Miracle-dz/UniFAR-FTUs huggingface dataset:
Clonally expanded &ggr;&dgr; T cells protect against Staphylococcus aureus skin reinfection

The mechanisms that mediate durable protection against Staphylococcus aureus skin reinfections are unclear, as recurrences are common despite high antibody titers and memory T cells. Here, we developed a mouse model of S. aureus skin reinfection to investigate protective memory responses. In contrast with WT mice, IL-1&bgr;–deficient mice exhibited poor neutrophil recruitment and bacterial clearance during primary infection that was rescued during secondary S. aureus challenge. The &ggr;&dgr; T cells from skin-draining LNs utilized compensatory T cell–intrinsic TLR2/MyD88 signaling to mediate rescue by trafficking and producing TNF and IFN-&ggr;, which restored neutrophil recruitment and promoted bacterial clearance. RNA-sequencing (RNA-seq) of the LNs revealed a clonotypic S. aureus–induced &ggr;&dgr; T cell expansion with a complementarity-determining region 3 (CDR3) aa sequence identical to that of invariant V&ggr;5+ dendritic epidermal T cells. However, this T cell receptor &ggr; (TRG) aa sequence of the dominant CDR3 sequence was generated from multiple gene rearrangements of TRGV5 and TRGV6, indicating clonotypic expansion. TNF- and IFN-&ggr;–producing &ggr;&dgr; T cells were also expanded in peripheral blood of IRAK4-deficient humans no longer predisposed to S. aureus skin infections. Thus, clonally expanded &ggr;&dgr; T cells represent a mechanism for long-lasting immunity against recurrent S. aureus skin infections.
Fruits of Black Chokeberry Aronia melanocarpa in the Prevention of Chronic Diseases

In recent years, growing attention has been focused on the utilization of natural sources of antioxidants in the prevention of chronic diseases. Black chokeberry (Aronia melanocarpa) represents a lesser known fruit species utilized mainly as juices, purees, jams, jellies and wine, as important food colorants or nutritional supplements. The fruit is valued as a great source of antioxidants, especially polyphenols, such as phenolic acids (neochlorogenic and chlorogenic acids) and flavonoids (anthocyanins, proanthocyanidins, flavanols and flavonols), particularly cyanidin-3-galactoside and cyanidin-3-arabinoside, as well as (−)-epicatechin units. The berries of A. melanocarpa, due to the presence and the high content of these bioactive components, exhibit a wide range of positive effects, such as strong antioxidant activity and potential medicinal and therapeutic benefits (gastroprotective, hepatoprotective, antiproliferative or anti-inflammatory activities). They could be also contributory toward the prevention of chronic diseases including metabolic disorders, diabetes and cardiovascular diseases, because of supportive impacts on lipid profiles, fasting plasma glucose and blood pressure levels.
Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders

The vagus nerve represents the main component of the parasympathetic nervous system, which oversees a vast array of crucial bodily functions, including control of mood, immune response, digestion, and heart rate. It establishes one of the connections between the brain and the gastrointestinal tract and sends information about the state of the inner organs to the brain via afferent fibers. In this review article, we discuss various functions of the vagus nerve which make it an attractive target in treating psychiatric and gastrointestinal disorders. There is preliminary evidence that vagus nerve stimulation is a promising add-on treatment for treatment-refractory depression, posttraumatic stress disorder, and inflammatory bowel disease. Treatments that target the vagus nerve increase the vagal tone and inhibit cytokine production. Both are important mechanism of resiliency. The stimulation of vagal afferent fibers in the gut influences monoaminergic brain systems in the brain stem that play crucial roles in major psychiatric conditions, such as mood and anxiety disorders. In line, there is preliminary evidence for gut bacteria to have beneficial effect on mood and anxiety, partly by affecting the activity of the vagus nerve. Since, the vagal tone is correlated with capacity to regulate stress responses and can be influenced by breathing, its increase through meditation and yoga likely contribute to resilience and the mitigation of mood and anxiety symptoms.
Efficient algorithms to discover alterations with complementary functional association in cancer

Recent large cancer studies have measured somatic alterations in an unprecedented number of tumours. These large datasets allow the identification of cancer-related sets of genetic alterations by identifying relevant combinatorial patterns. Among such patterns, mutual exclusivity has been employed by several recent methods that have shown its effectiveness in characterizing gene sets associated to cancer. Mutual exclusivity arises because of the complementarity, at the functional level, of alterations in genes which are part of a group (e.g., a pathway) performing a given function. The availability of quantitative target profiles, from genetic perturbations or from clinical phenotypes, provides additional information that can be leveraged to improve the identification of cancer related gene sets by discovering groups with complementary functional associations with such targets. In this work we study the problem of finding groups of mutually exclusive alterations associated with a quantitative (functional) target. We propose a combinatorial formulation for the problem, and prove that the associated computational problem is computationally hard. We design two algorithms to solve the problem and implement them in our tool UNCOVER. We provide analytic evidence of the effectiveness of UNCOVER in finding high-quality solutions and show experimentally that UNCOVER finds sets of alterations significantly associated with functional targets in a variety of scenarios. In particular, we show that our algorithms find sets which are better than the ones obtained by the state-of-the-art method, even when sets are evaluated using the statistical score employed by the latter. In addition, our algorithms are much faster than the state-of-the-art, allowing the analysis of large datasets of thousands of target profiles from cancer cell lines. We show that on two such datasets, one from project Achilles and one from the Genomics of Drug Sensitivity in Cancer project, UNCOVER identifies several significant gene sets with complementary functional associations with targets. Software available at: https://github.com/VandinLab/UNCOVER.
Increased NHE2 expression in rat intestinal epithelium during ontogeny is transcriptionally mediated.

We have previously described changes in intestinal brush-border membrane vesicle (BBMV) Na+/H+exchange activity and characterized Na+/H+exchanger (NHE3) expression during rat ontogeny. The current studies were designed to investigate developmental changes in NHE2 expression in rat intestine. In previous studies, pH-dependent uptake of Na+ in jejunal BBMV utilizing HOE-694 inhibition demonstrated that NHE2 functional protein levels were lowest in 2-wk-old rats, higher in 3-wk-old and adult rats, and highest in 6-wk-old rats [Collins et al. Am. J. Physiol. 273 ( Cell Physiol. 42): C1937-C1946, 1997]. In the current investigation, Northern blot analyses showed that NHE2 mRNA levels in the jejunum were similar in 6-wk-old, adult, and 3-wk-old rats and three- to fivefold lower in 2-wk-old rats. In situ hybridization of 2- and 6-wk-old rat intestine with NHE2-specific probes confirmed Northern blot observations. Polyclonal antibodies were developed against an NHE2-specific peptide from amino acids 652-661. Western blots with NHE2 antiserum showed that the intensity of a specific 90-kDa band was lowest in 2-wk-old animals and four- to sixfold higher in 3- and 6-wk-old and adult animals. Immunohistochemical analysis showed specific staining of NHE2 antiserum to only the apical intestinal membrane. Furthermore, nuclear run-on analyses showed a 1.7-fold higher NHE2 transcription rate in 6-wk-old rats than in 2-wk-old rats. Overall, the current data suggest that increases in NHE2 expression upon weaning are mediated by increased gene transcription.
Fork Protection and Therapy Resistance in Hereditary Breast Cancer

The BRCA-Fanconi anemia (FA) pathway preserves the genome and suppresses cancer and is a main determinant of chemotherapeutic efficacy. The hereditary breast cancer genes BRCA1 and BRCA2 function in DNA double-strand break repair mediating distinct steps of homologous recombination (HR). More recently, independent of DNA repair, functions in the replication stress response have come to light, providing insight as to how the BRCA-FA pathway also balances genome preservation with proliferation. The BRCA-FA proteins associate with the replisome and contribute to the efficiency and recovery of replication following perturbations that slow or arrest DNA replication. Although the full repertoire of functions in the replication stress response remains to be elucidated, the function of BRCA1 and BRCA2 in protecting stalled replication forks contributes along with HR to the sensitivity of BRCA-associated tumors to chemotherapy. Moreover, chemoresistance evolves from restoration of either HR and/or fork protection. Although mechanisms underlying the restoration of HR have been characterized, it remains less clear how restoration of fork protection is achieved. Here, we outline mechanisms of “rewired” fork protection and chemotherapy resistance in BRCA cancer. We propose that mechanisms are linked to permissive replication that limits fork remodeling and therefore opportunities for fork degradation. Combating this chemoresistance mechanism will require drugs that inactivate replication bypass mechanisms.
Reconstruction of the perfusion coefficient from temperature measurements using the conjugate gradient method

ABSTRACT We consider the inverse bio-heat transfer problem to determine the space- and time-dependent perfusion coefficient from temperature measurements. In this formulation, the problem is fully determined and the coefficient is identifiable if and only if the temperature has dense support. However, the problem is still ill-posed since small errors in the measured temperature cause large errors in the output perfusion coefficient due to the numerical differentiation of noisy data involved which represents an unstable procedure. In order to overcome this difficulty and restore stability, we employ for the first time the conjugate gradient method (CGM) for solving the inverse problem under investigation. Regularization is achieved by stopping the iteration process at an appropriate threshold dictated by the discrepancy principle. Numerical results show that the CGM is accurate and reasonably stable in retrieving the perfusion coefficient. Moreover, comparison with other methods shows improved efficiency and stability in inverting noisy data.
Chronic Discrimination and Sleep Problems in Late Life: Religious Involvement as Buffer

The association between chronic discrimination and sleep problems is important to examine in older adults because sleep is highly reactive to stress and impaired sleep has diverse adverse health effects. The association between chronic discrimination and sleep problems may, however, be confounded by a number of time-stable influences, and this association may also vary by religious involvement. In three waves (2006, 2010, and 2014) of the Health and Retirement Study (N = 7,130), the overall association between chronic discrimination and sleep problems is negated in econometric models that control for all time-stable sources of confounding. Religious involvement does not modify this association for men, but a significant association is found among women who do not attend religious services. These analyses suggest that the association between chronic discrimination and sleep quality in late life is substantially inflated due to unobserved time-stable confounders, although women who do not attend religious services may be at risk.
JAM3 maintains leukemia-initiating cell self-renewal through LRP5/AKT/&bgr;-catenin/CCND1 signaling

Leukemia-initiating cells (LICs) are responsible for the initiation, development, and relapse of leukemia. The identification of novel therapeutic LIC targets is critical to curing leukemia. In this report, we reveal that junctional adhesion molecule 3 (JAM3) is highly enriched in both mouse and human LICs. Leukemogenesis is almost completely abrogated upon Jam3 deletion during serial transplantations in an MLL-AF9–induced murine acute myeloid leukemia model. In contrast, Jam3 deletion does not affect the functions of mouse hematopoietic stem cells. Moreover, knockdown of JAM3 leads to a dramatic decrease in the proliferation of both human leukemia cell lines and primary LICs. JAM3 directly associates with LRP5 to activate the downstream PDK1/AKT pathway, followed by the downregulation of GSK3&bgr; and activation of &bgr;-catenin/CCND1 signaling, to maintain the self-renewal ability and cell cycle entry of LICs. Thus, JAM3 may serve as a functional LIC marker and play an important role in the maintenance of LIC stemness through unexpected LRP5/PDK1/AKT/GSK3&bgr;/&bgr;-catenin/CCND1 signaling pathways but not via its canonical role in cell junctions and migration. JAM3 may be an ideal therapeutic target for the eradication of LICs without influencing normal hematopoiesis.
The Results of Myringoplasty Using Cartilage Butterfly Technique(Inlay Tympanoplasty

Background and Objectives:Popular myringoplasty techniques include either an underlay or an onlay approach using tissues such as temporalis fascia or perichondrium as grafting materials. The "cartilage butterfly technique" using a tragal cartilage graft that resembled butterfly wings without incising canal skin was described by Eavey in 1998. This study des- cribes the results of using this technique and analyzes the postoperative hearings. Materials and Methods:Cartilage bu- tterfly inlay tympanoplasty was carried out in 28 patients to close small-to-medium tympanic membrane perforations from October 1998 to December 2000. We excluded one patient due to accidental removal of graft at another clinic. We evaluated the success rate and postoperative hearing results. Results:The graft take rate was 96.3% (26/27 at the end of the follow- up period (mean follow-up was 6.0 months. All of successful cases had cartilage grafts that were intact and dry at the last visit. One patient failed due to otorrhea and extruding graft. Two patients were not evaluated, because one had profound pre- operative hearing loss and the other was a cerebral palsy patient. Mean air-bone gap (A-B gap was improved from 16.3 dB to 9.8 dB. Ten patients had an A-B gap average between 0 and 10 dB, 14 patients between 11 and 20 dB, and no patient gr- eater than 20 dB. Conclusion:The cartilage butterfly technique was effective to close tympanic membrane perforations in selected patients. It could provide advantages in high success rate, ease, speed and patient comfort. (
Diabetes Risk Assessment in Latinas: Effectiveness of a Brief Diabetes Risk Questionnaire for Detecting Prediabetes in a Community-Based Sample

Objective. Numerous validated questionnaires use self-reported data to quantify individuals’ risk of having diabetes or developing it in the future. Evaluations of these tools have primarily used nationally representative data, limiting their application in clinical and community settings. This analysis tested the effectiveness of the American Diabetes Association (ADA) risk questionnaire for identifying prediabetes in a community-based sample of Latinas. Methods. Data were collected using the ADA risk questionnaire and assessing A1C. Among 204 participants without diabetes, we examined the association between individual characteristics and glycemic status. We then calculated the performance characteristics (sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]) of the ADA risk questionnaire for detecting prediabetes, using A1C results as the gold standard to define the outcome. Results. All participants were women of self-reported Hispanic/Latino ethnicity. Their mean ADA risk score was 5.6 ± 1.6. Latinas who had prediabetes were older, with significantly higher rates of hypertension and a higher ADA risk score than those without prediabetes. At a risk score ≥5—the threshold for high risk set by the ADA—the questionnaire had the following test performance characteristics: sensitivity 77.8%, specificity 41.7%, PPV 76.2%, and NPV 43.9%. Conclusion. The ADA risk questionnaire demonstrates reasonable performance for identifying prediabetes in a community-based sample of Latinas. Our data may guide other groups’ use of this tool in the same target population. Future research should examine the effectiveness of this questionnaire for recruiting diverse populations into diabetes prevention programs. In addition, unique diabetes risk assessment tools for specific target populations are needed and may outperform questionnaires developed using nationally representative data.
The Kinome of Pacific Oyster Crassostrea gigas, Its Expression during Development and in Response to Environmental Factors

Oysters play an important role in estuarine and coastal marine habitats, where the majority of humans live. In these ecosystems, environmental degradation is substantial, and oysters must cope with highly dynamic and stressful environmental constraints during their lives in the intertidal zone. The availability of the genome sequence of the Pacific oyster Crassostrea gigas represents a unique opportunity for a comprehensive assessment of the signal transduction pathways that the species has developed to deal with this unique habitat. We performed an in silico analysis to identify, annotate and classify protein kinases in C. gigas, according to their kinase domain taxonomy classification, and compared with kinome already described in other animal species. The C. gigas kinome consists of 371 protein kinases, making it closely related to the sea urchin kinome, which has 353 protein kinases. The absence of gene redundancy in some groups of the C. gigas kinome may simplify functional studies of protein kinases. Through data mining of transcriptomes in C. gigas, we identified part of the kinome which may be central during development and may play a role in response to various environmental factors. Overall, this work contributes to a better understanding of key sensing pathways that may be central for adaptation to a highly dynamic marine environment.
How much medium do you use for cell culture? Medium volume influences mineralization and osteoclastogenesis in vitro.

Bone is maintained by a balance between bone formation and resorption. This remodeling is controlled by a wide variety of systemic and local factors including hormones, cytokines and mechanical stresses. The present in vitro study examined the impact of medium volume, using 0.4, 0.6, 0.8, 1.0, 1.5 and 2.0 ml/well in a 24‑well plate, on the differentiation of osteoblasts and osteoclasts. There were no differences in the alkaline phosphatase activity of osteoblasts amongst the groups; however, the area of mineral deposition was decreased in a media volume‑dependent manner. A co‑culture of osteoblastic cells with bone marrow cells revealed a reduction in the total number of osteoclastic tartrate‑resistant acid phosphatase (TRAP)‑positive multinuclear cells (≥2 nuclei), whereas the formation of large osteoclastic TRAP‑positive multinuclear cells (≥8 nuclei) was increased, in a media volume‑dependent manner. There were also no differences in receptor activator of nuclear factor‑κB ligand mRNA and total osteoprotegerin (OPG) protein expression levels amongst the groups, however the concentration of OPG decreased in a media volume‑dependent manner. In conclusion, the present study demonstrated that the suppression of mineralization in osteoblastic cells and the stimulation of osteoclast fusion are dependent on the medium volume, indicating that media volume is an important factor in in vitro cell culture systems.
Down-regulation of glutamate release from hippocampal neurons by sialidase

Sialidase, which removes sialic acid residues in sialylglycoconjugates, is essential for hippocampal memory and synaptic plasticity. Enzyme activity of sialidase is rapidly increased in response to neural excitation. Because sialic acid bound to gangliosides such as the tetra-sialoganglioside GQ1b is crucial for calcium signalling and neurotransmitter release, neural activity-dependent removal of sialic acid may affect hippocampal neurotransmission. In the present study, we found that 2-deoxy-2, 3-didehydro-D-N-acetylneuraminic acid (DANA), a sialidase inhibitor, increased expression of ganglioside GQ1b/GT1a in hippocampal acute slices. Extracellular glutamate level in the rat hippocampus measured by using in vivo microdialysis was increased by the sialidase inhibitor 2, 3-dehydro-2-deoxy-N-glycolylneuraminic acid as well as DANA. Synaptic vesicle exocytosis and intracellular Ca2+ increase evoked by high-K+ were also enhanced by DANA in primary cultured hippocampal neurons. Expression of GQ1b/GT1a was rapidly decreased by depolarization with high-K+, suggesting that the increase in sialidase activity by neural excitation is sufficient for cleavage of sialic acid. Our findings indicate that sialidase down-regulates glutamate release from hippocampal neurons via Ca2+ signalling modulation. Neural activity-dependent desialylation by sialidase may be a negative-feedback factor against presynaptic activity.
How social network analysis can be used to monitor online collaborative learning and guide an informed intervention

To ensure online collaborative learning meets the intended pedagogical goals (is actually collaborative and stimulates learning), mechanisms are needed for monitoring the efficiency of online collaboration. Various studies have indicated that social network analysis can be particularly effective in studying students’ interactions in online collaboration. However, research in education has only focused on the theoretical potential of using SNA, not on the actual benefits they achieved. This study investigated how social network analysis can be used to monitor online collaborative learning, find aspects in need of improvement, guide an informed intervention, and assess the efficacy of intervention using an experimental, observational repeated-measurement design in three courses over a full-term duration. Using a combination of SNA-based visual and quantitative analysis, we monitored three SNA constructs for each participant: the level of interactivity, the role, and position in information exchange, and the role played by each participant in the collaboration. On the group level, we monitored interactivity and group cohesion indicators. Our monitoring uncovered a non-collaborative teacher-centered pattern of interactions in the three studied courses as well as very few interactions among students, limited information exchange or negotiation, and very limited student networks dominated by the teacher. An intervention based on SNA-generated insights was designed. The intervention was structured into five actions: increasing awareness, promoting collaboration, improving the content, preparing teachers, and finally practicing with feedback. Evaluation of the intervention revealed that it has significantly enhanced student-student interactions and teacher-student interactions, as well as produced a collaborative pattern of interactions among most students and teachers. Since efficient and communicative activities are essential prerequisites for successful content discussion and for realizing the goals of collaboration, we suggest that our SNA-based approach will positively affect teaching and learning in many educational domains. Our study offers a proof-of-concept of what SNA can add to the current tools for monitoring and supporting teaching and learning in higher education.