Miracle-dz/UniFAR-FTUs huggingface dataset:
Toxicokinetics and analytical toxicology of the abused opioid U-48800 - in vitro metabolism, metabolic stability, isozyme mapping, and plasma protein binding.

Due to the risk of new synthetic opioids (NSO) for human health, the knowledge of their toxicokinetic characteristics is important for clinical and forensic toxicology. U-48800 is an NSO structurally non-related to classical opioids such as morphine or fentanyl and offered for abuse. As no toxicokinetic data of U-48800 are currently available, the aims of this study were to identify the in vitro metabolites of U-48800 in pooled human liver S9 fraction (pS9), to map the isozymes involved in the initial metabolic steps, and to determine further toxicokinetic data such as metabolic stability, including the in vitro half-life (t1/2 ), and the intrinsic (CLint ) and hepatic clearance (CLh ). Furthermore, drug detectability studies in rat urine should be done using hyphenated mass spectrometry. In total, 13 phase I metabolites and one phase II metabolite were identified. N-Dealkylation, hydroxylation, and their combinations were the predominant metabolic reactions. The isozymes CYP2C19 and CYP3A4 were mainly involved in these initial steps. CYP2C19 poor metabolizers may suffer from an increased U-48800 toxicity. The in vitro half-life and intrinsic clearance could be rated as moderate, compared to structural related compounds. After administration of an assumed consumer dose to rats, unchanged parent compound was only found very low abundant but three metabolites were detected additionally. Due to species differences, metabolites found in rats might be different from those in humans. However, both phase I metabolites found in rat urine, the parent compound, and additionally the N-demethyl metabolite should be used as main targets in toxicological urine screening approaches.
Genetic variants in TRPM7 associated with unexplained stillbirth modify ion channel function

Abstract Stillbirth is the loss of a fetus after 22 weeks of gestation, of which almost half go completely unexplained despite post-mortem. We recently sequenced 35 arrhythmia-associated genes from 70 unexplained stillbirth cases. Our hypothesis was that deleterious mutations in channelopathy genes may have a functional effect in utero that may be pro-arrhythmic in the developing fetus. We observed four heterozygous, nonsynonymous variants in transient receptor potential melastatin 7 (TRPM7), a ubiquitously expressed ion channel known to regulate cardiac development and repolarization in mice. We used site-directed mutagenesis and single-cell patch-clamp to analyze the functional effect of the four stillbirth mutants on TRPM7 ion channel function in heterologous cells. We also used cardiomyocytes derived from human pluripotent stem cells to model the contribution of TRPM7 to action potential morphology. Our results show that two TRPM7 variants, p.G179V and p.T860M, lead to a marked reduction in ion channel conductance. This observation was underpinned by a lack of measurable TRPM7 protein expression, which in the case of p.T860M was due to rapid proteasomal degradation. We also report that human hiPSC-derived cardiomyocytes possess measurable TRPM7 currents; however, siRNA knockdown did not directly affect action potential morphology. TRPM7 variants found in the unexplained stillbirth population adversely affect ion channel function and this may precipitate fatal arrhythmia in utero.
γ‐Secretase inhibition affects viability, apoptosis, and the stem cell phenotype of endometriotic cells

Stem cells mediate cyclic regeneration of the endometrium. The upregulated expression of receptors and modulators of the notch signaling pathway in endometriosis suggests an involvement in the pathogenetic process. Here, we investigated the effects of notch pathway inhibition by a γ‐secretase inhibitor (GSI) on stemness‐associated properties of the epithelial endometriotic cell line 12Z and of primary endometriotic stroma cells.
Geometric considerations support the double‐displacement catalytic mechanism of l‐asparaginase

Twenty crystal structures of the complexes of l‐asparaginase with l‐Asn, l‐Asp, and succinic acid that are currently available in the Protein Data Bank, as well as 11 additional structures determined in the course of this project, were analyzed in order to establish the level of conservation of the geometric parameters describing interactions between the substrates and the active site of the enzymes. We found that such stereochemical relationships are highly conserved, regardless of the organism from which the enzyme was isolated, specific crystallization conditions, or the nature of the ligands. Analysis of the geometry of the interactions, including Bürgi–Dunitz and Flippin–Lodge angles, indicated that Thr12 (Escherichia coli asparaginase II numbering) is optimally placed to be the primary nucleophile in the most likely scenario utilizing a double‐displacement mechanism, whereas catalysis through a single‐displacement mechanism appears to be the least likely.
Borderlands of Industrial Modernity: Explorations into the History of Technology in Central Asia, 1850–2000

ABSTRACT:Central Asia is among the world regions that are least explored in terms of their history of technology. This essay reviews a wide array of academic literature that can serve as a base for historical research on technology and material culture in the region. It furthermore explores some of the most promising conceptual avenues for such an endeavor. The metaphor of a borderland, it argues, can be used beyond its geographical meaning to conceptualize the region's technological landscape. This landscape has been shaped by the coexistence of traditional artisanal practices and material cultures, the industrial and architectural legacies of Soviet rule as well as the region's recent reemergence as a hub between Russia, China, Europe, and the Middle East. Based on case studies from different disciplines, this essay therefore discusses technology's role in creating borderlands or territoriality, statehood, production, and everyday life in Central Asia.
Hyperammonemic encephalopathy: An unusual presentation of fibrolamellar hepatocellular carcinoma

Corresponding author : Douglas A. Simonetto Department of Gastroenterology and Hepatology, Mayo Clinic, 200 First ST SW, Rochester, MN 55905, USA Tel: +1-507-284-2174, Fax: +1-507-284-2174 E-mail: simonetto.douglas@mayo.edu https://orcid.org/0000-0003-4095-8144 Abbreviations: FLHCC, fibrolamellar hepatocellular carcinoma; HAE, hyperammonemic encephalopathy; HCC, hepatocellular carcinoma; OTC, ornithine transcarbamylase
Glymphatic imaging using MRI

In recent years, the existence of a mass transport system in the brain via cerebrospinal fluid (CSF) or interstitial fluid (ISF) has been suggested by many studies. The glymphatic system is hypothesized to be a waste clearance system of the CSF through the perivascular and interstitial spaces in the brain. Tracer studies have primarily been used to visualize or evaluate the waste clearance system in the brain, and evidence for this system has accumulated. The initial study that identified the glymphatic system was an in vivo tracer study in mice. In that study, fluorescent tracers were injected into the cisterna magna and visualized by two‐photon microscopy. MRI has also been used to evaluate glymphatic function primarily with gadolinium‐based contrast agents (GBCAs) as tracers. A number of GBCA studies evaluating glymphatic function have been conducted using either intrathecal or intravenous injections. Stable isotopes, such as 17O‐labeled water, may also be used as tracers since they can be detected by MRI. In addition to tracer studies, several other approaches have been used to evaluate ISF dynamics within the brain, including diffusion imaging. Phase contrast evaluation is a powerful method for visualizing flow within the CSF space. In order to evaluate the movement of water within tissue, diffusion‐weighted MRI represents another promising technique, and several studies have utilized diffusion techniques for the evaluation of the glymphatic system. This review will discuss the findings of these diffusion studies.
Behavioral therapies in headache: focus on mindfulness and cognitive behavioral therapy in children and adolescents

ABSTRACT Introduction: A wide proportion of children and adolescents with headache tends not to respond to various pharmacological treatments in use. The failure to respond to symptomatic treatment and prophylaxis is often due to the presence of a comorbid psychopathology undiagnosed or not properly treated. For these reasons and for the negative impact of headache on the quality of life of the patients and on the costs for the public health system, the adoption of an integrated multi-disciplinary perspective in the diagnosis and treatment of headache is needed. Areas covered: Several researchers have shown that behavioral treatment is effective as pharmacological treatment, not only for headache management but also to maintain a lifetime response to the headache treatment. In particular, Cognitive Behavioral Therapy (CBT) and Mindfulness have proven to be very resolutive both in the management of pain and in the management of stressful situations that can trigger the headache in children and adolescents with headache. Expert opinion: Although studies on behavioral treatments on children and adolescents with primary headaches are still few but a combined approach seems to be very useful in improving the quality of life of these subjects, especially in those who have internalizing disorders in comorbidities.
Moxibustion as a Therapy for Breast Cancer–Related Lymphedema in Female Adults: A Preliminary Randomized Controlled Trial

Objective: To evaluate the effect of moxibustion on relieving breast cancer–related lymphedema. Materials and Methods: A randomized controlled trial was conducted in our institution from March 2016 to March 2017. All patients (N = 48) with cancer-related lymphedema were allocated to 2 groups: a treatment group, in which moxibustion was performed, and a control group, in which pneumatic circulation was performed with compression garments worn every day. Therapeutic efficacy was evaluated by measuring arm circumference (wrist crease, 10 cm proximal to wrist crease, elbow crease, and 10 cm proximal to elbow crease) and determining the Revised Piper Fatigue Scale score and Visual Analog Scale score for swelling before and after treatment. Results: All patients were treated for 4 consecutive weeks. Compared with 0 week after treatment, the affected-side arm circumference after 4 weeks’ treatment decreased in both treatment and control groups; the difference value in the treatment group was superior to that in the control group. Compared with the controls, moxibustion resulted in a lower Visual Analog Scale score. The Revised Piper Fatigue total scores were improved in both the moxibustion and control group, and there was no significant difference between the 2 groups. Moxibustion reduced the behavioral, sensory, emotional, and cognitive Revised Piper Fatigue scores, but only the behavioral and sensory scores improved in the control group. Conclusion: Moxibustion has potential effect on breast cancer–related lymphedema. We present promising preliminary data for larger randomized trials to enable accurate evaluation of moxibustion as a lymphedema treatment.
Sensitive and Specific Detection of Low-Level Antibody Responses in Mild Middle East Respiratory Syndrome Coronavirus Infections

Middle East respiratory syndrome coronavirus (MERS-CoV) infections in humans can cause asymptomatic to fatal lower respiratory lung disease. Despite posing a probable risk for virus transmission, asymptomatic to mild infections can go unnoticed; a lack of seroconversion among some PCR-confirmed cases has been reported. We found that a MERS-CoV spike S1 protein–based ELISA, routinely used in surveillance studies, showed low sensitivity in detecting infections among PCR-confirmed patients with mild clinical symptoms and cross-reactivity of human coronavirus OC43–positive serum samples. Using in-house S1 ELISA and protein microarray, we demonstrate that most PCR-confirmed MERS-CoV case-patients with mild infections seroconverted; nonetheless, some of these samples did not have detectable levels of virus-neutralizing antibodies. The use of a sensitive and specific serologic S1-based assay can be instrumental in the accurate estimation of MERS-CoV prevalence.
Questionable Effect of Crosshatching Incision in Septoplasty

Objectives Crosshatching incision has been considered a useful method for correcting cartilaginous septal deviation. The aim of this study was to determine the utility and limitations of this approach. Methods This retrospective case-control study included 353 patients who underwent septoplasty performed by a senior surgeon between January 2004 and December 2010. Patients were classified into two groups according to whether crosshatching incision was performed (n=151) during septoplasty or not (n=202). All other techniques performed during septoplasty were identical. The parameters of surgical success (improvement of nasal obstruction, correction of deviation, and acoustic rhinometry results) and adverse effects were compared between the groups. Results There were no significant differences in the parameters of surgical success between the groups (improvement of nasal obstruction, P=0.333; correction of deviation, P=0.608; acoustic rhinometry results, P=0.322 for the difference in the minimal cross-sectional area; P=0.919 for difference in volume). Relative to patients who did not undergo the cross-hatching incision, patients with whom the technique was performed showed a significantly higher incidence of saddle nose (0/202 vs. 4/151 cases, P=0.033) and overcorrection (0/202 vs. 5/151 cases, P=0.014). Conclusion Crosshatching incision during septoplasty did not produce better surgical outcomes; however, it caused adverse effects such as saddle nose and overcorrection. Therefore, the use of crosshatching incision should be re-evaluated.
Single‐Cell Intravital Microscopy of Trastuzumab Quantifies Heterogeneous in vivo Kinetics

Cell‐to‐cell heterogeneity can substantially impact drug response, especially for monoclonal antibody (mAb) therapies that may exhibit variability in both delivery (pharmacokinetics) and action (pharmacodynamics) within solid tumors. However, it has traditionally been difficult to examine the kinetics of mAb delivery at a single‐cell level and in a manner that enables controlled dissection of target‐dependent and ‐independent behaviors. To address this issue, here we developed an in vivo confocal (intravital) microscopy approach to study single‐cell mAb pharmacology in a mosaic xenograft comprising a mixture of cancer cells with variable expression of the receptor HER2. As a proof‐of‐principle, we applied this model to trastuzumab therapy, a HER2‐targeted mAb widely used for treating breast and gastric cancer patients. Trastuzumab accumulated to a higher degree in HER2‐over expressing tumor cells compared to HER2‐low tumor cells (~5:1 ratio at 24 h after administration) but importantly, the majority actually accumulated in tumor‐associated phagocytes. For example, 24 h after IV administration over 50% of tumoral trastuzumab was found in phagocytes whereas at 48 h it was >80%. Altogether, these results reveal the dynamics of how phagocytes influence mAb behavior in vivo, and demonstrate an application of intravital microscopy for quantitative single‐cell measurement of mAb distribution and retention in tumors with heterogeneous target expression. © 2019 International Society for Advancement of Cytometry
Adolescent childbirth, miscarriage, and abortion: associations with changes in alcohol, marijuana, and cigarette use.

BACKGROUND Adolescent girls who become pregnant demonstrate greater risk for substance use than same-aged peers. However, it remains unclear how risk relates to normative changes in adolescence. Few studies have examined adolescent substance use changes before, during, and after pregnancy and considered how pregnancy outcomes (childbirth, miscarriage, abortion) differentially influence substance use changes. The present study examined associations between different adolescent pregnancy outcomes and within-person changes in substance use from prepregnancy to postpregnancy. METHODS Participants included 2,450 girls (52% Black) oversampled from low-income urban neighborhoods in Pittsburgh, PA. Participants self-reported pregnancy outcomes and substance use frequency (alcohol, cigarette, marijuana) annually from ages 11-20. Fixed effects regressions focused on first births, first miscarriages, and first abortions occurring from ages 12-19 to test the associations between pregnancy outcomes and within-individual changes in substance use from prepregnancy to postpregnancy. By design, models controlled for all potential time-stable confounds, and models included age and subsequent pregnancies as time-varying covariates. RESULTS Consistent with prior studies, girls who became pregnant (20%) reported greater early risk for substance use problems than never-pregnant adolescents, including earlier age of onset and more regular marijuana and cigarette use. Childbirth predicted a 26%-51% within-individual reduction in alcohol, marijuana, and cigarette use that remained significantly lower than prepregnancy levels after childbirth. Alcohol and marijuana use decreased (32%-47%) after miscarriage. Abortion was not associated with long-term changes in substance use; however, marijuana and cigarette use gradually increased (44%-46%) in the years leading up to the year of and after abortion, respectively, before returning to prepregnancy levels. CONCLUSIONS Findings highlight important differences in adolescent substance use patterns based on pregnancy outcome. For pregnant adolescents with heightened pre-existing risk for substance use, pregnancy may be a window of opportunity for substance use screening and behavioral intervention.
Intention matters to make you (im)moral: Positive-negative asymmetry in moral character evaluations

ABSTRACT Is intention, even if unfulfilled, enough to make a person appear to be good or bad? In this study, we investigated the influence of unfulfilled intentions of an agent on subsequent moral character evaluations. We found a positive-negative asymmetry in the effect of intentions. Factual information concerning failure to fulfill a positive intention mitigated the morality judgment of the actor, yet this mitigation was not as evident for the negative vignettes. Participants rated an actor who failed to fulfill their negative intention as highly immoral, as long as there was an external explanation to its unfulfillment. Furthermore, both emotional and cognitive (i.e., informativeness) processes mediated the effect of negative intention on moral character. For the positive intention, there was a significant mediation by emotions, yet not by informativeness. Results evidence the relevance of mental states in moral character evaluations and offer affective and cognitive explanations to the asymmetry.
Feasibility of neurochemically profiling mouse embryonic brain and its development in utero using 1H MRS at 14.1 T

We aimed to evaluate the feasibility of neurochemical profiling of embryonic mouse brain developments in utero and to seek potential in vivo evidence of an energy shift in a mitochondrial pyruvate carrier 1 (MPC1) deficient mouse model. C57BL/6 embryonic mouse brains were studied in utero by anatomical MRI and short echo localized proton (1H) MRS at 14.1 T. Two embryonic stages were studied, the energy shift (e.g., embryonic day 12.5–13, E12.5–13) and close to the birth (E17.5–18). In addition, embryonic brains devoid of MPC1 were studied at E12.5–13. The MRI provided sufficient anatomical contrasts for visualization of embryonic brain. Localized 1H MRS offered abundant metabolites through the embryonic development from E12.5 and close to the birth, e.g., E17.5 and beyond. The abundant neurochemical information at E12.5 provided metabolic status and processes relating to cellular development at this stage, i.e., the energy shift from glycolysis to oxidative phosphorylation, evidenced by accumulation of lactate in E12.5–13 embryonic brain devoid of MPC1. The further evolution of the neurochemical profile of embryonic brains at E17.5–18 is consistent with cellular and metabolic processes towards the birth. Localized 1H MRS study of embryonic brain development in utero is feasible, and longitudinal neurochemical profiling of embryonic brains offers valuable insight into early brain development.
Association of low Syndecan-1 expression with adverse histopathological parameters in gastric carcinomas.

PURPOSE Since syndecan-1 is an adhesion molecule involved in tumor invasion and metastasis, we evaluated the relationship between syndecan-1 expression and histopathological features of gastric carcinomas. METHODS Syndecan-1 expression was evaluated in 104 gastric carcinomas using immunohistochemistry. RESULTS High, moderate and low syndecan-1 expression in carcinoma cells was observed in 17/104, 25/104 and 62/104 cases, respectively. High, moderate and low syndecan-1 expression in stromal cells was observed in 5/104, 22/104 and 77/104 cases, respectively. Low epithelial syndecan-1 expression was significantly associated with increased depth of invasion (p=0.034) and lymph vessel invasion (p=0.035). Low stromal syndecan-1 expression was significantly associated with histologic type (intestinal vs diffuse/mixed; p=0.04), increased histologic grade (p=0.04) and large tumor size (p=0.026). CONCLUSION Low levels of tumor and stromal syndecan- 1 expression were associated with adverse histopathological parameters in gastric carcinoma. This suggests that syndecan-1 expression may be helpful for assessing the aggressiveness of gastric carcinomas.
Identification of Key Biomarkers and Potential Molecular Mechanisms in Oral Squamous Cell Carcinoma by Bioinformatics Analysis

The aim of this study was to explore the key genes, microRNA (miRNA), and the pathogenesis of oral squamous cell carcinoma (OSCC) at the molecular level through the analysis of bioinformatics, which could provide a theoretical basis for the screening of drug targets. Data of OSCC were obtained from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified via GEO2R analysis. Next, protein-protein interaction (PPI) network of DEGs was constructed through Search Tool for the Retrieval of Interacting Gene and visualized via Cytoscape, whereas the hub genes were screened out with Cytoscape. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed by Database for Annotation, Visualization and Integrated Discovery. The miRNA, which might regulate hub genes, were screened out with TargetScan and GO and KEGG analysis of miRNA was performed by DNA Intelligent Analysis-miRPath. Survival analyses of DEGs were conducted via the Kaplan-Meier plotter. Finally, the relationships between gene products and tumors were analyzed by Comparative Toxicogenomics Database. A total of 121 differential genes were identified. One hundred thirty-five GO terms and 56 pathways were obtained, which were mainly related to PI3K-Akt signals pathway, FoxO signaling pathway, Wnt signaling pathway, cell cycle, p53 signaling pathway, cellular senescence, and other pathways; 10 genes were identified as hub genes through modules analyses in the PPI network. Finally, a survival analysis of 10 hub genes was conducted, which showed that the low expression of matrix metalloproteinase (MMP)1, MMP3, and C-X-C motif chemokine ligand (CXCL)1 and the high expression of CXCL9 and CXCL10 resulted in a significantly poor 5-year overall survival rate in patients with OSCC. In this study, the DEGs of OSCC was analyzed, which assists us in a systematic understanding of the pathogenicity underlying occurrence and development of OSCC. The MMP1, MMP3, CXCL1, CXCL9, and CXCL10 genes might be used as potential targets to improve diagnosis and as immunotherapy biomarkers for OSCC.