiomyocytes at several time-points post cryoinjury. Intriguingly, after cryoinjuries that killed about 1/3 of the ventricular cardiomyocytes, pre-injury cardiomyocyte numbers were restored already within 30 days. Yet, many hearts retained small residual scars, and a subset of cardiomyocytes bordering these fibrotic areas remained smaller, lacked differentiated sarcomeric structures, and displayed defective calcium signaling. Thus, a subset of regenerated cardiomyocytes failed to fully mature. While lineage-tracing experiments have shown that regenerating cardiomyocytes are derived from differentiated cardiomyocytes, technical limitations have previously made it impossible to test whether cardiomyocyte trans-differentiation contributes to regeneration of non-myocyte cell lineages. Using Cre responder lines that are expressed in all major cell types of the heart, we found no evidence for cardiomyocyte transdifferentiation into endothelial, epicardial, fibroblast or immune cell lineages. Overall, our results imply a refined answer to the question whether zebrafish can completely regenerate the heart: in response to cryoinjury, preinjury cardiomyocyte numbers are indeed completely regenerated, while restoration of cardiomyocyte differentiation and function, as well as resorption of scar tissue, is less robustly achieved.
The Shared Resistome of Human and Pig Microbiota Is Mobilized by Distinct Genetic Elements

There is growing concern that antibiotic resistance genes could spread from the husbandry environment to human pathogens through dissemination mediated by mobile genetic elements. In this study, we investigated the contribution of mobile genetic elements to the abundance of highly prevalent antibiotic resistance genes found in commensal bacteria of both human and pig intestinal microbiota originating from the same region. ABSTRACT The extensive use of antibiotics in hospitals and in the animal breeding industry has promoted antibiotic resistance in bacteria, which has resulted in the emergence of a large number of antibiotic resistance genes in the intestinal tracts of humans and farmed animals. Genetic exchange of resistance genes between the two ecosystems is now well documented for pathogenic bacteria, but the repertoire of shared resistance genes in the commensal bacterial community and by which genetic modules they are disseminated are still unclear. By analyzing metagenomics data of human and pig intestinal samples collected in Shenzhen, China, a set of 27 highly prevalent antibiotic resistance genes was found to be shared between human and pig intestinal microbiota. The mobile genetic context for 11 of these core antibiotic resistance genes could be identified by mining their carrying scaffolds constructed from the 2 data sets, leading to the detection of 7 integrative and conjugative/mobilizable elements and 2 insertion sequence (IS)-related transposons. The comparison of the relative abundances between these detected mobile genetic elements and their associated antibiotic resistance genes revealed that for many genes, the estimated contribution of the mobile elements to the gene abundance differs strikingly depending on the host. These findings indicate that although some antibiotic resistance genes are ubiquitous across microbiota of human and pig populations, they probably rely on different genetic elements for their dissemination within each population. IMPORTANCE There is growing concern that antibiotic resistance genes could spread from the husbandry environment to human pathogens through dissemination mediated by mobile genetic elements. In this study, we investigated the contribution of mobile genetic elements to the abundance of highly prevalent antibiotic resistance genes found in commensal bacteria of both human and pig intestinal microbiota originating from the same region. Our results reveal that for most of these antibiotic resistance genes, their abundance is not explained by the same mobile genetic element in each host, suggesting that the human and pig microbial communities promoted a different set of mobile genetic carriers for the same antibiotic resistance genes. These results deepen our understanding of the dissemination of antibiotic resistance genes among and between human and pig gut microbiota.
Neighborhood Context and Drug Use Among Mexican Americans on and off the U.S.-Mexico Border.

OBJECTIVE Prior research has suggested that drug use rates may be high at the U.S.-Mexico border, but in more recent research rates varied significantly between border communities. This study reports findings on the mediating influence of neighborhood-level variables on the observed difference in past-year drug use rates between two border sites and an interior site, focusing on Mexican Americans. METHOD Data were analyzed from the U.S.-Mexico Study on Alcohol and Related Conditions (UMSARC) on 1,345 Mexican-origin respondents ages 18-40 from the border sites of Laredo and Brownsville/McAllen compared with the nonborder site of San Antonio, separately for men and women. Neighborhood-level variables (based on census tracts and block groups) included drug availability, neighborhood insecurity, crime victimization, crime witnessing, off-premise alcohol outlet density, on-premise alcohol outlet density, percentage crossing the border more than 100 times, neighborhood disadvantage, residential stability, and percentage of White/non-Hispanic. RESULTS When individual sociodemographic characteristics were controlled for, lower drug use among men in Brownsville/McAllen (vs. San Antonio) was partially mediated by lower drug availability and lower perceived neighborhood insecurity whereas increased drug use among women in both Laredo and Brownsville/McAllen was partially mediated by the lower proportion of White/non-Hispanic residents compared with San Antonio. CONCLUSIONS Neighborhood-level variables partially explain the heterogeneity in drug use across sites at the U.S.-Mexico border, but different factors appear to be operating for men compared with women. These findings suggest the potential importance of addressing neighborhood factors in reducing drug-related harm at the U.S.-Mexico border.
A conserved cysteine‐based redox mechanism sustains TFEB/HLH‐30 activity under persistent stress

Mammalian TFEB and TFE3, as well as their ortholog in Caenorhabditis elegans HLH‐30, play an important role in mediating cellular response to a variety of stress conditions, including nutrient deprivation, oxidative stress, and pathogen infection. In this study, we identify a novel mechanism of TFEB/HLH‐30 regulation through a cysteine‐mediated redox switch. Under stress conditions, TFEB‐C212 undergoes oxidation, allowing the formation of intermolecular disulfide bonds that result in TFEB oligomerization. TFEB oligomers display increased resistance to mTORC1‐mediated inactivation and are more stable under prolonged stress conditions. Mutation of the only cysteine residue present in HLH‐30 (C284) significantly reduced its activity, resulting in developmental defects and increased pathogen susceptibility in worms. Therefore, cysteine oxidation represents a new type of TFEB post‐translational modification that functions as a molecular switch to link changes in redox balance with expression of TFEB/HLH‐30 target genes.
Regeneration during Obesity: An Impaired Homeostasis

Simple Summary Regeneration represents the biological processes that allow cells and tissues to renew and develop. During obesity, a variety of changes and reactions are seen. This includes inflammation and metabolic disorders. These obesity-induced changes do impact the regeneration processes. Such impacts that obesity has on regeneration would affect tissues and organs development and would also have consequences on the outcomes of therapies that depend on cells regeneration (such as burns, radiotherapy and leukemia) given to patients suffering from obesity. Therefore, a particular attention should be given to patients suffering from obesity in biological, therapeutic and clinical contexts that depend on regeneration ability. Abstract Obesity is a health problem that, in addition to the known morbidities, induces the generation of a biological environment with negative impacts on regeneration. Indeed, factors like DNA damages, oxidative stress and inflammation would impair the stem cell functions, in addition to some metabolic and development patterns. At the cellular and tissulaire levels, this has consequences on growth, renewal and restoration which results into an impaired regeneration. This impaired homeostasis concerns also key metabolic tissues including muscles and liver which would worsen the energy balance outcome towards further development of obesity. Such impacts of obesity on regeneration shows the need of a specific care given to obese patients recovering from diseases or conditions requiring regeneration such as burns, radiotherapy and leukemia. On the other hand, since stem cells are suggested to manage obesity, this impaired regeneration homeostasis needs to be considered towards more optimized stem cells-based obesity therapies within the context of precision medicine.
Combining traditional and molecular epidemiology methods to quantify local HIV transmission among foreign-born residents

Objectives: We evaluated the ability for molecular epidemiology to augment traditional HIV surveillance beyond the detection of clusters for outbreak investigation. To do this, we address a question of interest to Public Health – Seattle and King County: what proportion of HIV diagnoses among people born outside of the United States are acquired locally? Design: King County residents diagnosed with HIV, 2010–2018. Methods: We linked HIV-1 pol gene sequences to demographic information obtained from the National HIV Surveillance System, Public Health – Seattle and King County case investigation and partner services interviews. We determined the likely location of HIV acquisition based on HIV testing, travel histories and cluster-based molecular analyses. Results: Among 2409 people diagnosed with HIV, 798 (33%) were born outside of the United States. We inferred the location of acquisition for 77% of people born outside of the United States: 26% likely acquired HIV locally in King County (of whom 69% were MSM, 16% heterosexual), and 51% likely acquired HIV outside of King County (primarily outside of the United States). Of this 77% of people for whom we inferred the location of HIV acquisition, 45% were determined using traditional epidemiology methods and an additional 32% were inferred using molecular epidemiology methods. Conclusion: We found that the National HIV Surveillance System misclassified the majority of HIV-infected foreign-born residents as ‘new’ local infections, and that these cases contribute to an overestimate of local incidence. Our findings highlight how molecular epidemiology can augment traditional HIV surveillance activities and provide useful information to local health jurisdictions beyond molecular cluster detection.
Female reproductive tract has low concentration of SARS-CoV2 receptors

There has been significant concern regarding fertility and reproductive outcomes during the SARS-CoV2 pandemic. Recent data suggests a high concentration of SARS-Cov2 receptors, ACE2 or TMPRSS2, in nasal epithelium and cornea, which explains person-to-person transmission. We investigated the prevalence of SARS-CoV2 receptors among reproductive tissues by exploring the single-cell sequencing datasets from uterus, myometrium, ovary, fallopian tube, and breast epithelium. We did not detect significant expression of either ACE2 or TMPRSS2 in the normal human myometrium, uterus, ovaries, fallopian tube, or breast. Furthermore, none of the cell types in the female reproductive organs we investigated, showed the co-expression of ACE2 with proteases, TMPRSS2, Cathepsin B (CTSB), and Cathepsin L (CTSL) known to facilitate the entry of SARS2-CoV2 into the host cell. These results suggest that myometrium, uterus, ovaries, fallopian tube, and breast are unlikely to be susceptible to infection by SARS-CoV2.
‘Real-world’ effectiveness of omalizumab in adults with severe allergic asthma: a meta-analysis

ABSTRACT Background: Severe asthma affects 5–10% of the 350 million people with asthma worldwide. Findings from the authors’ previous meta-analysis supported omalizumab use as an adjuvant treatment for severe allergic asthma. The publication of fourteen new articles necessitates an update of the meta-analysis. Objective: To evaluate the ‘real-world’ effectiveness of omalizumab in the treatment of acute allergic asthma in adults by calculating pooled effects estimates from data in published articles. Methods: Articles on omalizumab effectiveness in ‘real-world’ settings were identified. Effect sizes, including point estimates of the proportion of patients who met a given criteria, mean improvements relative to baseline, and change in the proportion of patients requiring oral corticosteroids compared to baseline were extracted. Meta-analysis of proportions was conducted to pool effect sizes based on proportions. Standardized mean differences (Hedges’ g) were calculated from means and standard deviations. Relative risk was calculated from changes in proportions. Variability within and between studies was evaluated. Results: Omalizumab increases the percentage of individuals rated ‘good’ or ‘excellent’ on the Global Evaluation of Treatment Effectiveness Scale. Omalizumab also improves respiratory function, quality-of-life, and asthma control while reducing medication usage, exacerbations, hospitalizations, and adverse events. Conclusion: ‘Real-world’ evidence continues to support the use of omalizumab as adjuvant treatment for severe allergic asthma.
Similarity in functional brain connectivity at rest predicts interpersonal closeness in the social network of an entire village

Significance In what ways are we similar to our friends? Here, we characterized the social network of residents of a remote village, a subset of whom contributed personality and neuroimaging data. We demonstrate that similarity in individuals’ resting-state functional connectomes predicts individuals’ proximity in their real-world social network, even when controlling for demographic characteristics and self-reported personality traits. Our results suggest that patterns of functional brain activity during rest encode latent similarities (e.g., in terms of how people think and behave) that are associated with friendship. Taken together, integrating neuroimaging and social network analysis can offer novel insights into how the brain shapes or is shaped by the social networks that it inhabits. People often have the intuition that they are similar to their friends, yet evidence for homophily (being friends with similar others) based on self-reported personality is inconsistent. Functional connectomes—patterns of spontaneous synchronization across the brain—are stable within individuals and predict how people tend to think and behave. Thus, they may capture interindividual variability in latent traits that are particularly similar among friends but that might elude self-report. Here, we examined interpersonal similarity in functional connectivity at rest—that is, in the absence of external stimuli—and tested if functional connectome similarity is associated with proximity in a real-world social network. The social network of a remote village was reconstructed; a subset of residents underwent functional magnetic resonance imaging. Similarity in functional connectomes was positively related to social network proximity, particularly in the default mode network. Controlling for similarities in demographic and personality data (the Big Five personality traits) yielded similar results. Thus, functional connectomes may capture latent interpersonal similarities between friends that are not fully captured by commonly used demographic or personality measures. The localization of these results suggests how friends may be particularly similar to one another. Additionally, geographic proximity moderated the relationship between neural similarity and social network proximity, suggesting that such associations are particularly strong among people who live particularly close to one another. These findings suggest that social connectivity is reflected in signatures of brain functional connectivity, consistent with the common intuition that friends share similarities that go beyond, for example, demographic similarities.
Summary Measures and Measures of Effect: Summarizing and Comparing Outcomes in Rehabilitation Research. Part 3: Time‐to‐Event Outcomes, Unequal Follow‐up Times, and Survival Analysis

Time-to-event outcomes are outcomes that occur at a specific moment in time a fall, a sports-related injury, a change in clinical state. Rehabilitation research studies that follow patients over time, whether prospectively or retrospectively, often have unequal follow-up time. How might we see authors summarize and compare occurrence of outcomes in this situation? How might authors present more detail about when events happened over the course of the study, for example, if there were a lot of events early on? The objectives of thisMethodology Matters feature are to (1) help rehabilitation clinicians understand how to recognize when research is using an outcome that could be treated as a time-to-event outcome; (2) illustrate a potential pitfall in studies with event-type outcomes failure to appropriately “handle” unequal follow-up time; and (3) introduce several types of methods that can be used to produce summary measures and measures of effect when follow-up times are unequal, including two common survival analysis strategies (Kaplan-Meier curves and Cox proportional hazards regression). As with previous features, we’ve purposefully excluded or “fudged” some concepts that are not necessary for clinician readers (and we hope methodologists can forgive us). Time-to-event outcome = an outcome that occurs at a specific point in time. This could be a clinical event (eg, a fall), or a clinically important change in state is observed (eg, a clinically meaningful increase in function).
Substituent Effect on Porphyrin Film-Gas Interaction by Optical Waveguide: Spectrum Analysis and Molecular Dynamic Simulation

Substituent effect on optical gas sensing performance in porphyrin-based optical waveguide detection system was studied by molecular dynamics simulation (MDS), absorption/emission spectrum analysis, and optical waveguide (OWG) detection. The affinities of porphyrin with seven types of substituents (–H, –OH, –tBu, –COOH, –NH2, –OCH3, –SO3−) on para position of meso-phenyl porphyrin toward gas molecules in adsorption process were studied in different size of boxes with the same pressure and concentration. Analyte gases (CO2, H2S, HCl, NO2) were exposed to porphyrin film in absorption spectrophotometer, and in OWG with evanescent field excited by a guiding laser light with 670 nm wavelength. The extent of interaction between host molecule and the guest analytes was analyzed by the number of gas molecules in vicinity of 0.3 nm around substituents of porphyrin molecules. Optical waveguide results reveal that sulfonate porphyrin is mostly responsive to hydrochloride, hydrosulfide gas and nitrogen dioxide gases with strong response intensity. Molecular dynamics and spectral analysis provide objective information about the molecular state and sensing properties. Molecular rearrangements induced by gas exposure was studied by spectral analysis and surface morphology before and after gas exposure taking hydrosulfide gas as an example. Film-gas interaction mechanism was discussed in terms of each gas and substituent group characters.
Presence of anti-nuclear antibodies is a risk factor for the appearance of anti-drug antibodies during infliximab or adalimumab therapy in patients with rheumatoid arthritis

This study aimed to directly analyze the potential relationship of anti-nuclear antibodies (ANA) before and after the administration of TNF-α inhibitors (TNFi) with the appearance of anti-drug antibodies (ADrA) in patients with rheumatoid arthritis (RA). A total of 121 cases, viz., 38, 53, and 30 cases treated with infliximab (IFX), adalimumab (ADA), and etanercept (ETN), respectively, were enrolled. The ANA titers were measured using indirect immunefluorescence assay (IF-ANA) and multiplex flow immunoassay (ANA Screen) before and serially during the therapy. The anti-IFX antibodies (HACA) and anti-ADA antibodies (AAA) were measured with a radioimmunoassay. ADrA turned positive in 14 (36.8%) among 38 patients treated with IFX, and 16 (30.2%) among 53 treated with ADA. All of them were positive for IF-ANA before TNFi administration, while ADrA never appeared in any of the 15 patients negative for IF-ANA (< 40). IF-ANA of high titers (≥ 320 and ≥ 640) before IFX treatment showed a significant association with the appearance of HACA 52 weeks after IFX (P = 0.040 and 0.017, respectively), whereas AAA appearance was not related to IF-ANA titers before treatment. Moreover, IF-ANA of high titers before IFX treatment was significantly associated with inefficacy and discontinuation of the treatment. The positivity of anti-SS-A antibodies before therapy might be a risk factor for ADrA appearance in patients treated with IFX or ADA. The percentage of patients whose IF-ANA titers increased was significantly higher with IFX than with ADA or ETN treatments (P = 0.026 and 0.022, respectively). High ANA titers and positive ANA Screen after IFX therapy showed a significant association with HACA appearance and possibly led to treatment failure. Among the three TNFi, only IFX showed a close relationship with IF-ANA and ADrA appearance, suggesting the interaction of immunogenicity with autoimmunity as well as the advantage of ANA measurement before TNFi therapy.