Miracle-dz/UniFAR-FTUs huggingface dataset:
FoxO1 is a crucial mediator of TGF-β/TAK1 signaling and protects against osteoarthritis by maintaining articular cartilage homeostasis

Significance Osteoarthritis (OA) is the most prevalent joint disease and has reached epidemic proportions in the United States. Currently, there are no effective therapeutic approaches to treat OA. Thus, there is an urgent need to develop mechanistically-based therapeutic strategies to treat this disease. In this study, we identified FoxO1 as a crucial mediator of the TGF-β pathway. We also showed that loss of FoxO1 in articular cartilage leads to OA-like pathologies and gain of FoxO1 in cartilage protects against surgically and loss-of-TGF-β-induced OA. Our study defines FoxO1 as a key downstream target of TGF-β signaling and the requisite role in the maintenance of postnatal articular cartilage homeostasis and implicates modulation of FoxO1 levels/activity as a potential therapeutic strategy for OA. Transforming growth factor-β (TGF-β) signaling is a critical regulator for articular cartilage tissue maintenance and chondrocyte homeostasis. Nonetheless, the regulatory networks and downstream signaling pathways that govern the chondroprotective function of TGF-β in the context of osteoarthritis (OA) are not fully defined. Recent studies reveal that mice with postnatal deletion of triple forkhead box class Os (FoxOs) (1, 3, and 4) spontaneously develop OA-like pathologies. The OA phenotype largely recapitulates that observed in mice with loss of TGF-βR2. In the present study, we investigated the role of FoxOs as downstream mediators of TGF-β signaling and define their role in articular cartilage homeostasis. Among the three FoxOs (1, 3, and 4), TGF-β signaling exclusively regulates FoxO1 in a TGF-β activated kinase 1 (TAK1)-dependent manner. Furthermore, FoxO1 was genetically ablated in mice in a tissue-specific manner in articular cartilage or overexpressed in adult cartilage immediately followed by meniscal/ligament injury (MLI). Histological and microcomputed tomography (micro-CT) analyses demonstrated that loss of FoxO1 postnatally in articular cartilage leads to OA-like pathologies, and gain of FoxO1 in adult cartilage has both preventative and therapeutic effects on surgically induced OA. Mechanistically, FoxO1 was found to maintain articular chondrocyte homeostasis through induction of anabolic and autophagy-related gene expressions. Importantly, overexpression of FoxO1 markedly rescued the OA phenotypes caused by deficiency in TGF-β signaling in chondrocytes. Our study identifies that TGF-β/TAK1-FoxO1 is a key signaling cascade in regulation of articular cartilage autophagy and homeostasis and is a potentially important therapeutic target for OA-like joint diseases.
Immune-related biomarker risk score predicts prognosis in prostate cancer

In this study, we constructed a model using a Cox proportional hazards model based on the expression of eight immune-related genes that were associated with prognosis in prostate cancer: EDNRB, ANGPTL2, TNFSF15, TNFRSF10D, EDN2, BMP2, NLRP14, and PLK1. We then identified associations between risk scores calculated with the model, tumor microenvironment characteristics, and immune cell infiltration. Prostate cancer patients in the high score group had poorer prognoses, and validation with the external GSE54460 dataset confirmed that the scoring model predicted biochemical recurrence with AUC values of 0.749 at 1 year, 0.804 at 3 years, and 0.774 at 5 years. Proportions of infiltrated M2 macrophages and regulatory T cells were increased in the high risk group, while CD8+ T cells were increased in the low risk group. Network analysis revealed that PLK1 may be a key regulator of the immune-suppressive microenvironment in prostate cancer. Double immunofluorescence labeling of a prostate cancer tissue microarray indicated that PLK1 expression correlated positively with numbers of infiltrating macrophages. These results indicate that an immune- related, gene-based risk score effectively reflects immune microenvironment characteristics and predicts prognosis in prostate cancer.
Circulating senescent angiogenic T cells are linked with endothelial dysfunction and systemic inflammation in hypertension

Supplemental Digital Content is available in the text Objective: Angiogenic T cells (Tang cells), a recently discovered T-cell subset, have been reported involved in the repair of endothelial injury. The purpose of this study was to explore the correlation of immunologic senescence and pro-inflammatory capacity of Tang cells with endothelial dysfunction in hypertensive patients. Methods: Immunological characteristics of Tang cells (CD3+CD31+CXCR4+) from hypertensive patients with or without endothelial dysfunction were elucidated by surface immunophenotyping and intracellular cytokine staining. Endothelial function was measured by flow-mediated dilation (FMD). Results: The frequency of CD28null subset in CD4+ Tang cells was notably elevated in hypertensive patients with endothelial dysfunction, which was negatively associated with FMD. The high frequency of CD28nullCD4+ Tang cells was an independent risk factor of endothelial dysfunction with good diagnostic performance in ROC curve analysis. Immunophenotyping revealed that this specific subset of Tang cells exhibited senescent profile and has low hTERT expression. CD28nullCD4+ Tang cells produced high levels of inflammatory cytokines, IL-6, IFN-γ and TNF-α, and significantly correlated with the systemic inflammation in hypertensive patients with endothelial dysfunction. Conclusion: Collectively, our findings demonstrate for the first time that CD28null subset in CD4+ Tang cells with senescent and pro-inflammatory phenotype is dependently correlated with impaired FMD and systemic inflammation, which might contribute to the immunopathologic mechanism of endothelial dysfunction. Identification of a pathogenic CD4+ Tang-cell subset lacking CD28 may offer opportunities for the evaluation and management of endothelial dysfunction in hypertension.
Reduced Vancomycin Susceptibility, MRSA and Treatment Failure in Pediatric Staphylococcus aureus Bloodstream Infections.

BACKGROUND Clinical implications of reduced vancomycin susceptibility (RVS) among pediatric Staphylococcus aureus bloodstream infections are unknown. METHODS We identified all children at 2 children's hospitals with ≥1 blood culture positive for S. aureus. We compared patient and clinical factors for RVS and non-RVS infections using Wilcoxon rank-sum and chi-squared tests. Treatment failure and the duration of bacteremia for RVS versus non-RVS and for methicillin-resistant Staphylococcus aureus (MRSA) versus methicillin-susceptible Staphylococcus aureus (MSSA) infections were compared using multivariable logistic and Poisson regressions, respectively. For MRSA infections, the association of empiric vancomycin monotherapy with treatment failure was assessed using multivariable logistic regression. RESULTS RVS was present in 72% (309/426) of cases. No patient or infection characteristics, including methicillin resistance, were associated with RVS. RVS was associated with an increased duration of bacteremia compared with non-RVS infections, aIRR = 1.15 (95% confidence interval: 1.02-1.30). The odds of treatment failure was similar for RVS and non-RVS infections, aOR = 1.04 (0.62-1.74). In contrast, MRSA infections were more likely to have treatment failure than MSSA infections, aOR = 3.03 (95% confidence interval: 1.84-5.00). For MRSA infections, empiric vancomycin monotherapy was associated with an increased odds of treatment failure compared with non-vancomycin or combination anti-MRSA antibiotics, aOR = 3.23 (1.12-9.26). CONCLUSIONS RVS was common and was associated with a longer duration of bacteremia but not with treatment failure. Treatment failure was more common for MRSA than for MSSA bloodstream infections. Empiric vancomycin monotherapy increased the odds of treatment failure for MRSA infections.
Label-Free Visualization and Tracking of Gold Nanoparticles in Vasculature Using Multiphoton Luminescence

Gold nanoparticles continue to generate interest for use in several biomedical applications. Recently, researchers have been focusing on exploiting their dual diagnostic/therapeutic theranostic capabilities. Before clinical translation can occur, regulatory agencies will require a greater understanding of their biodistribution and safety profiles post administration. Previously, the real-time identification and tracking of gold nanoparticles in free-flowing vasculature had not been possible without extrinsic labels such as fluorophores. Here, we present a label-free imaging approach to examine gold nanoparticle (AuNP) activity within the vasculature by utilizing multiphoton intravital microscopy. This method employs a commercially available multiphoton microscopy system to visualize the intrinsic luminescent signal produced by a multiphoton absorption-induced luminescence effect observed in single gold nanoparticles at frame rates necessary for capturing real-time blood flow. This is the first demonstration of visualizing unlabeled gold nanoparticles in an unperturbed vascular environment with frame rates fast enough to achieve particle tracking. Nanoparticle blood concentration curves were also evaluated by the tracking of gold nanoparticle flow in vasculature and verified against known pre-injection concentrations. Half-lives of these gold nanoparticle injections ranged between 67 and 140 s. This label-free imaging approach could provide important structural and functional information in real time to aid in the development and effective analysis of new metallic nanoparticles for various clinical applications in an unperturbed environment, while providing further insight into their complex uptake and clearance pathways.
The Diversity of Primates: From Biomedicine to Conservation Genomics.

Until now, the field of primate genomics has focused on two major themes: understanding human evolution and advancing biomedical research. We propose that it is now time for a third theme to receive attention: conservation genomics. As a result of anthropogenic effects, the majority of primate species have become threatened with extinction. A more robust primate conservation genomics will allow for genetically informed population management. Thanks to a steady decline in the cost of sequencing, it has now become feasible to sequence whole primate genomes at the population level. Furthermore, technological advances in noninvasive genomic methods have made it possible to acquire genome-scale data from noninvasive biomaterials. Here, we review recent advances in the analysis of primate diversity, with a focus on genomic data sets across the radiation. Expected final online publication date for the Annual Review of Animal Biosciences, Volume 9 is February 16, 2021. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Estimating and forecasting spatial population dynamics of apex predators using transnational genetic monitoring

Significance We are experiencing the accelerated loss and reconfiguration of biological diversity. Meanwhile, those charged with natural resource management are struggling to meet the challenges of monitoring and managing wildlife populations across vast areas crisscrossed by political borders. What if, akin to weather maps, we could track and forecast the dynamics of wildlife populations across space and time? Using the world’s most extensive large carnivore monitoring program, we showcase the application of an effective tool for spatially explicit quantification of wildlife population dynamics at scales that are relevant to management and conservation. The ongoing recovery of terrestrial large carnivores in North America and Europe is accompanied by intense controversy. On the one hand, reestablishment of large carnivores entails a recovery of their most important ecological role, predation. On the other hand, societies are struggling to relearn how to live with apex predators that kill livestock, compete for game species, and occasionally injure or kill people. Those responsible for managing these species and mitigating conflict often lack fundamental information due to a long-standing challenge in ecology: How do we draw robust population-level inferences for elusive animals spread over immense areas? Here we showcase the application of an effective tool for spatially explicit tracking and forecasting of wildlife population dynamics at scales that are relevant to management and conservation. We analyzed the world’s largest dataset on carnivores comprising more than 35,000 noninvasively obtained DNA samples from over 6,000 individual brown bears (Ursus arctos), gray wolves (Canis lupus), and wolverines (Gulo gulo). Our analyses took into account that not all individuals are detected and, even if detected, their fates are not always known. We show unequivocal quantitative evidence of large carnivore recovery in northern Europe, juxtaposed with the finding that humans are the single-most important factor driving the dynamics of these apex predators. We present maps and forecasts of the spatiotemporal dynamics of large carnivore populations, transcending national boundaries and management regimes.
Diabetic Retinopathy Environment-Wide Association Study (EWAS) in NHANES 2005–2008

Several circulating biomarkers are reported to be associated with diabetic retinopathy (DR). However, their relative contributions to DR compared to known risk factors, such as hyperglycaemia, hypertension, and hyperlipidaemia, remain unclear. In this data driven study, we used novel models to evaluate the associations of over 400 laboratory parameters with DR compared to the established risk factors. Methods: we performed an environment-wide association study (EWAS) of laboratory parameters available in National Health and Nutrition Examination Survey (NHANES) 2007–2008 in individuals with diabetes with DR as the outcome (test set). We employed independent variable (feature) selection approaches, including parallelised univariate regression modelling, Principal Component Analysis (PCA), penalised regression, and RandomForest™. These models were replicated in NHANES 2005–2006 (replication set). Our test and replication sets consisted of 1025 and 637 individuals with available DR status and laboratory data respectively. Glycohemoglobin (HbA1c) was the strongest risk factor for DR. Our PCA-based approach produced a model that incorporated 18 principal components (PCs) that had an Area under the Curve (AUC) 0.796 (95% CI 0.761–0.832), while penalised regression identified a 9-feature model with 78.51% accuracy and AUC 0.74 (95% CI 0.72–0.77). RandomForest™ identified a 31-feature model with 78.4% accuracy and AUC 0.71 (95% CI 0.65–0.77). On grouping the selected variables in our RandomForest™, hyperglycaemia alone achieved AUC 0.72 (95% CI 0.68–0.76). The AUC increased to 0.84 (95% CI 0.78–0.9) when the model also included hypertension, hypercholesterolemia, haematocrit, renal, and liver function tests.
EMG-Force and EMG-Target Models During Force-Varying Bilateral Hand-Wrist Contraction in Able-Bodied and Limb-Absent Subjects

System identification models relating forearm electromyogram (EMG) signals to phantom wrist radial-ulnar deviation force, pronation-supination moment and/or hand open-close force (EMG-force) are hampered by lack of supervised force/moment output signals in limb-absent subjects. In 12 able-bodied and 7 unilateral transradial limb-absent subjects, we studied three alternative supervised output sources in one degree of freedom (DoF) and 2-DoF target tracking tasks: (1) bilateral tracking with force feedback from the contralateral side (non-dominant for able-bodied/ sound for limb-absent subjects) with the contralateral force as the output, (2) bilateral tracking with force feedback from the contralateral side with the target as the output, and (3) dominant/limb-absent side unilateral target tracking without feedback and the target used as the output. “Best-case” EMG-force errors averaged ~ 10% of maximum voluntary contraction (MVC) when able-bodied subjects’ dominant limb produced unilateral force/moment with feedback. When either bilateral tracking source was used as the model output, statistically larger errors of 12–16 %MVC resulted. The no-feedback alternative produced errors of 25–30 %MVC, which was nearly half the tested force range of ± 30 %MVC. Therefore, the no-feedback model output was not acceptable. We found little performance variation between DoFs. Many subjects struggled to perform 2-DoF target tracking.
Cost-effectiveness of Interventions to Increase HPV Vaccine Uptake

Using a simulation model of HPV, we find 3 interventions to increase HPV vaccination are a high-value use of state funding over 50 years. BrightcoveDefaultPlayer10.1542/6193513362001PEDS-VA_2020-0395 Video Abstract OBJECTIVES: We sought to prioritize interventions for increasing human papillomavirus (HPV) vaccination coverage based on cost-effectiveness from a US state perspective to inform decisions by policy makers. METHODS: We developed a dynamic simulation model of HPV transmission and progression scaled to a medium-sized US state (5 million individuals). We modeled outcomes over 50 years comparing no intervention to a one-year implementation of centralized reminder and recall for HPV vaccination, school-located HPV vaccination, or quality improvement (QI) visits to primary care clinics. We used probabilistic sensitivity analysis to assess a range of plausible outcomes associated with each intervention. Cost-effectiveness was evaluated relative to a conservative willingness-to-pay threshold; $50 000 per quality-adjusted life-year (QALY) . RESULTS: All interventions were cost-effective, relative to no intervention. QI visits had the lowest cost and cost per QALY gained ($1538 versus no intervention). Statewide implementation of centralized reminder and recall cost $28 289 per QALY gained versus QI visits. School-located vaccination had the highest cost but was cost-effective at $18 337 per QALY gained versus QI visits. Scaling to the US population, interventions could avert 3000 to 14 000 future HPV cancers. When varying intervention cost and impact over feasible ranges, interventions were typically preferred to no intervention, but cost-effectiveness varied between intervention strategies. CONCLUSIONS: Three interventions for increasing HPV vaccine coverage were cost-effective and offered substantial health benefits. Policy makers seeking to increase HPV vaccination should, at minimum, dedicate additional funding for QI visits, which are consistently effective at low cost and may additionally consider more resource-intensive interventions (reminder and recall or school-located vaccination).
Diet and Chemotherapy: The Effects of Fasting and Ketogenic Diet on Cancer Treatment

Introduction: Diet may influence various aspects of human health. In fact, it is well known that diet can favour or not the development of various human pathologies, like diabetes, hypertension, and hypercholesterolaemia. Interestingly, diet has an influence in cancer development too (e.g., this relation has been studied for pancreatic, colonic, gastric, and breast cancers). Between the mechanisms that could explain this relation, there is epigenetic. In fact, thanks to epigenetic reprogramming, certain substances introduced with diet could affect gene expression, especially of those genes involved in cells’ proliferation and growth. In recent years, some studies have been published about the role that diet could have on chemotherapy outcome. Especially, various studies have analysed the effects of fasting and ketogenic diet (KD) during chemotherapy. The aim of this study is to summarize scientific evidences about diet and its effects on chemotherapy on humans and to better understand if these approaches deserve to be further investigated and might be suitable and beneficial during cancer treatment. Materials and Methods: We performed an electronic literature search of the PubMed database, using the combination of following terms: “fasting” or “ketogenic” with “chemotherapy,” “cancer treatment. ” We included studies on humans about fasting and KD during chemotherapy, excluding reviews, case series including <10 patients, studies conducted on animals or limited to radiotherapy treatment, and studies that were mostly about molecular mechanisms. Results/Discussion In our analysis we included 4 studies (1 randomized controlled trial, 1 retrospective study, and 2 prospective pilot studies) about KD and 4 studies (1 prospective cohort study, 1 case series report, and 2 randomized trials) about fasting during oncological treatments. Authors suggested an improvement of quality of life (QoL) and fatigue in patients under chemotherapy, especially in the 8 days after chemotherapy treatment. We found that both fasting and KD demonstrated to be tolerable and feasible during oncological treatments. Conversely, data about survival outcomes are still controversial, but it should be underlined that it was not the outcome of these preliminary studies. Conclusions: All comparatives studies have demonstrated that even fasting then KD results in a reduction of collateral effects of adjuvant chemotherapy (due to reduction of drugs toxicity) and a better QoL than in patients that follow no diet. Unfortunately, despite the fact that various laboratory and animal studies confirm advantages from KD and fasting, few data are today disposable on humans: further studies are needed to confirm data exposed in this review.
Regenerated Cell Therapy for Stress Urinary Incontinence: A Meta-Analysis

Abstract Purpose To evaluate the efficacy and safety of regenerated cell therapy for stress urinary incontinence (UI) in humans. Methods We searched articles from PubMed, Embase, and the Cochrane Library database published before February 24, 2020. Of 396 records identified, 23 articles on human clinical research met our criteria, including a total of 890 patients. Stata/SE12.0 software was used to analyze cure, efficiency (cure rate plus improvement rate), and complication rates. Results No significant differences in cure rates and effective rates were observed for any cell type in males. However, in females, the myocytes with fibroblasts subgroup (82%) and nucleated cells with platelets subgroup (89%) exhibited significantly higher cure rates compared with the other two subgroups (25% and 36%). Pooled effective rates of myocytes and fibroblasts (92%) and nucleated cells with platelets (97%) were also higher compared with the other two subgroups (72% and 60%). Pooled complication rates were 23% and 26% in males and females, respectively, and there were some differences among subgroups. Although some studies reported postoperative complications, no serious complications were reported and most recovered within 1–2 weeks. Conclusions Limited studies have indicated the safety and effectiveness of regenerated cells for treating stress UI in the follow-up period, which may be an ideal method to treat stress UI in the future. Moreover, nucleated cells with platelets and myocytes with fibroblasts were markedly effective, but whether cell injection therapies elicit superior effects need further confirmation.