Miracle-dz/UniFAR-FTUs huggingface dataset:
Acetate and Butyrate Improve β-cell Metabolism and Mitochondrial Respiration under Oxidative Stress

Islet dysfunction mediated by oxidative and mitochondrial stress contributes to the development of type 1 and 2 diabetes. Acetate and butyrate, produced by gut microbiota via fermentation, have been shown to protect against oxidative and mitochondrial stress in many cell types, but their effect on pancreatic β-cell metabolism has not been studied. Here, human islets and the mouse insulinoma cell line MIN6 were pre-incubated with 1, 2, and 4 mM of acetate or butyrate with and without exposure to the apoptosis inducer and metabolic stressor streptozotocin (STZ). Both short-chain fatty acids (SCFAs) enhanced the viability of islets and β-cells, but the beneficial effects were more pronounced in the presence of STZ. Both SCFAs prevented STZ-induced cell apoptosis, viability reduction, mitochondrial dysfunction, and the overproduction of reactive oxygen species (ROS) and nitric oxide (NO) at a concentration of 1 mM but not at higher concentrations. These rescue effects of SCFAs were accompanied by preventing reduction of the mitochondrial fusion genes MFN, MFN2, and OPA1. In addition, elevation of the fission genes DRP1 and FIS1 during STZ exposure was prevented. Acetate showed more efficiency in enhancing metabolism and inhibiting ROS, while butyrate had less effect but was stronger in inhibiting the SCFA receptor GPR41 and NO generation. Our data suggest that SCFAs play an essential role in supporting β-cell metabolism and promoting survival under stressful conditions. It therewith provides a novel mechanism by which enhanced dietary fiber intake contributes to the reduction of Western diseases such as diabetes.
Supporting the Old but Neglecting the Young? The Two Faces of Ageism

Ageism is the most prevalent form of prejudice and is experienced by both older and younger people. Little is known about whether these experiences are interdependent or have common origins. We analyze data from 8,117 older (aged 70 and over) and 11,647 younger respondents (15–29 years) in representative samples from 29 countries in the European Social Survey. Using multilevel structural equation modeling, we test the hypothesis that older people are less likely, and younger people more likely, to suffer age discrimination if they live in a country with stronger structural support for older people. We also test the hypothesis that although stronger social norm against age discrimination reduce age discrimination suffered by older people it does not inhibit discrimination against younger people. These hypotheses are supported, and the results underline the neglected problem of ageism toward youth. Findings highlight that strategies for reducing age prejudice must address ageism as a multigenerational challenge, requiring attention to intergenerational cohesion and resource distribution between ages.
Behavioral economic demand as a unifying language for addiction science: Promoting collaboration and integration of animal and human models.

The intersection of pharmacological, psychological, and economic theory within behavioral economics has helped advance an understanding of substance use disorder. A notable contribution of this approach is the conceptualization of reinforcement from a behavioral economic demand perspective. Demand analyses provide a multidimensional view of reinforcement in which distinct behavioral mechanisms are measured that impact decision making and drug consumption. This review describes the state of research on behavioral economic demand as a common language for addiction science researchers across varied model systems and stages of a translational continuum. We first provide an overview of the theoretical concepts and procedures used to evaluate demand in animal and human models. The potential for demand to serve as a common language for diverse research groups in psychopharmacology and addiction science (e.g., those evaluating neurobehavioral outcomes, medications development, clinical practice) is then described. An overview is also provided of existing empirical studies that, while small in number, suggest good linguistic and conceptual overlap between animal and human demand models when studying biological, environmental, and pharmacological individual difference vulnerabilities underlying drug-taking behavior. Refinement of methodological procedures and incorporation of more nuanced environmental features should help improve correspondence between animal and human demand studies as well as clinical translation of such findings. Our hope is that this review and commentary ultimately serves as inspiration for new collaborative efforts involving behavioral economic demand between animal and human researchers who share a common goal of improving substance use treatment outcomes and broader psychological wellbeing. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
Inferring Lifetime Status of Point-of-Interest

A Point-of-Interest (POI) refers to a specific location that people may find useful or interesting. In modern cities, a large number of POIs emerge, grow, stabilize for a period, then finally disappear. The stages (e.g., emerge and grow) in this process are called lifetime statuses of a POI. While a large body of research has been devoted to identifying and recommending POIs, there are few studies on inferring the lifetime status of POIs. Indeed, the predictive analytics of POI lifetime status can be valuable for various tasks, such as urban planning, business site selection, and real estate appraisal. In this article, we propose a multitask learning approach, named inferring POI lifetime status, to inferring the POI lifetime status with multifaceted data sources. Specifically, we first define three types of POI lifetime status, i.e., booming, decaying, and stable. Then, we formulate a serial classification problem to predict the sequential/successive lifetime statuses of POIs over time. Leveraging geographical data and human mobility data, we examine and integrate three aspects of features related to the prosperity of POIs, i.e., region popularity, region demands, and peer competitiveness. Next, as the booming/decaying POIs are relatively rare in our data, we perform stable class decomposition to alleviate the imbalance between stable POIs and booming/decaying POIs. Finally, we develop a POI lifetime status classifier by exploiting the multitask learning framework as well as the multiclass kernel-based vector machines. We perform extensive experiments using large-scale and real-world datasets of New York City. The experimental results validate the effectiveness of our approach to automatically inferring POI lifetime status.
Challenges in the collaborative evolution of a proof language and its ecosystem. (Défis dans l'évolution collaborative d'un langage de preuve et de son écosystème)

In this thesis, I present the application of software engineering methods and knowledge to the development, maintenance, and evolution of Coq —an interactive proof assistant based on type theory— and its package ecosystem. Coq has been developed at Inria since 1984, but has only more recently seen a surge in its user base, which leads to greater concerns about its maintainability, and the involvement of external contributors in the evolution of both Coq and its ecosystem of plugins and libraries. Recent years have seen important changes in the development processes of Coq, of which I have been a witness and an actor (adoption of GitHub as a development platform, first for its pull request mechanism, then for its bug tracker, adoption of continuous integration, switch to shorter release cycles, increased involvement of external contributors in the open source development and maintenance process). The contributions of this thesis include a historical description of these changes, the refinement of existing processes, the design of new processes, the design and implementation of new tools to help the application of these processes, and the validation of these changes through rigorous empirical evaluation. Involving external contributors is also very useful at the level of the package ecosystem. This thesis additionally contains an analysis of package distribution methods, and a focus on the problem of the long-term maintenance of single-maintainer packages.
Non-Phosphorylatable PEA-15 Sensitises SKOV-3 Ovarian Cancer Cells to Cisplatin

The efficacy of cisplatin-based chemotherapy in ovarian cancer is often limited by the development of drug resistance. In most ovarian cancer cells, cisplatin activates extracellular signal-regulated kinase1/2 (ERK1/2) signalling. Phosphoprotein enriched in astrocytes (PEA-15) is a ubiquitously expressed protein, capable of sequestering ERK1/2 in the cytoplasm and inhibiting cell proliferation. This and other functions of PEA-15 are regulated by its phosphorylation status. In this study, the relevance of PEA-15 phosphorylation state for cisplatin sensitivity of ovarian carcinoma cells was examined. The results of MTT-assays indicated that overexpression of PEA-15AA (a non-phosphorylatable variant) sensitised SKOV-3 cells to cisplatin. Phosphomimetic PEA-15DD did not affect cell sensitivity to the drug. While PEA-15DD facilitates nuclear translocation of activated ERK1/2, PEA-15AA acts to sequester the kinase in the cytoplasm as shown by Western blot. Microarray data indicated deregulation of thirteen genes in PEA-15AA-transfected cells compared to non-transfected or PEA-15DD-transfected variants. Data derived from The Cancer Genome Atlas (TCGA) showed that the expression of seven of these genes including EGR1 (early growth response protein 1) and FLNA (filamin A) significantly correlated with the therapy outcome in cisplatin-treated cancer patients. Further analysis indicated the relevance of nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signalling for the favourable effect of PEA-15AA on cisplatin sensitivity. The results warrant further evaluation of the PEA-15 phosphorylation status as a potential candidate biomarker of response to cisplatin-based chemotherapy.
Two waves of pro-inflammatory factors are released during the influenza A virus (IAV)-driven pulmonary immunopathogenesis

Influenza A virus (IAV) infection is a complicated process. After IAVs spread to the lung, extensive pro-inflammatory cytokines and chemokines are released, which largely determine the outcome of infection. Using a single-cell RNA sequencing (scRNA-seq) assay, we systematically and sequentially analyzed the transcriptome of more than 16,000 immune cells in the pulmonary tissue of infected mice, and demonstrated that two waves of pro-inflammatory factors were released. A group of IAV-infected PD-L1+ neutrophils were the major contributor to the first wave at an earlier stage (day 1–3 post infection). Notably, at a later stage (day 7 post infection) when IAV was hardly detected in the immune cells, a group of platelet factor 4-positive (Pf4+)-macrophages generated another wave of pro-inflammatory factors, which were probably the precursors of alveolar macrophages (AMs). Furthermore, single-cell signaling map identified inter-lineage crosstalk between different clusters and helped better understand the signature of PD-L1+ neutrophils and Pf4+-macrophages. Our data characteristically clarified the infiltrated immune cells and their production of pro-inflammatory factors during the immunopathogenesis development, and deciphered the important mechanisms underlying IAV-driven inflammatory reactions in the lung.
Knowledge, attitude and practices on cholera in an arid county, Kenya, 2018: A mixed-methods approach

Background Cholera remains a public health problem in Kenya despite increased efforts to create awareness. Assessment of knowledge, attitude and practice (KAP) in the community is essential for the planning and implementation of preventive measures. We assessed cholera KAP in a community in Isiolo County, Kenya. Methods This cross-sectional study involved a mixed-methods approach utilizing a questionnaire survey and focus group discussions (FGDs). Using multistage sampling with household as the secondary sampling unit, interviewers administered structured questionnaires to one respondent aged ≥18 years old per household. We created knowledge score by allotting one point for each correct response, considered any total score ≥ median score as high knowledge score, calculated descriptive statistics and used multivariate logistic regression to examine factors associated with high knowledge score. In FGDs, we randomly selected the participants aged ≥18 years and had lived in Isiolo for >1 year, conducted the FGDs using an interview guide and used content analysis to identify salient emerging themes. Results We interviewed 428 participants (median age = 30 years; Q1 = 25, Q3 = 38) comprising 372 (86.9%) females. Of the 425/428 (99.3%) who had heard about cholera, 311/425 (73.2%) knew that it is communicable. Although 273/428 (63.8%) respondents knew the importance of treating drinking water, only 216/421 (51.3%) treated drinking water. Those with good defecation practice were 209/428 (48.8%). Respondents with high knowledge score were 227/428 (53.0%). Positive attitude (aOR = 2.88, 95% C.I = 1.34–6.20), treating drinking water (aOR = 2.21, 95% C.I = 1.47–3.33), age <36 years (aOR = 1.75, 95% C.I = 1.11–2.74) and formal education (aOR = 1.71, 95% C.I = 1.08–2.68) were independently associated with high knowledge score. FGDs showed poor latrine coverage, inadequate water treatment and socio-cultural beliefs as barriers to cholera prevention and control. Conclusions There was a high knowledge score on cholera with gaps in preventive practices. We recommend targeted health education to the old and uneducated persons and general strengthening of health education in the community.
Effect of Ozone and Electron Beam Irradiation on Degradation of Zearalenone and Ochratoxin A

Zearalenone (ZEN) and ochratoxin A (OTA) are key concerns of the food industry because of their toxicity and pollution scope. This study investigated the effects of ozone and electron beam irradiation (EBI) on the degradation of ZEN and OTA. Results demonstrated that 2 mL of 50 μg/mL ZEN was completely degraded after 10 s of treatment by 2.0 mg/L ozone. The degradation rate of 1 μg/mL ZEN by 16 kGy EBI was 92.76%. Methanol was superior to acetonitrile in terms of degrading ZEN when the irradiation dose was higher than 6 kGy. The degradation rate of 2 mL of 5 μg/mL OTA by 50 mg/L ozone at 180 s was 34%, and that of 1 μg/mL OTA by 16 kGy EBI exceeded 90%. Moreover, OTA degraded more rapidly in acetonitrile. Ozone performed better in the degradation of ZEN, whereas EBI was better for OTA. The conclusions provide theoretical and practical bases for the degradation of different fungal toxins.
NOTO Transcription Factor Directs Human Induced Pluripotent Stem Cell-Derived Mesendoderm Progenitors to a Notochordal Fate

The founder cells of the Nucleus pulposus, the centre of the intervertebral disc, originate in the embryonic notochord. After birth, mature notochordal cells (NC) are identified as key regulators of disc homeostasis. Better understanding of their biology has great potential in delaying the onset of disc degeneration or as a regenerative-cell source for disc repair. Using human pluripotent stem cells, we developed a two-step method to generate a stable NC-like population with a distinct molecular signature. Time-course analysis of lineage-specific markers shows that WNT pathway activation and transfection of the notochord-related transcription factor NOTO are sufficient to induce high levels of mesendoderm progenitors and favour their commitment toward the notochordal lineage instead of paraxial and lateral mesodermal or endodermal lineages. This study results in the identification of NOTO-regulated genes including some that are found expressed in human healthy disc tissue and highlights NOTO function in coordinating the gene network to human notochord differentiation.
Co-Encapsulation of Mitoxantrone and β-Elemene in Solid Lipid Nanoparticles to Overcome Multidrug Resistance in Leukemia

Multidrug resistance (MDR) due to P-glycoprotein (P-gp) overexpression is a major obstacle to successful leukemia chemotherapy. The combination of anticancer chemotherapy with a chemosensitizer of P-gp inhibitor is promising to overcome MDR, generate synergistic effects, and maximize the treatment effect. Herein, we co-encapsulated a chemotherapeutic drug of mitoxantrone (MTO) and a P-gp inhibitor of β-elemene (βE) in solid lipid nanoparticles (MTO/βE-SLNs) for reversing MDR in leukemia. The MTO/βE-SLNs with about 120 nm particle size possessed good colloidal stability and sustained release behavior. For the cellular uptake study, doxorubicin (DOX) was used as a fluorescence probe to construct SLNs. The results revealed that MTO/βE-SLNs could be effectively internalized by both K562/DOX and K562 cells through the pathway of caveolate-mediated endocytosis. Under the optimized combination ratio of MTO and βE, the in vitro cytotoxicity study indicated that MTO/βE-SLNs showed a better antitumor efficacy in both K562/DOX and K562 cells than other MTO formulations. The enhanced cytotoxicity of MTO/βE-SLNs was due to the increased cellular uptake and blockage of intracellular ATP production and P-gp efflux by βE. More importantly, the in vivo studies revealed that MTO/βE-SLNs could significantly prolong the circulation time and increase plasma half-life of both MTO and βE, accumulate into tumor and exhibit a much higher anti-leukemia effect with MDR than other MTO formulations. These findings suggest MTO/βE-SLNs as a potential combined therapeutic strategy for overcoming MDR in leukemia.
Dengue: Status of current and under‐development vaccines

Dengue is an emerging mosquito‐borne viral infection with increasing reports of outbreaks. The clinical picture ranges from a benign febrile illness through to severe and potentially fatal manifestations. No specific anti‐viral treatment exists, and therapy only consists of supportive care. During the last three decades, several attempts to develop an effective vaccine have been made. The first dengue vaccine to obtain licensure was Dengvaxia, which was authorized in 2015 and is currently available in over 20 countries. Its use has been approved with strict limitations regarding age and serostatus of the recipients, highlighting the necessity for a more safe and efficacious vaccine. At present several vaccine, candidates are undergoing clinical and pre‐clinical trials. The most advanced candidates are TDV and TDV 003/005, two live‐attenuated vaccines, but another 15 vaccines are under development, introducing novel immunization strategies to the traditional dengue vaccine scenario. This work reviews the current research status on dengue vaccines.
Neuropeptide Y Acts Directly on Cartilage Homeostasis and Exacerbates Progression of Osteoarthritis Through NPY2R

Neuropeptide Y (NPY) is known to regulate bone homeostasis; however, its functional role as a risk factor during osteoarthritis (OA) remains elusive. In this study, we aim to investigate the direct effect of NPY on degradation of cartilage and progression of OA and explore the molecular events involved. NPY was overexpressed in human OA cartilage accompanied with increased expression of NPY1 receptor (NPY1R) and NPY2 receptor (NPY2R). Stressors such as cold exposure resulted in the peripheral release of NPY from sympathetic nerves, which in turn promoted upregulation of NPY and NPY2R in articular cartilage in vivo. Intra‐articular administration of NPY significantly promoted chondrocyte hypertrophy and cartilage matrix degradation, with a higher OARSI score than that of control mice, whereas inhibition of NPY2R but not NPY1R with its specific antagonist remarkably ameliorated NPY‐mediated effects. Moreover, NPY activated mTORC1 pathway in articular chondrocytes, whereas the administration of rapamycin (an mTORC1 inhibitor) in vitro abrogated NPY‐mediated effects. Mechanistically, mTORC1 downstream kinase S6K1 interacted with and phosphorylated SMAD1/5/8 and promoted SMAD4 nuclear translocation, resulting in upregulation of Runx2 expression to promote chondrocyte hypertrophy and cartilage degradation. In conclusion, our findings provided the direct evidence and the crucial role of NPY in cartilage homeostasis. © 2020 American Society for Bone and Mineral Research.
Increased pupil dilation to happy faces in children with hyperactive/impulsive symptoms of ADHD

Abstract Attention-deficit/hyperactivity disorder (ADHD) is associated with disrupted emotional processes including impaired regulation of approach behavior and positive affect, irritability, and anger. Enhanced reactivity to emotional cues may be an underlying process. Pupil dilation is an indirect index of arousal, modulated by the autonomic nervous system and activity in the locus coeruleus-noradrenergic system. In the current study, pupil dilation was recorded while 8- to 12- year old children (n = 71, 26 with a diagnosis of ADHD and 45 typically developing), viewed images of emotional faces. Parent-rated hyperactive/impulsive symptoms were uniquely linked to higher pupil dilation to happy, but not fearful, angry, or neutral faces. This was not explained by comorbid externalizing symptoms. Together, these results suggest that hyperactive/impulsive symptoms are associated with hyperresponsiveness to approach-related emotional cues across a wide range of symptom severity.
Detectable 2019-nCoV viral RNA in blood is a strong indicator for the further clinical severity

ABSTRACT The novel coronavirus (2019-nCoV) infection caused pneumonia. we retrospectively analyzed the virus presence in the pharyngeal swab, blood, and the anal swab detected by real-time PCR in the clinical lab. Unexpectedly, the 2109-nCoV RNA was readily detected in the blood (6 of 57 patients) and the anal swabs (11 of 28 patients). Importantly, all of the 6 patients with detectable viral RNA in the blood cohort progressed to severe symptom stage, indicating a strong correlation of serum viral RNA with the disease severity (p-value = 0.0001). Meanwhile, 8 of the 11 patients with annal swab virus-positive was in severe clinical stage. However, the concentration of viral RNA in the anal swab (Ct value = 24 + 39) was higher than in the blood (Ct value = 34 + 39) from patient 2, suggesting that the virus might replicate in the digestive tract. Altogether, our results confirmed the presence of virus RNA in extra-pulmonary sites.
Oxidative and nitrosative stresses in cerebral malaria: can we target them to avoid a bad prognosis?

There is currently a global effort to reduce malaria morbidity and mortality. However, malaria still results in the deaths of thousands of people every year. Malaria is caused by Plasmodium spp. , parasites transmitted through the bite of an infected female Anopheles mosquito. Treatment timing plays a decisive role in reducing mortality and sequelae associated with the severe forms of the disease such as cerebral malaria (CM). The available antimalarial therapy is considered effective but parasite resistance to these drugs has been observed in some countries. Antimalarial drugs act by increasing parasite lysis, especially through targeting oxidative stress pathways. Here we discuss the roles of reactive oxygen species and reactive nitrogen intermediates in CM as a result of host-parasite interactions. We also present evidence of the potential contribution of oxidative and nitrosative stress-based antimalarial drugs to disease treatment and control.