Miracle-dz/UniFAR-FTUs huggingface dataset:
Opposing Roles of Peroxisome Proliferator-activated Receptor α and Growth Hormone in the Regulation of CYP4A11 Expression in a Transgenic Mouse Model*

CYP4A11 transgenic mice (CYP4A11 Tg) were generated to examine in vivo regulation of the human CYP4A11 gene. Expression of CYP4A11 in mice yields liver and kidney P450 4A11 levels similar to those found in the corresponding human tissues and leads to an increased microsomal capacity for ω-hydroxylation of lauric acid. Fasted CYP4A11 Tg mice exhibit 2–3-fold increases in hepatic CYP4A11 mRNA and protein, and this response is absent in peroxisome proliferator-activated receptor α (PPARα) null mice. Dietary administration of either of the PPARα agonists, fenofibrate or clofibric acid, increases hepatic and renal CYP4A11 levels by 2–3-fold, and these responses were also abrogated in PPARα null mice. Basal liver CYP4A11 levels are reduced differentially in PPARα−/− females (>95%) and males (<50%) compared with PPARα−/+ mice. Quantitative and temporal differences in growth hormone secretion are known to alter hepatic lipid metabolism and to underlie sexually dimorphic gene expression, respectively. Continuous infusion of low levels of growth hormone reduced CYP4A11 expression by 50% in PPARα-proficient male and female transgenic mice. A larger decrease was observed for the expression of CYP4A11 in PPARα−/− CYP4A11 Tg male mice to levels similar to that of female PPARα-deficient mice. These results suggest that PPARα contributes to the maintenance of basal CYP4A11 expression and mediates CYP4A11 induction in response to fibrates or fasting. In contrast, increased exposure to growth hormone down-regulates CYP4A11 expression in liver.
Prospective Analysis of Oncogenic Driver Mutations and Environmental Factors: Japan Molecular Epidemiology for Lung Cancer Study.

PURPOSE Oncogenic driver mutations are critical for lung cancer development and serve as therapeutic targets. However, their associations with environmental factors are not fully understood. We aimed to elucidate the relationship between tumor developmental biology and exposure to environmental factors. PATIENTS AND METHODS This was a prospective, multicenter, molecular epidemiology study. Eligible patients were those with newly diagnosed stages I to IIIB non-small-cell lung cancer (NSCLC) who underwent surgery. The tumors were examined for somatic mutations in 72 cancer-associated genes by targeted deep sequencing, estrogen receptor β (ERβ) expression using immunohistochemical staining, and infection with any of 37 types of human papillomavirus (HPV) using a polymerase chain reaction-based microarray system. Detailed information on patient demographics and environmental factors was obtained from a comprehensive questionnaire. RESULTS From July 2012 to December 2013, 957 patients were enrolled, and molecular analyses were performed on 876 samples (from 441 ever- and 435 never-smokers). Oncogenic driver mutations in P53 and KRAS increased proportionally with smoking status, whereas mutations in EGFR and SMAD4 decreased. KRAS mutations in smokers and SMAD4 mutations were observed more frequently in proportion to body mass index. TP53 and NFE2L2 mutations were observed more frequently in advanced NSCLC stages. As for never-smokers, no environmental factors were significantly associated with mutational changes. EGFR mutations and TP53 mutations were observed more frequently in women and in men, respectively. Mutations in these two genes were also potentially associated with ERβ expression. Only three patients (0.3%) were HPV positive. CONCLUSION The mutational spectrum is associated with smoking, body mass index, and other environmental factors, as well as with ERβ expression. Little association was observed between HPV and NSCLC.
The Role of Copper in Neurodegenerative Disease

Copper is an essential trace metal which plays a fundamental role in the biochemistry of the human nervous system. Menkes disease and Wilson disease are inherited disorders of copper metabolism and the dramatic neurodegenerative phenotypes of these two diseases underscore the essential nature of copper in nervous system development as well as the toxicity of this metal when neuronal copper homeostasis is perturbed. Ceruloplasmin contains 95% of the copper found in human plasma and inherited loss of this essential ferroxidase is associated with progressive neurodegeneration of the retina and basal ganglia. Gain-of-function mutations in the cytosolic copper enzyme superoxide dismutase result in the motor neuron degeneration of amyotrophic lateral sclerosis and current evidence suggests a direct pathogenic role for copper in this process. Recent studies have also implicated copper in the pathogenesis of neuronal injury in Alzheimer's disease and the prion-mediated encephalopathies, suggesting that further elucidation of the mechanisms of copper trafficking and metabolism within the nervous system will be of direct relevance to our understanding of the pathophysiology and treatment of neurodegenerative disease.
Dual-Band Bandpass Filters Using Stub-Loaded Resonators

Dual-band bandpass filters using novel stub-loaded resonators (SLRs) are presented in this letter. Characterized by both theoretical analysis and full-wave simulation, the proposed SLR is found to have the advantage that the even-mode resonant frequencies can be flexibly controlled whereas the odd-mode resonant frequencies are fixed. Based on the proposed SLR, a dual-band filter is implemented with three transmission zeros. To further improve the selectivity, a filter with four transmission zeros on either side of both passbands is designed by introducing spur-line. The measured results validate the proposed design.
Molecular biology research to benefit patients with Entamoeba histolytica infection

The development of molecular microbiology has made it possible for us to deepen our understanding of the pathogenesis of amebiasis. Research using the trophozoite form of Entamoeba histolytica has clearly shown us the importance of the interface between the parasite and host cells in vitro. Immuno‐pathogenesis after excystation was similarly well advanced by the use of a novel murine model of amebic colitis. However, it is still challenging to apply these findings to clinical and epidemiological settings. This is mainly because of the lack of a complete infection animal model of amebiasis by oral–fecal infection. Moreover, in vitro experiments have predominantly been performed using the same axenic cultured strain HM‐1: IMSS isolated about 50 years ago, whereas highly diverse strains are prevalent all over the world. Translational research informed by clinical observations has the greatest potential for the development of effective interventions. Here, we highlight discoveries of the experiments designed from cohort observation and discuss remaining problems to be solved.
Effect of Crohn's Disease on Bone Metabolism In Vitro: A Role for Interleukin‐6

Circulating proinflammatory cytokines may be involved in osteopenia associated with Crohn's disease (CD). Therefore, the effect of interleukin (IL)‐6, IL‐1β, and tumor necrosis factor (TNF) α contained in Crohn's serum on bone formation was examined in a bone organ culture system. Initially, serum levels of IL‐6, IL‐1β, and TNF‐α were determined by ELISA in newly diagnosed, untreated children with CD and healthy age‐matched controls. Serum IL‐6 levels were significantly higher in patients with CD than in controls (23.9 ± 2.8 pg/ml vs. 0.7 pg/ml ± 0.2; p < 0.001), whereas IL‐1β and TNF‐α serum levels were not. In the organ culture studies, 20‐day‐old fetal rat parietal bones were incubated for 96 h with CD or control serum, serum preincubated with a neutralizing antibody to each cytokine or a nonimmune immunoglobulin control, and with IL‐6. Bone formation measured by assaying calcium content and dry weight was significantly decreased in bones exposed to Crohn's serum. Light microscopy of the bones treated with CD serum revealed a discontinuous, uneven mineralized bone matrix and disorganized osteoblasts with altered morphology. Incubation with an antibody that neutralized IL‐6 activity prevented the change in osteoblast and bone morphology. TNF‐α and IL‐1β antibodies had no apparent effects. Collagen synthesis and DNA content were not affected by CD serum. Also, addition of IL‐6 to the culture medium decreased mineralization. These results suggest that IL‐6 is a mediator of the effects of Crohn's serum on in vitro mineralization and may be a contributing factor to the osteopenia associated with CD.
Temporal sequence of gene expression leading caudal prosencephalon to develop a midbrain/hindbrain phenotype

Transplantation of prosomeres 1‐2 into the cerebellar plate were used, by using chick/quail chimeras, to analyse the temporal sequence of the genetic cascade leading the graft to develop a midbrain/hindbrain phenotype. Our results show that (1) at Hamburger and Hamilton (HH) stage 13, Pax2 and En2 are already induced within the graft, before all other genes of the cascade, whereas misexpression of Fgf8 is also observed within the contiguous host cerebellar plate; (2) within the graft, Otx2 repression and Gbx2 induction (see Hidalgo‐Sánchez et al. [ 1999 ] Development 126:3191–3203) are secondary events that affect, from stages HH14–15, the areas in contact with the host Gbx2/Fgf8‐expressing cerebellar plate; (3) at these stages, the repressed Otx2 territory extends beyond the areas induced to express Gbx2, with the two territories not abutting before HH17–18; (4) Fgf8 expression becomes progressively induced within the Otx2‐repressed/Gbx2‐induced territory, starting at HH15–16. Our results support the hypothesis that the host‐Gbx2/graft‐Otx2 interface could trigger the genetic cascade induced within the graft and that the Gbx2‐induced domain could play a key role during the establishment of the induced intragraft midbrain/hindbrain boundary. © 2001 Wiley‐Liss, Inc.
The formate channel FocA exports the products of mixed-acid fermentation

Formate is a major metabolite in the anaerobic fermentation of glucose by many enterobacteria. It is translocated across cellular membranes by the pentameric ion channel/transporter FocA that, together with the nitrite channel NirC, forms the formate/nitrite transporter (FNT) family of membrane transport proteins. Here we have carried out an electrophysiological analysis of FocA from Salmonella typhimurium to characterize the channel properties and assess its specificity toward formate and other possible permeating ions. Single-channel currents for formate, hypophosphite and nitrite revealed two mechanistically distinct modes of gating that reflect different types of structural rearrangements in the transport channel of each FocA protomer. Moreover, FocA did not conduct cations or divalent anions, but the chloride anion was identified as further transported species, along with acetate, lactate and pyruvate. Formate, acetate and lactate are major end products of anaerobic mixed-acid fermentation, the pathway where FocA is predominantly required, so that this channel is ideally adapted to act as a multifunctional export protein to prevent their intracellular accumulation. Because of the high degree of conservation in the residues forming the transport channel among FNT family members, the flexibility in conducting multiple molecules is most likely a general feature of these proteins.
Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses

Significance Kaposi’s sarcoma-associated herpesvirus (KSHV) is a DNA virus that is linked to several human malignancies. The cGMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway is able to detect KSHV during primary infection and regulates the reactivation of KSHV from latency. We screened KSHV proteins for their ability to inhibit this pathway and block IFN-β activation. One KSHV protein, vIRF1, inhibited this pathway by preventing STING from interacting with TBK1 and inhibiting STING’s phosphorylation and concomitant activation. Moreover, depletion of vIRF1 in the context of KSHV infection prevented efficient viral reactivation and replication, and increased the host IFN response to KSHV. Collectively, our results demonstrate that the modulation of this pathway is important for viral transmission and the lifelong persistence of gammaherpesviruses in the human population. Infection of cells with DNA viruses triggers innate immune responses mediated by DNA sensors. cGMP-AMP synthase (cGAS) is a key DNA sensor that produces the cyclic dinucleotide cGMP-AMP (cGAMP) upon activation, which binds to and activates stimulator of interferon genes (STING), leading to IFN production and an antiviral response. Kaposi’s sarcoma-associated herpesvirus (KSHV) is a DNA virus that is linked to several human malignancies. We report that KSHV infection activates the cGAS-STING pathway, and that cGAS and STING also play an important role in regulating KSHV reactivation from latency. We screened KSHV proteins for their ability to inhibit this pathway and identified six viral proteins that block IFN-β activation through this pathway. This study is the first report identifying multiple viral proteins encoded by a human DNA virus that inhibit the cGAS-STING DNA sensing pathway. One such protein, viral interferon regulatory factor 1 (vIRF1), targets STING by preventing it from interacting with TANK binding kinase 1 (TBK1), thereby inhibiting STING’s phosphorylation and concomitant activation, resulting in an inhibition of the DNA sensing pathway. Our data provide a unique mechanism for the negative regulation of STING-mediated DNA sensing. Moreover, the depletion of vIRF1 in the context of KSHV infection prevented efficient viral reactivation and replication, and increased the host IFN response to KSHV. The vIRF1-expressing cells also inhibited IFN-β production following infection with DNA pathogens. Collectively, our results demonstrate that gammaherpesviruses encode inhibitors that block cGAS-STING–mediated antiviral immunity, and that modulation of this pathway is important for viral transmission and the lifelong persistence of herpesviruses in the human population.
Corticomuscular Coherence With Time Lag With Application to Delay Estimation

Functional coupling between the motor cortex and muscle activity is usually detected and characterized using the spectral method of corticomuscular coherence (CMC). This functional coupling occurs with a time delay, which, if not properly accounted for, may decrease the coherence and make the synchrony difficult to detect. In this paper, we introduce the concept of CMC with time lag (CMCTL), that is the coherence between segments of motor cortex electroencephalogram (EEG) and electromyography (EMG) signals displaced from a central observation point. This concept is motivated by the need to compensate for the unknown delay between coupled cortex and muscle processes. We demonstrate using simulated data that under certain conditions the time lag between EEG and EMG segments at points of local maxima of CMCTL corresponds to the average delay along the involved corticomuscular conduction pathways. Using neurophysiological data, we then show that CMCTL with appropriate time lag enhances the coherence between cortical and muscle signals, and that time lags which correspond to local maxima of CMCTL provide estimates of delays involved in corticomuscular coupling that are consistent with the underlying physiology.
Sequential Engagement of FcεRI on Mast Cells and Basophil Histamine H4 Receptor and FcεRI in Allergic Rhinitis

Histamine H4 receptor (H4R)–deficient mice (H4R−/−), H4R antagonist–treated wild-type (WT) mice, and WT mice depleted of basophils failed to develop early (EPR) or late phase (LPR) nasal responses following allergen sensitization and challenge. Basophil transfer from WT but not H4R−/− mice restored the EPR and LPR in H4R−/− mice. Following passive sensitization with OVA-specific IgE, FcεRI−/− recipients of WT basophils plus OVA and histamine developed an EPR and LPR. OVA-IgE passively sensitized FcεRI−/− recipients of H4R−/− basophils and OVA and histamine challenge failed to develop an EPR or LPR, and basophils were not detected in nasal tissue. In contrast, recipients of basophils from IL-13−/− and IL-4−/−/IL-13−/− mice developed an EPR but not an LPR. These results demonstrate the development of allergic rhinitis proceeded in two distinct stages: histamine release from FcεRI-activated mast cells, followed by histamine-mediated recruitment of H4R-expressing basophils to the nasal cavity and activation through FcεRI.
A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice.

Tropomyosin, an essential component of the sarcomere, regulates muscle contraction through Ca(2+)-mediated activation. Familial hypertrophic cardiomyopathy (FHC) is caused by mutations in numerous cardiac sarcomeric proteins, including myosin heavy and light chains, actin, troponin T and I, myosin binding protein C, and alpha-tropomyosin. This study developed transgenic mouse lines that encode an FHC mutation in alpha-tropomyosin; this mutation is an amino acid substitution at codon 180 (Glu180Gly) which occurs in a troponin T binding region. Non-transgenic and control mice expressing wild-type alpha-tropomyosin demonstrate no morphological or physiological changes. Expression of exogenous mutant tropomyosin leads to a concomitant decrease in endogenous alpha-tropomyosin without altering the expression of other contractile proteins. Histological analysis shows that initial pathological changes, which include ventricular concentric hypertrophy, fibrosis and atrial enlargement, are detected within 1 month. The disease-associated changes progressively increase and result in death between 4 and 5 months. Physiological analyses of the FHC mice using echocardiography, work-performing heart analyses, and force measurements of cardiac myofibers, demonstrate dramatic functional differences in diastolic performance and increased sensitivity to calcium. This report demonstrates that mutations in alpha-tropomyosin can be severely disruptive of sarcomeric function, which consequently triggers a dramatic hypertrophic response that culminates in lethality.
Abnormal circadian blood pressure regulation in children with nocturnal enuresis

Abstract Introduction: To investigate autonomic nervous system function in enuretic children by performing ambulatory blood pressure monitor (ABPM) for 24 h. Methods: Twenty-eight children ranging in age from 6 to 15 years with primary nocturnal enuresis and 27 age-matched healthy controls were enrolled and they get 24 h ABPM. Hypertension was defined as standard deviation score (SDS) > 1.64 (i.e., >95th percentile) adjusted for gender and height. Urinalysis, urine electrolyte levels, urinary culture, and urinary system ultrasound were carried out in all children. They have also requested to have a diary about daily fluid intake and urine volume. Results: Although the mean 24-h and daytime diastolic blood pressure (BP) did not differ between the groups, systolic BP (SBP) was significantly higher in enuretic children (p < 0.05). The mean night-time SBP, DBP values, SDS and BP loads were found to be significantly higher than those in the controls (p < 0.01). A lack of nocturnal decrease was more prevalent in the enuretic children compared with the control subjects, the difference was statistically significant for DBP but not for SBP. Patients with elevated night-time BP load was found to have higher frequency of urinary incontinence per week as well as per night when compared with enuretic children with normal night-time BP load (r = 0.72, r = 0.69, p < 0.01, respectively). Conclusion: Subtle abnormalities of circadian BP regulation in enuretic children indicated by a selective elevation of nocturnal SBP, DBP, and MAP, and attenuated nocturnal dipping may reflect sympathetic hyper activation and its possible role in pathogenesis of enuresis.
Underlying Cause of Death in Demented and Non-Demented Elderly Canadians

This paper examines the associations between clinical dementia and underlying cause of death (UCD) in a population-based sample of seniors who took part in the Canadian Study of Health and Aging (CSHA). Cause-of-death data were obtained via death certificates for 2,924 of 2,982 deceased subjects. Among the decedents were 823 clinically demented and 670 clinically non-demented participants. Using logistic regression we examined factors associated with a particular UCD in the overall group and also in the subgroup of demented seniors. Dementia was found to be associated with an increased risk of death from pneumonia. Both Alzheimer’s disease and vascular dementia appear to decrease the risk of mortality from neoplasm. To our knowledge, this study is the first of its kind that combines a large, representative sample with thorough clinical assessment of cognitive status.
Educational Achievement and Chronic Pain Disability: Mediating Role of Pain-Related Cognitions

ObjectiveThis study examined the relation between level of educational achievement (LOE) and the clinical morbidity associated with chronic pain. SettingA multidisciplinary pain rehabilitation program located within a university hospital. PatientsTwo hundred ninety-nine consecutive patients with chronic spinal pain, average age 39.6 years (SD = 10.7) and with an average duration of pain of 41.9 months (SD = 51.6). Outcome MeasuresAge, duration of pain, sex, and compensation and litigation status were controlled for in the statistical analysis because each was found to be significantly associated with LOE. Pain intensity was assessed by the McGill Pain Questionnaire. Affective distress was assessed by the Global Severity Index from the Brief Symptom Inventory. Severity of depressive symptoms was derived from scores from the Center for Epidemiological Studies—Depression Scale. Pain beliefs and pain coping strategies were assessed by the Survey of Pain Attitudes and the Coping Strategies Questionnaire, respectively. Finally, self-report of pain-related disability was assessed by the Pain Disability Index. Results and ConclusionsAfter controlling for relevant covariates, LOE was unrelated to pain intensity, severity of depressive symptoms, or affective distress, but was inversely related to self-reported disability. Persons with lower LOEs possessed a greater belief that pain is a “signal of harm,” unrelated to emotional experience, disabling and uncontrollable. They also endorsed more passive and maladaptive coping strategies, including a tendency to catastrophize about their pain. Path analysis indicated that, after controlling for the influence of both the belief that pain is a “signal of harm” and catastrophizing on the association between LOE and disability, this relation loses statistical significance. These results suggest that pain-related cognitions mediate the relation between LOE and pain disability and that persons with lower LOEs are more likely to develop maladaptive pain beliefs and coping strategies.