Miracle-dz/UniFAR-FTUs huggingface dataset:
Activation of Pregnane X Receptor–Cytochrome P450s Axis: A Possible Reason for the Enhanced Accelerated Blood Clearance Phenomenon of PEGylated Liposomes In Vivo

Recently, we reported that repeated injection of PEGylated liposomes (PEG-L) at certain intervals to the same rat lead to the disappearance of their long-circulation properties, referred to as the “accelerated blood clearance (ABC) phenomenon”. Evidence from our recent studies suggested that cytochrome P450s (P450s) contribute to induction of the ABC phenomenon, a possibility that had been previously ignored. However, few details are known about the mechanism for induction of P450s. The present study was undertaken to investigate the roles in the ABC phenomenon of pregnane X receptor (PXR) and constitutive androstane receptor (CAR), the major upstream transcriptional regulators of the P450 genes, including CYP3A1, CYP2C6, and CYP1A2. The results demonstrated that expression of rat PXR and CAR was significantly increased in the ABC phenomenon and was accompanied by elevated CYP3A1, CYP2C6, and CYP1A2 levels. Further findings revealed that PXR but not CAR protein was substantially upregulated in the hepatocyte nucleus, together with marked nuclear colocalization of the PXR–retinoid X receptor alpha (RXRα) transcriptionally active heterodimer, indicating that nuclear translocation of PXR was induced in the ABC phenomenon, whereas nuclear translocation of CAR was not observed. Notably, pretreatment with the specific PXR inducer dexamethasone significantly induced accelerated systemic clearance of the subsequent injection of PEG-L, associating with increased nuclear colocalization of PXR-RXRα. These results revealed that the induction of P450s in the ABC phenomenon may be attributable largely to the activation of PXR induced by sequential injections of PEG-L, thus confirming the crucial involvement of the PXR-P450s axis in promoting the ABC phenomenon. Significance Statement The results of this study revealed that the induction of P450s in the ABC phenomenon may be largely attributable to the activation of PXR induced by sequential injections of PEG-L, thus confirming the crucial involvement of the PXR-P450s axis in promoting the ABC phenomenon. The data may help to extend our insights into 1) the role of P450s, which are regulated by the liver-enriched nuclear receptor PXR, in the ABC phenomenon, and 2) the therapeutic potential of targeting the PXR-P450 axis for reducing the magnitude of the ABC phenomenon in clinical practice.
Brain Marker Links Stress and Nicotine Abstinence.

BACKGROUND Subjective stress is a well-documented predictor of early smoking relapse, yet our understanding of stress and tobacco use is limited by reliance on self-reported measures of stress. We utilized a validated functional neuroimaging paradigm to examine whether stress exposure during early abstinence alters objective measures of brain function. METHODS 75 participants underwent blood oxygen level dependent (BOLD) functional magnetic resonance imaging (FMRI) during the Montreal Imaging Stress Task (MIST) on two occasions: once during smoking satiety and once following biochemically confirmed 24-hour abstinence (order counter-balanced). The primary outcome measure was brain response during stress (vs. control) blocks of the MIST, assessed using whole-brain analysis corrected for multiple comparisons using clusters determined by Z≥3.1. RESULTS Abstinence (vs. satiety) was associated with significantly increased activation in the left inferior frontal gyrus, a brain region associated with inhibitory control. Abstinence-induced change in brain response to stress was positively associated with change in self-reported stress. CONCLUSIONS This study provides objective evidence that the brain response to stress is altered during the first 24 hours of a quit attempt compared to smoking satiety. IMPLICATIONS These results point to the potential value of inoculating smokers with stress management training prior to a quit attempt.
Carbon-based resistive memory

We propose carbon as new resistive memory material for non-volatile memories and compare three allotropes of carbon, namely carbon nanotubes, graphene-like conductive carbon and insulating carbon for their possible application as resistance-change material in high density non-volatile memories. Repetitive high-speed switching and the potential for multi-level programming have been successfully demonstrated.
The Influence of Offline and Online Intrinsic Motivations on Online Health Information Seeking

ABSTRACT We examine how intrinsic motivations in two health interaction contexts – online and doctor’s office visit – influence online health information seeking (OHIS). Many studies have approached OHIS through short-term gratification of informational needs. Our study uses a conceptual framework of intrinsic human motivation to better understand OHIS as a form of sustained behavior. We applied Self Determination Theory’s three key constructs (Autonomy, Competence, and Relatedness) within a locus of patient-physician relations. Our findings, based on a survey of 993 online health information seekers in India, show that support for Autonomy in the online context explains all three categories of OHIS behaviors: Diagnosis and Treatment Information Seeking, General Health Information Seeking, and Office Visit Information Seeking. Support for Relatedness in the online context explains only Office Visit Information Seeking. However, support for Autonomy, Competence, and Relatedness in the office visit experience could not explain why people engage in OHIS overall. Motivations for the office visit are not associated with the online experience, suggesting that online and offline are not just two kinds of substitute health interaction contexts.
Amino acid substitution equivalent to human chorea-acanthocytosis I2771R in yeast Vps13 protein affects its binding to phosphatidylinositol 3-phosphate

Abstract The rare human disorder chorea-acanthocytosis (ChAc) is caused by mutations in hVPS13A gene. The hVps13A protein interacts with actin and regulates the level of phosphatidylinositol 4-phosphate (PI4P) in the membranes of neuronal cells. Yeast Vps13 is involved in vacuolar protein transport and, like hVps13A, participates in PI4P metabolism. Vps13 proteins are conserved in eukaryotes, but their molecular function remains unknown. One of the mutations found in ChAc patients causes amino acids substitution I2771R which affects the localization of hVps13A in skeletal muscles. To dissect the mechanism of pathogenesis of I2771R, we created and analyzed a yeast strain carrying the equivalent mutation. Here we show that in yeast, substitution I2749R causes dysfunction of Vps13 protein in endocytosis and vacuolar transport, although the level of the protein is not affected, suggesting loss of function. We also show that Vps13, like hVps13A, influences actin cytoskeleton organization and binds actin in immunoprecipitation experiments. Vps13-I2749R binds actin, but does not function in the actin cytoskeleton organization. Moreover, we show that Vps13 binds phospholipids, especially phosphatidylinositol 3-phosphate (PI3P), via its SHR_BD and APT1 domains. Substitution I2749R attenuates this ability. Finally, the localization of Vps13-GFP is altered when cellular levels of PI3P are decreased indicating its trafficking within the endosomal membrane system. These results suggest that PI3P regulates the functioning of Vps13, both in protein trafficking and actin cytoskeleton organization. Attenuation of PI3P-binding ability in the mutant hVps13A protein may be one of the reasons for its mislocalization and disrupted function in cells of patients suffering from ChAc.
Sleepy driving and risk of obstructive sleep apnea among truck drivers in Saudi Arabia

Abstract Objective: Truck drivers represent a group at a particularly higher risk of motor vehicle accidents (MVAs). Sleepy driving and obstructive sleep apnea (OSA) among truck drivers are major risk factors for MVAs. No study has assessed the prevalence of sleepy driving and risk of OSA among truck drivers in Saudi Arabia. Therefore, this study aimed to assess sleepy driving and risk of OSA among these truck drivers. Methods: This study included 338 male truck drivers working in Saudi Arabia. A validated questionnaire regarding sleepy driving and OSA was used. The questionnaire included sociodemographic assessment, the Epworth Sleepiness Scale (ESS), the Berlin Questionnaire (BQ), and driving-related items. Results: The drivers had a mean age of 42.9 ± 9.7 years. The majority (94.7%) drove more than 5 h a day. A history of MVAs during the last 6 months was reported by 6.5%. Approximately 95% of the participants reported that they had accidentally fallen asleep at least once while driving over the past 6 months, and 49.7% stated that this had happened more than 5 times during the last 6 months. Based on the BQ score, a high risk of OSA was detected in 29% of the drivers. “Not getting good-quality sleep” (odds ratio [OR] = 2.89; 95% confidence interval [CI], 1.08–7.75; P = .014) and driving experience from 6 to 10 years (OR = 3.37; 95% CI, 1.28–8.91; P = .034) were the only independent predictors of MVAs in the past 6 months. Conclusions: Sleepy driving and a high risk of OSA was prevalent among the study population of male truck drivers in Saudi Arabia. Not getting good-quality sleep and driving experience from 6 to 10 years contributes to the accident risk among these truck drivers.
Early-generated interneurons regulate neuronal circuit formation during early postnatal development

A small subset of interneurons that are generated earliest as pioneer neurons are the first cohort of neurons that enter the neocortex. However, it remains largely unclear whether these early-generated interneurons (EGIns) predominantly regulate neocortical circuit formation. Using inducible genetic fate mapping to selectively labeled EGIns and pseudo-random interneurons (pRIns), we found that EGIns exhibited more mature electrophysiological and morphological properties and higher synaptic connectivity than pRIns at early postnatal stages. In addition, when stimulating one cell, the proportion of EGIns that influence spontaneous network synchronization is significantly higher than that of pRIns. Importantly, toxin-mediated ablation of EGIns after birth significantly reduce spontaneous network synchronization and decrease inhibitory synaptic transmission during the first postnatal week. These results suggest that EGIns can shape developing networks and may contribute to the refinement of neuronal connectivity before the establishment of the adult neuronal circuit.
Silver(I) Complexes of the Pharmaceutical Agents Metronidazole and 4-Hydroxymethylpyridine: Comparison of Cytotoxic Profile for Potential Clinical Application

In previous papers, we have reported on the high antifungal and significant antibacterial activity against Gram-positive and Gram-negative bacteria of the water-soluble silver(I) complexes of metronidazole and derivatives of pyridine compared to silver nitrate. In the present study, the cytotoxic activity of the silver(I) complexes of metronidazole and 4-hydroxymethylpyridine was compared with that of silver nitrate. Metronidazole and 4-hydroxymethylpyridine were investigated using Balb/c 3T3 and HepG2 cell lines in order to evaluate the potential clinical application of silver(I) complexes. The cells were exposed for 72 h to compounds at eight concentrations. The cytotoxic concentrations (IC50) of the study compounds were assessed within four biochemical endpoints: mitochondrial activity, lysosomal activity, cellular membrane integrity, and total protein content. The investigated silver(I) complexes displayed comparable cytotoxicity to that of silver nitrate used in clinics. Mean cytotoxic concentrations calculated for investigated silver(I) complexes from concentration–response curves ranged from 2.13 to 26.5 µM. HepG2 cells were less sensitive to the tested complexes compared to fibroblasts (Balb/c 3T3). However, the most affected endpoint for HepG2 cells was cellular membrane damage. The cytotoxicity of both silver complexes was comparable for Balb/c 3T3 cells. The cytotoxic potential of the new silver(I) compounds compared to that of silver nitrate used in medicine indicates that they are safe and could be used in clinical practice. The presented results are yet more stimulating to further studies that evaluate the therapeutic use of silver complexes.
Locomotor kinematics and EMG activity during quadrupedal vs. bipedal gait in the Japanese macaque.

Several qualitative features distinguish bipedal from quadrupedal locomotion in mammals. Here we show quantitative differences between quadrupedal and bipedal gait in the Japanese monkey in terms of gait patterns, trunk/hindlimb kinematics and electromyographic (EMG) activity, obtained from three macaques during treadmill walking. We predicted that, as a consequence of an almost upright body axis, bipedal gait would show properties consistent with temporal and spatial optimization countering higher trunk/hindlimb loads and a less stable center of mass (CoM). A comparatively larger step width, a ~9% longer duty cycle and ~20% increased relative duration of the double support phase were all in line with such a strategy. Bipedal joint kinematics showed strongest differences in proximal, and least in distal hindlimb joint excursions compared to quadrupedal gait. Hindlimb joint coordination (cyclograms) revealed more periods of single-joint rotations during bipedal gait, and predominance of proximal joints during single-support. The CoM described a symmetrical, quasi-sinusoidal left/right path during bipedal gait, with an alternating shift toward the weight-supporting limb during stance. Trunk/hindlimb EMG activity was non- uniformally increased during bipedal gait: most prominently in proximal antigravity muscles during stance (up to 10-fold). Non-antigravity hindlimb EMG showed altered temporal profiles during lift-off or touchdown. Muscle co-activation was more, but muscle synergies less frequent during bipedal gait. Together, this shows that behavioral and EMG properties of bipedal vs. quadrupedal gait are quantitatively distinct, and suggests that the neural control of bipedal primate locomotion underwent specific adaptations to generate these particular behavioral features to counteract increased load and instability.
Comparing the accuracy of PCR-capillary electrophoresis and cuticle microhistological analysis for assessing diet composition in ungulates: A case study with Pyrenean chamois

The study of diet composition is required to understand the interactions between animal and plant ecosystems. Different non-invasive techniques applied on faecal samples have commonly been used for such purposes, with cuticle microhistological analysis (CMA) and emerging DNA-based methods being the most relevant. In this work, we refined and optimized a qualitative DNA-based approach combining PCR amplification of long trnL(UAA) and ITS2 fragments and capillary electrophoresis (PCR-CE), instead of short trnL(UAA) fragments and massive sequencing technologies commonly reported. To do so, we developed a controlled diet assay using a stabled Pyrenean chamois specimen (Rupicapra pyrenaica pyrenaica), which included representative herbaceous and shrubby plant species. We also assessed the impact of sample freshness on the diet determination of this mountain caprinae by exposing faecal samples to the outdoor environment for three weeks. Faecal samples from both experiments were analysed by qualitative PCR-CE and semi-quantitative CMA in order to compare the pros and cons of both approaches. Our results show that all of the offered plant species were detected by both methodologies although CMA over-detected shrubs compared to herbaceous species. At the same time, sample degradation due to sustained climate exposure is a limiting factor for molecular analysis, but not for CMA. Taken all together, our results suggest that the qualitative information obtained by CMA and PCR-CE can be interchangeable when faecal samples are fresh (less than one week after deposition) but, afterwards, molecular analysis underestimates diet composition probably due to DNA degradation. CMA, however, can accurately be used at least three weeks after defecation. Moreover, by combining the results of simultaneous PCR amplification of two complementary genes, this optimized PCR-CE methodology provides a reliable, feasible and more affordable alternative for multiple and routine analyses of complex samples. Neither CMA nor PCR-CE seems to solve comprehensively the quatification of herbivore diets and thus further research needs to be done.
Supports: A Key Factor in Faculty Implementation of Evidence-Based Teaching

Evidence-based teaching (EBT), such as active learning and formative assessment, benefits student learning but is not present in many college science classrooms. The choices faculty make about how to teach their science courses are influenced by their personal beliefs and motivations, as well as their departmental structures and institutional cultures. With data from 584 science, technology, engineering, and mathematics (STEM) faculty trained in EBT, we compare which of the following factors most relate to faculty’s use of EBT: 1) faculty’s personal motivations (e.g., teaching value, confidence, beliefs about intelligence); and 2) their experiences with their institutional teaching environments (e.g., departmental support, student enthusiasm). Faculty’s perceived supports in their teaching environments (e.g., having supportive colleagues, being able to access curricular resources) were by far most predictive of their use of EBT. Faculty’s personal motivations had little to no relationship when supports were included in these models. The effects were robust, even when controlling for faculty gender, minority status, and teaching experience. Much of the literature has focused on perceived barriers to EBT implementation (e.g., lack of time, constrained teaching space). The current data indicate that a focus on building supports for faculty may have the greatest impact on increasing the presence of EBT in college STEM courses.
A Pilot Study on Anti-Obesity Mechanisms of Kappaphycus Alvarezii: The Role of Native κ-Carrageenan and the Leftover Sans-Carrageenan Fraction

Kappaphycus is a commercially important edible red alga widely cultivated for carrageenan production. Here, we aimed to investigate the anti-obesity mechanism of Kappaphycus alvarezii by comparing the effects of whole seaweed (T), extracted native κ-carrageenan (CGN), and the leftover fraction sans-carrageenan (SCGN) supplementations (5%, w/w) on diet-induced obese C57BL/6J mice. A high-fat diet induced both a raised body fat percentage and serum cholesterol level, increased adipocytes size, abnormal levels of adipocytokines, and promoted gut dysbiosis. Our results showed that, overall, both CGN and SCGN were more effective in reversing obesity and related metabolic syndromes to normal levels than T. Furthermore, these findings suggested that CGN- and SCGN-modulated gut dysbiosis induced by a high-fat diet, which may play an influencing role in adiponectin dysregulation. Our data also showed some evidence that CGN and SCGN have distinct effects on selected genes involved in lipid metabolism. In conclusion, both κ-carrageenan and SCGN have novel anti-obesity potential with possible different mechanisms of action.
Decreased histone deacetylase activity in chronic obstructive pulmonary disease.

BACKGROUND Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation that is greater in patients with advanced disease. We asked whether there is a link between the severity of disease and the reduction in histone deacetylase (HDAC) activity in the peripheral lung tissue of patients with COPD of varying severity. HDAC is a key molecule in the repression of production of proinflammatory cytokines in alveolar macrophages. METHODS HDAC activity and histone acetyltransferase (HAT) activity were determined in nuclear extracts of specimens of surgically resected lung tissue from nonsmokers without COPD, patients with COPD of varying severity, and patients with pneumonia or cystic fibrosis. Alveolar macrophages from nonsmokers, smokers, and patients with COPD and bronchial-biopsy specimens from nonsmokers, healthy smokers, patients with COPD, and those with mild asthma were also examined. Total RNA extracted from lung tissue and macrophages was used for quantitative reverse-transcriptase-polymerase-chain-reaction assay of HDAC1 through HDAC8 and interleukin-8. Expression of HDAC2 protein was quantified with the use of Western blotting. Histone-4 acetylation at the interleukin-8 promoter was evaluated with the use of a chromatin immunoprecipitation assay. RESULTS Specimens of lung tissue obtained from patients with increasing clinical stages of COPD had graded reductions in HDAC activity and increases in interleukin-8 messenger RNA (mRNA) and histone-4 acetylation at the interleukin-8 promoter. The mRNA expression of HDAC2, HDAC5, and HDAC8 and expression of the HDAC2 protein were also lower in patients with increasing severity of disease. HDAC activity was decreased in patients with COPD, as compared with normal subjects, in both the macrophages and biopsy specimens, with no changes in HAT activity, whereas HAT activity was increased in biopsy specimens obtained from patients with asthma. Neither HAT activity nor HDAC activity was changed in lung tissue from patients with cystic fibrosis or pneumonia. CONCLUSIONS Patients with COPD have a progressive reduction in total HDAC activity that reflects the severity of the disease.
MAPK Phosphatase 7 Regulates T Cell Differentiation via Inhibiting ERK-Mediated IL-2 Expression

Members of the MAPK phosphatase (MKP) protein family play critical roles in immune responses through differential regulation of MAPK activation. In this study, we show that MKP7, also known as dual-specificity phosphatase 16, was required for CD4+ T cell responses in vivo. Mkp7−/− CD4+ T cells exhibited enhanced ERK and JNK activation, and produced increased amount of IL-2 compared with Mkp7+/+ cells upon activation. Mkp7−/− CD4+ T cells were selectively defective in Th17 differentiation in vitro, which was rescued by blocking IL-2 or inhibition of ERK activation. Furthermore, mice carrying Mkp7−/− T cells were deficient in generation of Th17 and T follicular helper cells in vivo, and were resistant to autoimmune experimental encephalomyelitis. Our results thus demonstrate an essential role of MKP7 in effector T cell function.
A Fast and Simple Algorithm for Identifying 2-Monotonic Positive Boolean Functions

Consider the problem of identifying min T(f) and max F(f) of a positive (i.e., monotone) Boolean function f, by using membership queries only, where min T(f) (max F(f)) denotes the set of minimal true vectors (maximal false vectors) of f. As the existence of a polynomial total time algorithm (i.e., polynomial time in the length of input and output) for this problem is still open, we consider here a restricted problem: given an unknown positive function f of n variables, decide whether f is 2-monotonic or not, and if f is 2-monotonic, output both min T(f) and max. F(f). For this problem, we propose a simple algorithm, which is based on the concept of maximum latency, and show that it uses O(n2m) time and O(n2m) queries, where m=¦ min T(f)¦+¦ max F(f)¦. This answers affirmatively the conjecture raised in [3, 4], and is an improvement over the two algorithms discussed therein: one uses O(n3m) time and O(n3m) queries, and the other uses O(nm2+n2m) time and O(nm) queries.