Miracle-dz/UniFAR-FTUs huggingface dataset:
Modulation of expression/function of intestinal P-glycoprotein under disease states

ABSTRACT Introduction: ATP-binding cassette (ABC) transporters, especially P-glycoprotein (P-gp), and various metabolic enzymes, in particular, CYP3A, expressed in the small intestine cooperatively limit the absorption of orally administered P-gp substrate drugs. The expression and/or function of intestinal P-gp, however, is easily modulated by various factors. Areas covered: Through extensive literature searches primarily utilizing PubMed, the authors reviewed factors that may cause inter- or intra-individual variations of the pharmacokinetics of orally administered P-gp substrate drugs due to the modulation of intestinal P-gp expression/function. The information on P-gp modulating factors can help to develop safer and more reliable oral formulations and pharmacotherapy. Expert opinion: In clinical pharmacotherapy with orally administered P-gp substrate drugs, the pharmacological action may exhibit a large interindividual variation among patients. Factors modulating intestinal P-gp expression/function listed here include: circadian rhythm (or drug dosing time), drug–drug interactions, formulation/excipients (vehicle, nonionic surfactants), food/supplements, gene polymorphism, obesity, colorectal carcinomas, diarrhea, hepatic failure, inflammation, inflammatory bowel disease, ischemia/reperfusion, organ transplant, renal failure, and others. We will discuss the methods for reducing the effect of modulated intestinal P-gp function on the pharmacokinetics of orally administered P-gp substrate drugs to achieve safer and more reliable oral formulations and pharmacotherapy.
Developmental dynamics of neurogenesis and gliogenesis in the postnatal mammalian brain in health and disease: Historical and future perspectives

The mature mammalian brain has long been thought to be a structurally rigid, static organ since the era of Ramón y Cajal in the early 20th century. Evidence accumulated over the past three decades, however, has completely overturned this long‐held view. We now know that new neurons and glia are continuously added to the brain at postnatal stages, even in mature adults of various mammalian species, including humans. Moreover, these newly added cells contribute to structural plasticity and play important roles in higher order brain function, as well as repair after damage. A major source of these new neurons and glia is neural stem cells (NSCs) that persist in specialized niches in the brain throughout life. With this new view, our understanding of normal brain physiology and interventional approaches to various brain disorders has changed markedly in recent years. This article provides a brief overview on the historical changes in our understanding of the developmental dynamics of neurogenesis and gliogenesis in the postnatal and adult mammalian brain and discusses the roles of NSCs and other progenitor populations in such cellular dynamics in health and disease of the postnatal mammalian brain.
High prevalence and incidence of rectal Chlamydia infection among men who have sex with men in Japan

Background Rectal Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections have been neglected and epidemiological data are unavailable in Japan. Thus, we evaluated the prevalence and incidence of rectal CT/NG in a cohort of HIV-negative men who have sex with men (MSM), which was established at the National Center for Global Health and Medicine (NCGM), in Tokyo, Japan, in January 2017. Methods HIV-negative MSM aged ≥16 years old were included. The prevalence of rectal CT/NG among HIV-negative MSM was compared with that among an existing HIV-positive MSM cohort at NCGM. The HIV-negative MSM cohort was examined for rectal and pharyngeal CT/NG every 3 months. Urethral CT/NG was evaluated at the physician’s discretion. The incidences of CT/NG were evaluated in December 2018. Results Of 502 MSM initially included in this study, 13 men were diagnosed with HIV infection at enrollment and were subsequently excluded from the analysis. We evaluated 561 HIV-positive MSM for rectal CT/NG. The mean ages of the two cohorts were 33.6 and 46.2 years old, respectively (p<0.001). The prevalences of rectal CT were 16.4% and 15.9% (p = 0.707) and the prevalences of rectal NG were 4.1% and 2.3% (p = 0.101), for the HIV-negative and HIV-positive MSM cohorts, respectively. Of 489 HIV-negative MSM, 328 were followed at least twice, with 261.1 person-years during the study period. The incidences of rectal CT/NG were 17.2 and 3.8/100 person-years and the incidences of pharyngeal CT/NG were 2.0 and 11.0/100 person-years for the two cohorts, respectively. Approximately 37.9% of incident cases were attributed to recurrent infection. Conclusions The prevalence and incidence of rectal CT/NG were high among MSM in Tokyo, Japan, suggesting that urgent countermeasures for early diagnosis and treatment are necessary.
Behavioral Conceptualization and Treatment of Chronic Pain.

Pain is considered a hardwired signal of bodily disturbance belonging to a basic motivational system that urges the individual to act and to restore the body's integrity, rather than just a sensory and emotional experience. Given its eminent survival value, pain is a strong motivator for learning. Response to repeated pain increases when harm risks are high (sensitization) and decreases in the absence of such risks (habituation). Discovering relations between pain and other events provides the possibility to predict (Pavlovian conditioning) and control (operant conditioning) harmful events. Avoidance is adaptive in the short term but paradoxically may have detrimental long-term effects. Pain and pain-related responses compete with other demands in the environment. Exposure-based treatments share the aim of facilitating or restoring the pursuit of individual valued life goals in the face of persistent pain, and further improvements in pain treatment may require a paradigm shift toward more personalized approaches. Expected final online publication date for the Annual Review of Clinical Psychology, Volume 16 is May 7, 2020. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Relation between the weak itinerant magnetism in A2Ni7 compounds (A  =  Y, La) and their stacked crystal structures

The weak itinerant magnetic properties of A2Ni7 compounds with A = {Y, La} have been investigated using electronic band structure calculations in the relation with their polymorphic crystal structures. These compounds crystallizes in two structures resulting from the stacking of two and three blocks of [A2Ni4 + 2 ANi5] units for hexagonal 2H-La2Ni7 (Ce2Ni7 type) and rhombohedral 3R-Y2Ni7 (Gd2Co7 type) respectively. Experimentally, 2H-La2Ni7 is a weak itinerant antiferromagnet whereas 3R-Y2Ni7 is a weak itinerant ferromagnet. From the present first principles calculation within non-spin polarized state, both compounds present an electronic density of state with a sharp and narrow peak centered at the Fermi level corresponding to flat bands from 3d-Ni. This induces a magnetic instability and both compounds are more stable in a ferromagnetic (FM) order compared to a paramagnetic state (ΔE ≈ −35 meV/f.u.). The magnetic moment of each of the five Ni sites varies with their positions relative to the [A2Ni4] and [ANi5] units: they are minimum in the [A2Ni4] unit and maximum at the interface between two [ANi5] units. For 2H-La2Ni7, an antiferromagnetic (AFM) structure has been proposed and found with an energy comparable to that of the FM state. This AFM structure is described by two FM unit blocks of opposite Ni spin sign separated by a non-magnetic layer at z = 0 and ½. The Ni (2a) atoms belonging to this intermediate layer are located in the [La2Ni4] unit and are at a center of symmetry of the hexagonal cell (P63/mmc) where the resultant molecular field is cancelled. Further non-collinear spin calculations have been performed to determine the Ni moment orientations which are found preferentially parallel to the c axis for both FM and AFM structures.
Undernutrition is associated with perturbations in T cell-, B cell-, monocyte- and dendritic cell- subsets in latent Mycobacterium tuberculosis infection

Undernutrition, as described by low body mass index (BMI), is a foremost risk factor for the progression of active Tuberculosis (TB). Undernutrition is also known to impact the baseline frequencies of innate and adaptive immune cells in animal models. To verify whether undernutrition has any influence on the baseline frequencies of immune cells in latent Mycobacterium tuberculosis infection (LTBI), we examined the frequencies of T cell-, B cell, monocyte- and dendritic cell (DC)- subsets in individuals with LTBI and low BMI (LBMI) and contrasted them with LTBI and normal BMI (NBMI) groups. LBMI was characterized by decreased frequencies and absolute cell counts of T cells, B cells and NK cells in comparison with NBMI. LBMI individuals demonstrated significantly enhanced frequencies of naïve and effector CD4+ and CD8+ T cells and significantly decreased frequencies of central memory, effector memory CD4+ and CD8+ T cells and regulatory T cells. Among B cell subsets, LBMI individuals demonstrated significantly diminished frequencies of naïve, immature, classical memory, activated memory, atypical memory and plasma cells. In addition, LBMI individuals showed significantly decreased frequencies of classical monocytes, myeloid DCs and plasmacytoid DCs and significantly increased frequencies of intermediate and non-classical monocytes and myeloid derived suppressor cells. BMI exhibited a positive correlation with B cell and NK cell counts. Our data, therefore, demonstrates that coexistent undernutrition in LTBI is characterized by the occurrence of a significant modulation in the frequency of innate and adaptive immune cell subsets.
The Roles of Body Composition and Specific Strength in the Relationship Between Race and Physical Performance in Older Adults.

BACKGROUND Socioeconomics may explain black-white differences in physical performance; few studies examine racial differences among socioeconomically similar groups. Performance is also affected by body composition and specific strength, which differ by race. We assessed whether racial differences in physical performance exist among older adults with high education and similar income and whether body composition and specific strength attenuate observed differences. METHODS Cross-sectional analysis of 536 men (18% black) and 576 women (28% black) aged more than 60 years from the Baltimore Longitudinal Study of Aging. Body composition was evaluated using dual-energy x-ray absorptiometry. Specific strength was assessed by quadricep peak torque divided by height-normalized thigh cross-sectional area and grip strength divided by body mass index-normalized appendicular lean mass. Physical performance was assessed using usual gait speed and fast 400 m walk time. Sex-stratified linear regression models, adjusted for age, height, education, and recent income, determined whether body composition or specific strength attenuated associations between race and physical performance. RESULTS Blacks were younger, with higher weight and appendicular lean mass. Black women had higher percent fat and specific strength. In both sexes, blacks had poorer physical performance after adjustment for socioeconomic factors. In women, neither body composition nor specific strength altered the association with gait speed. In men, neither body composition nor specific strength attenuated racial differences in either performance measure. CONCLUSIONS Poorer physical performance among black compared to white older adults persists among persons with high education and similar income and cannot generally be attributed to differences in body composition or specific strength.
Blood Pressure After Endovascular Thrombectomy

Supplemental Digital Content is available in the text. Background and Purpose— The optimal level for blood pressure after endovascular thrombectomy in acute ischemic stroke is not well established. We sought to evaluate the association of post-endovascular thrombectomy systolic blood pressure (SBP) levels with clinical outcomes. Methods— We included endovascular thrombectomy–treated patients registered from 2014 to 2017 in the Safe Implementation of Treatments in Stroke International Thrombectomy Registry. The mean 24-hour SBP after endovascular thrombectomy treatment was analyzed both as a continuous variable and in intervals. The primary outcome was 3-month functional independence (modified Rankin Scale score of 0–2). The secondary outcomes were symptomatic intracerebral hemorrhage (SICH) and 3-month mortality. The SBP interval with the highest proportion of functional independence was chosen as reference. All analyses were performed for successful or unsuccessful recanalization (modified Treatment in Cerebral Ischemia score ≥2b or <2b, respectively). The results were adjusted for known confounders in logistic regression models. Results— In the multivariable analyses, a higher SBP value as a continuous variable was associated unfavorably with all outcomes in patients with successful recanalization (n=2920) and with more SICH in patients with unsuccessful recanalization (n=711). SBP interval ≥160 mm Hg was associated with less functional independence (adjusted odds ratio, 0.28 [95% CIs, 0.15–0.53]) and more SICH (adjusted odds ratio, 6.82 [95% CIs, 1.53–38.09]) compared with reference 100 to 119 mm Hg in patients with successful recanalization. SBP ≥160 mm Hg was associated with more SICH (adjusted odds ratio, 6.62 [95% CIs, 1.07–51.05]) compared with reference 120 to 139 mm Hg in patients with unsuccessful recanalization. Conclusions— Higher SBP values were associated with less functional independence at 3 months in patients with successful recanalization and with more SICH regardless of recanalization status.
The Na+/K+ ATPase Inhibitor Ouabain Attenuates Stemness and Chemoresistance of Osteosarcoma Cells

Background The purpose of this study was to explore the effects of the Na+/K+ ATPase inhibitor ouabain in regulating osteosarcoma (OS) cell stemness. Material/Methods Western blot, qPCR, sphere-forming analysis, DNA methylation analysis, and Ca2+ concentration detection were performed to evaluate the stem-like traits of cells and ouabain-induced effects and related mechanisms on OS cell stemness. Cell viability assessment was performed to evaluate the effect of ouabain on OS cell chemosensitivity. Results Ouabain reduced the ALDH1 activity, the expression of critical stemness regulators, sphere size and number, and migration, invasion, and adhesion ability, but had little effects on cell viability. Additionally, the intracellular Ca2+ concentration and methylation level of the critical stemness regulators were higher in OS cells than in spheres formed by OS cells. Mechanistic studies revealed that ouabain leads to DNA methylation of stemness markers through increasing intracellular Ca2+ concentration. Notably, inhibition of Ca2+ channel or DNA methylation rescued the inhibition of ouabain on OS cell stemness. Additionally, ouabain enhances cisplatin sensitivity of OS cells, which is involved in Ca2+ channel and DNA methylation. Conclusions This work provides a potential compound for treating OS patients, especially OS patients with chemoresistance.
Microsporidia with Vertical Transmission Were Likely Shaped by Nonadaptive Processes

Abstract Microsporidia have the leanest genomes among eukaryotes, and their physiological and genomic simplicity has been attributed to their intracellular, obligate parasitic life-style. However, not all microsporidia genomes are small or lean, with the largest dwarfing the smallest ones by at least an order of magnitude. To better understand the evolutionary mechanisms behind this genomic diversification, we explore here two clades of microsporidia with distinct life histories, Ordospora and Hamiltosporidium, parasitizing the same host species, Daphnia magna. Based on seven newly assembled genomes, we show that mixed-mode transmission (the combination of horizontal and vertical transmission), which occurs in Hamiltosporidium, is found to be associated with larger and AT-biased genomes, more genes, and longer intergenic regions, as compared with the exclusively horizontally transmitted Ordospora. Furthermore, the Hamiltosporidium genome assemblies contain a variety of repetitive elements and long segmental duplications. We show that there is an excess of nonsynonymous substitutions in the microsporidia with mixed-mode transmission, which cannot be solely attributed to the lack of recombination, suggesting that bursts of genome size in these microsporidia result primarily from genetic drift. Overall, these findings suggest that the switch from a horizontal-only to a mixed mode of transmission likely produces population bottlenecks in Hamiltosporidium species, therefore reducing the effectiveness of natural selection, and allowing their genomic features to be largely shaped by nonadaptive processes.
Treatment of Displaced Olecranon Fractures: A Systematic Review

Background and Aims: The incidence of olecranon fractures is rising. Displaced fractures are usually operated either by tension band wiring or plate fixation. The aim of this review is to evaluate the best current evidence on the management of displaced olecranon fractures. Materials and Methods: Randomized controlled trials were systematically gathered in May 2018 from CENTRAL, MEDLINE, Embase, CINAHL, Scopus, and PEDro databases. The methodological quality of articles was assessed according to the Cochrane Collaboration’s domain-based framework. Prospero database registration number: CRD42018096650. Results: Of 1518 identified records, finally, 5 were relevant. Four trials were found on tension band wiring: two compared tension band wiring with plate fixation (n = 108), one compared plate fixation with an olecranon memory connector (n = 40), and one trial compared tension band wiring with a modified tension band wiring called Cable Pin System (n = 62). In addition, one trial compared operative and conservative treatment in elderly (n = 19). The risk of bias was considered low in two and high in three of the trials. The follow-up time was 5–36 months, and outcome measures varied from patient-rated and physician-rated measures to radiological outcomes. In the analysis, there was no difference between tension band wiring and plate fixation. The data were insufficient for further quantitative analysis. Conclusion: No differences were found in clinical or patient-rated outcome measures between the two most frequent fixation methods (tension band wiring and plate fixation) of displaced olecranon fractures. Current data are not sufficient to evaluate other treatment methods; however, conservative treatment might serve as an option for selected patients in the elderly population.
Distinct alterations of gut morphology and microbiota characterize accelerated diabetes onset in nonobese diabetic mice

The rising prevalence of type 1 diabetes (T1D) over the past decades has been linked to lifestyle changes, but the underlying mechanisms are largely unknown. Recent findings point to gut-associated mechanisms in the control of T1D pathogenesis. In nonobese diabetic (NOD) mice, a model of T1D, diabetes development accelerates after deletion of the Toll-like receptor 4 (TLR4). We hypothesized that altered intestinal functions contribute to metabolic alterations, which favor accelerated diabetes development in TLR4-deficient (TLR4−/−) NOD mice. In 70–90-day-old normoglycemic (prediabetic) female NOD TLR4+/+ and NOD TLR4−/− mice, gut morphology and microbiome composition were analyzed. Parameters of lipid metabolism, glucose homeostasis, and mitochondrial respiratory activity were measured in vivo and ex vivo. Compared with NOD TLR4+/+ mice, NOD TLR4−/− animals showed lower muscle mass of the small intestine, higher abundance of Bacteroidetes, and lower Firmicutes in the large intestine, along with lower levels of circulating short-chain fatty acids (SCFA). These changes are associated with higher body weight, hyperlipidemia, and severe insulin and glucose intolerance, all occurring before the onset of diabetes. These mice also exhibited insulin resistance–related abnormalities of energy metabolism, such as lower total respiratory exchange rates and higher hepatic oxidative capacity. Distinct alterations of gut morphology and microbiota composition associated with reduction of circulating SCFA may contribute to metabolic disorders promoting the progression of insulin-deficient diabetes/T1D development.
Analysis of caesarean section and neonatal outcome using the Robson classification in a rural district hospital in Tanzania: an observational retrospective study

Objective Caesarean section (CS) rates have increased worldwide in recent decades. In 2015, the WHO proposed the use of the 10-group Robson classification as a global standard for assessing, monitoring and comparing CS rates both within healthcare facilities over time and between them. The aim of this study was to assess the pattern of CS rates according to the Robson classification and describe maternal and perinatal outcomes by group at the Tosamaganga Hospital in rural Tanzania. Design Observational retrospective study. Setting St. John of the Cross Tosamaganga Hospital, a referral centre in rural Tanzania. Participants 3012 women who gave birth in Tosamaganga Hospital from 1 January to 30 June 2014 and from 1 March to 30 November 2015. Results The overall CS rate was 35.2%, and about 90% of women admitted for labour were in Robson groups 1 through 5. More than 40% of the CS carried out in the hospital were performed on nulliparous women at term with a single fetus in cephalic presentation (groups 1 and 3), and the most frequent indication for the procedure was previous uterine scar (39.2%). The majority of severe neonatal outcomes were observed in groups 1 (27.7%), 10 (24.5%) and 3 (19.1%). Conclusion We recorded a high CS rate in Tosamaganga Hospital, particularly in low-risk patients groups (Robson groups 1 and 3). Our analysis of Robson classification and neonatal outcomes suggests the need to improve labour management at the hospital and to provide timely referrals in order to prevent women from arriving there in critical conditions.
Pharmacokinetics of doxorubicin following concomitant intravenous administration of olaratumab (IMC‐3G3) to patients with advanced soft tissue sarcoma

Olaratumab, a fully human monoclonal antibody, selectively binds to human platelet‐derived growth factor receptor alpha and blocks ligand binding. This study assessed the effect of olaratumab on the pharmacokinetics (PK) of doxorubicin and the safety of olaratumab alone and in combination with doxorubicin.
MouseBytes, an open-access high-throughput pipeline and database for rodent touchscreen-based cognitive assessment

Open Science has changed research by making data accessible and shareable, contributing to replicability to accelerate and disseminate knowledge. However, for rodent cognitive studies the availability of tools to share and disseminate data is scarce. Automated touchscreen-based tests enable systematic cognitive assessment with easily standardised outputs that can facilitate data dissemination. Here we present an integration of touchscreen cognitive testing with an open-access database public repository (mousebytes.ca), as well as a Web platform for knowledge dissemination (https://touchscreencognition.org). We complement these resources with the largest dataset of age-dependent high-level cognitive assessment of mouse models of Alzheimer’s disease, expanding knowledge of affected cognitive domains from male and female mice of three strains. We envision that these new platforms will enhance sharing of protocols, data availability and transparency, allowing meta-analysis and reuse of mouse cognitive data to increase the replicability/reproducibility of datasets.