Miracle-dz/UniFAR-FTUs huggingface dataset:
Intestinal Dysbiosis and Markers of Systemic Inflammation in Viscerally and Generally Obese Persons Living With HIV.

BACKGROUND The intestinal microbiota contributes to the pathogenesis of obesity and metabolic disorders. People living with HIV (PLWH) have a higher risk for the development of visceral adiposity with accompanying worsened cardiovascular risk. SETTING Convenience sample from an HIV clinic and research unit. METHODS To understand the relationship between adiposity and intestinal dysbiosis, we compared the gut microbiota and inflammatory markers in a cross-sectional study of viscerally obese, generally obese, and lean PLWH. Fecal intestinal microbiota was characterized by 16S ribosomal DNA sequencing. Abdominal CTs quantified subcutaneous adipose tissue and visceral adipose tissue (SAT; VAT). Serum high sensitivity C-reactive protein, adiponectin, leptin, IL-6, MCP-1, and sCD14 were assayed. RESULTS We studied 15, 9, and 11 participants with visceral obesity, general obesity, and lean body type, respectively. The generally obese group were all women and 2/3 African American, whereas the visceral obesity and lean groups were predominantly white and men who have sex with men. Markers of systemic inflammation and sCD14 were higher in general obesity compared with lean. sCD14 was positively correlated with VAT, but not SAT. Bacterial diversity was significantly reduced in participants with visceral and general obesity and composition of intestinal microbiota was significantly different from lean body types. Bacterial alpha diversity was negatively correlated with VAT area, waist/hip ratio, and sCD14, but not with SAT area. CONCLUSIONS In this exploratory study, obesity in general was associated with dysbiotic intestinal microbiota. The relationships of VAT to bacterial diversity and sCD14 suggest that dysbiosis in viscerally obese PLWH could be associated with heightened inflammatory state.
Disentangling the Far Transfer of Language Comprehension Gains Using Latent Mediation Models.

While we know that interventions targeting oral language can be effective, little is known about what drives these effects. In this study, we examine whether gains in transfer measures are mediated through the specific words that are trained in a language intervention. Based on a large-scale randomized controlled trial of language intervention in four- to five-year-old children, latent mediation models were used to disentangle oral language gains in transfer measures. The results first showed that the effects of the language intervention and the transfer effects are generated through expressive rather than receptive measures of language. Second, we found that the effects of the intervention on intermediate transfer measures of language were mediated through the ability to define the trained words. Third, and critically, for far transfer measures that did not contain any of the trained words, the effects were mediated through the trained words. The findings relate to theories of transfer and support the idea that far transfer is possible, at least within the same domain. In addition, it seems that effects on receptive language skills are difficult to obtain and that what is improved is instead the children's ability to express themselves and use procedures to explain words. Thus, in order to optimize intervention effects, future studies should focus on expressive language.
Energy Deficit Required for Exercise-induced Improvements in Glycemia the Next Day.

PURPOSE This study determined the impact of an exercise-induced energy deficit on postprandial and 24h glycemic control the day after a session of exercise. METHODS Fifteen healthy participants (m/f=5/10, 27±6 yrs, BMI=24±3 kg·m, VO2peak=36±9 mL·kg·min) completed two separate 5-day experimental trials performed under "free-living" conditions. On day 1 of each trial, participants were fitted with a continuous glucose monitor (CGM) and abstained from exercise. Day 2 served as a non-exercise control (NoEx). On day 3, participants exercised at ~1500h (65% VO2peak) until they expended 350 kcals (~45min). The diet during both experimental trials were identical with the exception of meals after this exercise session. During one trial, the dinner after exercise did not replenish the 350 kcals expended during exercise, thereby establishing an exercise energy deficit (ExDEF). During the other experimental trial, the dinner after exercise contained an additional 350 kcals to compensate for the energy expended during exercise, and thereby maintained energy balance after exercise (ExBAL). Free-living glycemia was measured the day before exercise (NoEx) and the day after exercise under ExDEF and ExBAL conditions. RESULTS The day after exercise, 3h postprandial area under curve (AUC) was lower after breakfast in ExDEF compared with ExBAL (16.0±1.8 vs. 17.0±1.6 mmol·L·h·3h, P=0.01), but did not differ between groups after lunch (P=0.24), dinner (P=0.39), or evening snack (P=0.45). Despite differences in the glycemic response to breakfast, 24h glycemia did not differ between ExDEF and ExBAL (AUC= 128±10 vs. 131±10 mmol·L·h·24h, respectively; P=0.54). CONCLUSION An exercise-induced energy deficit lowered the glycemic response to breakfast the next day - but this energy deficit did not impact total 24h glycemia the day after exercise in metabolically healthy adults.
A review and meta‐analysis of the epidemiology and clinical presentation of coxsackievirus A6 causing hand‐foot‐mouth disease in China and global implications

Coxsackievirus A6 (CV‐A6) has been associated with increasingly occurred sporadic hand‐foot‐mouth disease (HFMD) cases and outbreak events in many countries. In order to understand epidemiological characteristics of CV‐A6, we collected the information describing HFMD caused by CV‐A6 to describe the detection rate, severe rate and onychomadesis rate, which is defined as one or more nails defluvium, caused by CV‐A6 from 2007 to 2017. The results showed that there was an outbreak of CV‐A6 every other year, and overall trend of the epidemic of CA6‐associated HFMD was increasing in China. The detection rate of CV‐A6 in other countries was 32.0% (95% CI: 25.0%~40.0%) before 2013 and 28.0% (95% CI: 20.0%~36.0%) after 2013, respectively. Although the severe rate of HFMD caused by CV‐A6 was low (0.10%, 95% CI: 0.01%~0.20%), CV‐A6 can cause a high incidence of onychomadesis (28.0%, 95%CI: 21.9%‐34.3%). Thus, it would be worthwhile to research and develop an effective multivalent vaccine for CV‐A6 to achieve a more powerful prevention of HMFD.
Antitumor astins originate from the fungal endophyte Cyanodermella asteris living within the medicinal plant Aster tataricus

Significance Astins are natural products that bind to a crucial human regulatory protein, the stimulator of interferon genes (STING), which is a promising new therapeutic target for cancer and immune disorders. Astins have long been regarded as phytochemicals of a Chinese medicinal plant. Here, we show that they are produced by the newly identified fungal endophyte Cyanodermella asteris via a nonribosomal biosynthetic pathway. Moreover, we provide evidence that key astin variants are produced during symbiosis with the aster plant. The production of specific phytochemical variants during symbiotic interactions is poorly studied and might be more widespread than previously expected. These findings pave the way for a cost-effective biotechnological astin production. Medicinal plants are a prolific source of natural products with remarkable chemical and biological properties, many of which have considerable remedial benefits. Numerous medicinal plants are suffering from wildcrafting, and thus biotechnological production processes of their natural products are urgently needed. The plant Aster tataricus is widely used in traditional Chinese medicine and contains unique active ingredients named astins. These are macrocyclic peptides showing promising antitumor activities and usually containing the highly unusual moiety 3,4-dichloroproline. The biosynthetic origins of astins are unknown despite being studied for decades. Here we show that astins are produced by the recently discovered fungal endophyte Cyanodermella asteris. We were able to produce astins in reasonable and reproducible amounts using axenic cultures of the endophyte. We identified the biosynthetic gene cluster responsible for astin biosynthesis in the genome of C. asteris and propose a production pathway that is based on a nonribosomal peptide synthetase. Striking differences in the production profiles of endophyte and host plant imply a symbiotic cross-species biosynthesis pathway for astin C derivatives, in which plant enzymes or plant signals are required to trigger the synthesis of plant-exclusive variants such as astin A. Our findings lay the foundation for the sustainable biotechnological production of astins independent from aster plants.
Short and Long Term Clinical and Immunologic Follow up after Bone Marrow Mesenchymal Stromal Cell Therapy in Progressive Multiple Sclerosis—A Phase I Study

Bone marrow derived mesenchymal stromal cells (BM-MSCs) have emerged as a possible new therapy for Multiple Sclerosis (MS), however studies regarding efficacy and in vivo immune response have been limited and inconclusive. We conducted a phase I clinical study assessing safety and clinical and peripheral immune responses after MSC therapy in MS. Seven patients with progressive MS were intravenously infused with a single dose of autologous MSC (1–2 × 106 MSCs/kg body weight). The infusions were safe and well tolerated when given during clinical remission. Five out of seven patients completed the follow up of 48 weeks post-infusion. Brain magnetic resonance imaging (MRI) showed the absence of new T2 lesions at 12 weeks in 5/6 patients, while 3/5 had accumulated new T2 lesions at 48 weeks. Patient expanded disability status scales (EDSS) were stable in 6/6 at 12 weeks but declined in 3/5 patients at 48 weeks. Early changes of circulating microRNA levels (2 h) and increased proportion of FOXP3+ Tregs were detected at 7 days post-infusion compared to baseline levels. In conclusion, MSC therapy was safe and well tolerated and is associated with possible transient beneficial clinical and peripheral immunotolerogenic effects.
Role of BDNF in the pathophysiology and treatment of depression: Activity‐dependent effects distinguish rapid‐acting antidepressants

The pathophysiology and treatment of depression have been the focus of intense research and while there is much that remains unknown, modern neurobiological approaches are making progress. This work demonstrates that stress and depression are associated with atrophy of neurons and reduced synaptic connectivity in brain regions such as the hippocampus and prefrontal cortex that contribute to depressive behaviors, and conversely that antidepressant treatment can reverse these deficits. The role of neurotrophic factors, particularly brain‐derived neurotrophic factor (BDNF), has been of particular interest as these factors play a key role in activity‐dependent regulation of synaptic plasticity. Here, we review the literature demonstrating that exposure to stress and depression decreases BDNF expression in the hippocampus and PFC and conversely that antidepressant treatment can up‐regulate BDNF in the adult brain and reverse the effects of stress. We then focus on rapid‐acting antidepressants, particularly the NMDA receptor antagonist ketamine, which produces rapid synaptic and antidepressant behavioral actions that are dependent on activity‐dependent release of BDNF. This rapid release of BDNF differs from typical monoaminergic agents that require chronic administration to produce a slow induction of BDNF expression, consistent with the time lag for the therapeutic action of these agents. We review evidence that other classes of rapid‐acting agents also require BDNF release, demonstrating that this is a common, convergent downstream mechanism. Finally, we discuss evidence that the actions of ketamine are also dependent on another growth factor, vascular endothelial growth factor (VEGF) and its complex interplay with BDNF.
ADHD symptoms in relation to internalizing and externalizing symptoms in children: the mediating role of sluggish cognitive tempo

Abstract Objective: Although internalizing and externalizing disorders have received considerable attention among young population, the mechanisms that explain the relationships of internalization and externalization symptoms with attention deficit/hyperactivity disorder (ADHD) in children and adolescents are not well understood. Since sluggish cognitive tempo (SCT) symptoms had significant associations with ADHD, and internalization/externalization disorders, we examined whether SCT may mediate between ADHD symptoms and internalizing/externalizing problems during childhood. Methods: We performed a retrospective chart-review of 95 children and adolescents (76 boys and 19 girls, aged 6–16) with ADHD. The severity of ADHD was evaluated by Turgay DSM-IV-Based Disruptive Behavioral Disorders Screening and Rating Scale (T-DSMIV-S) completed by teachers. Measures of SCT, internalisation and externalisation symptoms, social, thought, and attentional problems were based on the Teacher Report Form (TRF) that was completed by subjects’ primary teachers. Results: The withdrawn scores were significantly correlated with SCT scores, social problems, and ADHD-inattention. There was an inverse correlation between withdrawn and ADHD-hyperactivity/impulsivity scores. The mediation test using bootstrapping method showed that the indirect coefficient for SCT was significant, after controlling of ADHD-inattention and social problems covariates, consistent with partial mediation. Conclusion: Our results may demonstrate that while externalization symptoms were associated with hyperactivity/impulsivity symptoms of ADHD, the internalization symptoms were significantly related to SCT in youngs with ADHD. Specifically, although social withdrawal was significantly related to ADHD-inattention, this relationship was mediated by the severity of SCT.
Molecular Insights into miRNA-Driven Resistance to 5-Fluorouracil and Oxaliplatin Chemotherapy: miR-23b Modulates the Epithelial–Mesenchymal Transition of Colorectal Cancer Cells

Although treatment of colorectal cancer with 5-florouracil and oxaliplatin is widely used, it is frequently followed by a relapse. Therefore, there is an urgent need for profound understanding of chemotherapy resistance mechanisms as well as the profiling of predictive markers for individualized treatment. In this study, we identified the changes in 14 miRNAs in 5-fluouracil and 40 miRNAs in oxaliplatin-resistant cell lines by miRNA sequencing. The decrease in miR-224-5p expression in the 5-fluorouracil-resistant cells correlated with drug insensitivity due to its overexpression-induced drug-dependent apoptosis. On the other hand, the miR-23b/27b/24-1 cluster was overexpressed in oxaliplatin-resistant cells. The knockout of miR-23b led to the partial restoration of oxaliplatin susceptibility, showing the essential role of miR-23b in the development of drug resistance by this cluster. Proteomic analysis identified target genes of miR-23b and showed that endothelial–mesenchymal transition (EMT) was implicated in oxaliplatin insensibility. Data revealed that EMT markers, such as vimentin and SNAI2, were expressed moderately higher in the oxaliplatin-resistant cells and their expression increased further in the less drug-resistant cells, which had miR-23b knockout. This establishes that the balance of EMT contributes to the drug resistance, showing the importance of the miR-23b-mediated fine-tuning of EMT in oxaliplatin-resistant cancer cells.
Profilin as a dual regulator of actin and microtubule dynamics

Although originally identified as G‐actin sequestering proteins, profilins are emerging as critical regulators of actin dynamics, capable of interacting with multiple acting binding proteins, and being able to link membrane lipids to cytoskeleton components. Recently, in addition to its actin, poly‐proline, and phosphatidylinositol binding domains, profilin has been shown to contain residues specialized in microtubule binding. Here we will discuss in a critical perspective the emerging body of data supporting that profilins are central mediators of actin microfilament and microtubule interaction. We will also address the unanswered questions in the field, including the nature of the interaction of profilin with microtubules, and its effect on microtubule dynamics. These recent discoveries deepen our understanding on how different cytoskeleton components are integrated within cells.
Long-term ticagrelor for secondary prevention in patients with prior myocardial infarction and no history of coronary stenting: insights from PEGASUS-TIMI 54.

AIMS PEGASUS-TIMI 54 demonstrated that long-term dual antiplatelet therapy (DAPT) with aspirin and ticagrelor reduced the risk of major adverse cardiovascular events (MACE), with an acceptable increase in bleeding, in patients with prior myocardial infarction (MI). While much of the discussion around prolonged DAPT has been focused on stented patients, patients with prior MI without prior coronary stenting comprise a clinically important subgroup. METHODS AND RESULTS This was a pre-specified analysis from PEGASUS-TIMI 54, which randomized 21 162 patients with prior MI (1-3 years) and additional high-risk features to ticagrelor 60 mg, 90 mg, or placebo twice daily in addition to aspirin. A total of 4199 patients had no history of coronary stenting at baseline. The primary efficacy outcome (MACE) was the composite of cardiovascular death, MI, or stroke. Patients without history of coronary stenting had higher baseline risk of MACE [13.2% vs. 8.0%, adjusted hazard ratio (HR) 1.41, 95% confidence interval (CI) 1.15-1.73, in the placebo arm]. The relative risk reduction in MACE with ticagrelor (pooled doses) was similar in patients without (HR 0.82, 95% CI 0.68-0.99) and with prior stenting (HR 0.85, 95% CI 0.75-0.96; P for interaction = 0.76). CONCLUSION Long-term ticagrelor reduces thrombotic events in patients with prior MI regardless of whether they had prior coronary stenting. These data highlight the benefits of DAPT in prevention of spontaneous atherothrombotic events and indicate that long-term ticagrelor may be considered in high-risk patients with prior MI even if they have not been treated with stenting. CLINICALTRIALS.GOV IDENTIFIER NCT01225562.
Focal adhesion kinase confers pro‐migratory and antiapoptotic properties and is a potential therapeutic target in Ewing sarcoma

Oncogenesis of Ewing sarcoma (EwS), the second most common malignant bone tumor of childhood and adolescence, is dependent on the expression of chimeric EWSR1-ETS fusion oncogenes, most often EWSR1-FLI1 (E/F). E/F expression leads to dysregulation of focal adhesions (FAs) enhancing the migratory capacity of EwS cells. Here we show that, in EwS cell lines and tissue samples, focal adhesion kinase (FAK) is expressed and phosphorylated at Y397 in an E/F-dependent way involving Ezrin. Employing different EwS cell as in vitro models, we found that key malignant properties of E/F are mediated via substrate-independent autophosphorylation of FAK on Y397. This phosphorylation results in enhanced FA formation, Rho-dependent cell migration, and impaired caspase-3-mediated apoptosis in vitro. Conversely, treatment with the FAK inhibitor Y15 enhanced caspase-mediated apoptosis and EwS cell migration, independent from the respective EWSR1-ETS fusion type, mimicking an anoikis-like phenotype. Our findings were confirmed in vivo using an avian chorioallantoic membrane (CAM) model. Our results provide a first rationale for the therapeutic use of FAK inhibitors to impair metastatic dissemination of EwS.
A Machine Learning Approach to Identify a Circulating MicroRNA Signature for Alzheimer Disease.

BACKGROUND Accurate diagnosis of Alzheimer disease (AD) involving less invasive molecular procedures and at reasonable cost is an unmet medical need. We identified a serum miRNA signature for AD that is less invasive than a measure in cerebrospinal fluid. METHODS From the Oxford Project to Investigate Memory and Aging (OPTIMA) study, 96 serum samples were profiled by a multiplex (>500 analytes) microRNA (miRNA) reverse transcription quantitative PCR analysis, including 51 controls, 32 samples from patients with AD, and 13 samples from patients with mild cognitive impairment (MCI). Clinical diagnosis of a subset of AD and the controls was confirmed by postmortem (PM) histologic examination of brain tissue. In a machine learning approach, the AD and control samples were split 70:30 as the training and test cohorts. A multivariate random forest statistical analysis was applied to construct and test a miRNA signature for AD identification. In addition, the MCI participants were included in the test cohort to assess whether the signature can identify early AD patients. RESULTS A 12-miRNA signature for AD identification was constructed in the training cohort, demonstrating 76.0% accuracy in the independent test cohort with 90.0% sensitivity and 66.7% specificity. The signature, however, was not able to identify MCI participants. With a subset of AD and control participants with PM-confirmed diagnosis status, a separate 12-miRNA signature was constructed. Although sample size was limited, the PM-confirmed signature demonstrated improved accuracy of 85.7%, largely owing to improved specificity of 80.0% with comparable sensitivity of 88.9%. CONCLUSION Although additional and more diverse cohorts are needed for further clinical validation of the robustness, the miRNA signature appears to be a promising blood test to diagnose AD.
13-gene DNA Methylation Analysis from Oral Brushing: A Promising Non Invasive Tool in the Follow-up of Oral Cancer Patients

Background: This study aimed to evaluate the prognostic value of a non-invasive sampling procedure based on 13-gene DNA methylation analysis in the follow-up of patients previously treated for oral squamous cell carcinoma (OSCC). Methods: The study population included 49 consecutive patients treated for OSCC. Oral brushing sample collection was performed at two different times: before any cancer treatment in the tumor mass and during patient follow-up almost 6 months after OSCC treatment, within the regenerative area after OSCC resection. Each sample was considered positive or negative in relation to a predefined cut-off value. Results: Before any cancer treatment, 47/49 specimens exceeded the score and were considered as positive. Six months after OSCC resection, 16/49 specimens also had positive scores in the samples collected from the regenerative area. During the follow-up period, 7/49 patients developed locoregional relapse: 6/7 patients had a positive score in the regenerative area after OSCC resection. The presence of a positive score after oral cancer treatment was the most powerful variable related to the appearance of locoregional relapse. Conclusion: 13-gene DNA methylation analysis by oral brushing may have a clinical application as a prognostic non-invasive tool in the follow-up of patients surgically treated for OSCC.