Miracle-dz/UniFAR-FTUs huggingface dataset:
Effect of 33% Xenon Inhalation on Whole‐Brain Blood Flow and Metabolism in Awake and Fentanyl‐Anesthetized Monkeys

Background and Purpose Despite the documented diagnostic value of local cerebral blood flow maps by xenon-enhanced computed tomography, reports of cerebral blood flow activation by inhaled 33% Xe raised concerns about the method's safety and accuracy. We evaluated the effect of 33% Xe inhalation on cerebral blood flow and cerebral metabolic rates for oxygen and glucose in four awake and six fentanyl-anesthetized rhesus monkeys. Methods Platinum microelectrodes and catheters in the torcular Herophili were used to measure cerebral blood flow by hydrogen clearance, and oxygen and glucose concentrations. Cerebral variables were measured after 5 and 35 minutes of exposure to room air followed randomly by 67% O2 in 33% N2 or Xe. Five- and 35-minute measurements were combined because the duration of exposure had no effect Results In awake monkeys, 33% Xe compared with 33% N2 reduced (p<0.05) cerebral blood flow from 75±12 to 66±9 (mean±SD) ml · 100 g−1 · min−1 and oxygen consumption from 6.1±0.7 to 5.1±0.6 ml · 100 g−1 · min−1. In fentanyl-anesthetized monkeys, cerebral variables during 33% N2 versus 33% Xe were cerebral blood flow, 84±26 versus 79±23 ml · 100 g−1 · min−1; oxygen consumption, 5.0±0.7 versus 4.9±0.5 ml · 100 g−1 · min−1; and glucose consumption, 8.4±1.9 versus 7.9±2.0 mg · 100 g−1 · min−1. Conclusions In awake monkeys, 33% Xe reduced rather than activated cerebral blood flow and oxygen consumption by 12% and 16%, respectively; it had no effect in fentanyl-anesthetized monkeys.
Brachial Flow-Mediated Vasodilator Responses in Population-Based Research: Methods, Reproducibility and Effects of Age, Gender and Baseline Diameter

Background Brachial artery ultrasound has been proposed as an inexpensive, accurate way to assess cardiovascular risk in populations. However, analysis and interpretation of these data are not uniform. Methods We analysed the relationship between relative and absolute changes in brachial artery diameter in response to flow-mediated dilation and age, gender and baseline diameter among 4040 ultrasound examinations from subjects aged 14 to 98 years. Results Reproducibility studies demonstrated intra- and interreader and intrasubject correlations from 0.67 to 0.84 for repeated measures of per cent change in diameter. Per cent change in diameter after flow stimulus was 3.58 ± 0.10% (mean ± standard deviation). Corresponding values for baseline diameter and absolute change in diameter were 4.43 ± 0.87 mm and 0.15 ± 0.01 mm, respectively. Baseline diameter and its variance were inversely related to per cent change in diameter (P < 0.001). In contrast, absolute change in diameter was more uniform throughout the range of baseline diameters. Baseline diameter was directly related, and per cent change in diameter inversely related, to age (P < 0.001 for all three measures). Time to maximum vasodilator response increased with age (P < 0.001). Women (n=2315) had significantly larger per cent change in diameter than men (n=1725) (P < 0.001). However, after adjustment for age and baseline diameter, per cent and absolute change were 5% smaller in women than men (P < 0.05 for both). In multivariate analysis, age was overwhelmingly the most important determinant of absolute change in diameter (P < 0.001). Conclusions Automated analysis of brachial flow-mediated vasodilator responses is both feasible and reproducible in large-scale clinical and population-based research.
EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics

Objective: Systemic lupus erythematosus (SLE) is a complex disease with variable presentations, course and prognosis. We sought to develop evidence-based recommendations addressing the major issues in the management of SLE. Methods: The EULAR Task Force on SLE comprised 19 specialists and a clinical epidemiologist. Key questions for the management of SLE were compiled using the Delphi technique. A systematic search of PubMed and Cochrane Library Reports was performed using McMaster/Hedges clinical queries’ strategies for questions related to the diagnosis, prognosis, monitoring and treatment of SLE. For neuropsychiatric, pregnancy and antiphospholipid syndrome questions, the search was conducted using an array of relevant terms. Evidence was categorised based on sample size and type of design, and the categories of available evidence were identified for each recommendation. The strength of recommendation was assessed based on the category of available evidence, and agreement on the statements was measured across the 19 specialists. Results: Twelve questions were generated regarding the prognosis, diagnosis, monitoring and treatment of SLE, including neuropsychiatric SLE, pregnancy, the antiphospholipid syndrome and lupus nephritis. The evidence to support each proposition was evaluated and scored. After discussion and votes, the final recommendations were presented using brief statements. The average agreement among experts was 8.8 out of 10. Conclusion: Recommendations for the management of SLE were developed using an evidence-based approach followed by expert consensus with high level of agreement among the experts.
Limited role of CD28-mediated signals in T helper subset differentiation

The role of CD28-mediated signals in T helper cell maturation is not fully understood. We tested the requirement for costimulation through CD28 in several systems of CD4+, T cell differentiation. In vivo priming of mice with genetic disruption of CD28 (CD28-/-) yielded normal levels of antigen-specific interferon gamma production but markedly diminished levels of interleukin 4 (IL-4) after in vitro restimulation. In response to the pathogenic microbe, Leishman a major, C57BL6 CD28-/- mice were fully capable of controlling infection and exhibited a normal T helper 1 response. BALB/c CD28-/- mice unexpectedly exhibited normal susceptibility to L. major. BALB/c CD28-/- mice developed high levels of IL-4 mRNA and protein induction in the draining lymph nodes. In addition, susceptibility of BALB/c CD28-/- mice was reversed by neutralization of IL-4 in vivo. We also activated transgenic CD28-bearing T cells from the BALB and C57BL background in vitro in the presence of CTLA4Ig. BALB cells had greater IL-4 producing capacity than C57BL cells in the absence of costimulation. Diverse factors including costimulatory signals, genetic polymorphism, and the nature of the immunogen all influence T helper phenotype commitment, but these results provide evidence that CD28 is not an absolute requirement for generating either Th1 or Th2 responses.
Correlates of adiposity in a Caribbean pre-school population

Abstract Objective To evaluate ethnic and anthropometric correlates of adiposity among a nationally representative, multi-ethnic, Trinidadian pre-school population. Design Cross-sectional study conducted between June 2008 and July 2009. Setting Government and privately owned Early Childhood Care and Education Centres in Trinidad. Subjects A total of 596 pre-school children (aged 31–73 months) from thirty-four schools had their weight, height, mid-upper arm circumference, waist circumference, biceps and triceps skinfold thicknesses measured by a registered dietitian using standard procedures. Percentage body fat was estimated using a foot-to-foot bioelectric impedance analyser (Tanita 531, Tokyo, Japan). Date of birth, religion and ethnicity were extracted from school records and pre-schoolers’ ethnicity was categorized as East Indian, African, Mixed (a combination of two or more ethnicities), Chinese or Caucasian. Results Anthropometric variables explained significantly more of the variance in adiposity among girls (67·4–88·1 %) than boys (24·4–39·2 %; P < 0·0 0 1). Pre-schoolers of African descent were significantly taller, heavier and had higher abdominal fat and mid-upper arm circumference than their East Indian and Mixed counterparts (all P < 0·001). The overall prevalence of excess adiposity (≥25 % body fat) as determined by bioelectrical impedance was 14·6 %, while 2·9 % of the children were undernourished according to WHO weight-for-age criteria. Differences in anthropometry were non-existent between children attending government and private pre-schools. Conclusions Gender, ethnicity and anthropometry all explained excess adiposity in these pre-schoolers. These findings highlight the need to elucidate the mechanisms that may be involved in explaining these differences, particularly those of ethnic origin.
Biology of Leptoypha hospita (Hemiptera: Tingidae), a Potential Biological Control Agent of Chinese Privet

ABSTRACT The biology of Leptoypha hospita Drake et Poor (Hemiptera: Tingidae), a potential biological control agent from China for Chinese privet, Ligustrum sinense Lour. , was studied in quarantine in the United States. Both nymphs and adults feed on Chinese privet mesophyll cells that lead to a bleached appearance of leaves and dieback of branch tips. L. hospita has five nymphal instars with the mean duration of the life cycle from egg to new adult being 25 d. Females laid an average of 240 eggs per female and continued laying until death. Adults lived ≈75 d on average. Because it feeds on Chinese privet, has multiple generations per year and a high reproductive rate, L. hospita may be a good biological control agent for this invasive plant.
Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice

Hearing relies on the mechanosensory inner and outer hair cells (OHCs) of the organ of Corti, which convert mechanical deflections of their actin-rich stereociliary bundles into electrochemical signals. Several actin-associated proteins are essential for stereocilia formation and maintenance, and their absence leads to deafness. One of the most abundant actin-bundling proteins of stereocilia is plastin 1, but its function has never been directly assessed. Here, we found that plastin 1 knock-out (Pls1 KO) mice have a moderate and progressive form of hearing loss across all frequencies. Auditory hair cells developed normally in Pls1 KO, but in young adult animals, the stereocilia of inner hair cells were reduced in width and length. The stereocilia of OHCs were comparatively less affected; however, they also showed signs of degeneration in ageing mice. The hair bundle stiffness and the acquisition of the electrophysiological properties of hair cells were unaffected by the absence of plastin 1, except for a significant change in the adaptation properties, but not the size of the mechanoelectrical transducer currents. These results show that in contrast to other actin-bundling proteins such as espin, harmonin or Eps8, plastin 1 is dispensable for the initial formation of stereocilia. However, the progressive hearing loss and morphological defects of hair cells in adult Pls1 KO mice point at a specific role for plastin 1 in the preservation of adult stereocilia and optimal hearing. Hence, mutations in the human PLS1 gene may be associated with relatively mild and progressive forms of hearing loss.
Mechanism-Aware Neural Machine for Dialogue Response Generation

To the same utterance, people's responses in everyday dialogue may be diverse largely in terms of content semantics, speaking styles, communication intentions and so on. Previous generative conversational models ignore these 1-to-n relationships between a post to its diverse responses, and tend to return high-frequency but meaningless responses. In this study we propose a mechanism-aware neural machine for dialogue response generation. It assumes that there exists some latent responding mechanisms, each of which can generate different responses for a single input post. With this assumption we model different responding mechanisms as latent embeddings, and develop a encoder-diverter-decoder framework to train its modules in an end-to-end fashion. With the learned latent mechanisms, for the first time these decomposed modules can be used to encode the input into mechanism-aware context, and decode the responses with the controlled generation styles and topics. Finally, the experiments with human judgements, intuitive examples, detailed discussions demonstrate the quality and diversity of the generated responses with 9.80% increase of acceptable ratio over the best of six baseline methods.
PROTECTIVE EFFECTS OF DEBO ON ZINC-INDUCED APOPTOSIS OF C6 GLIAL CELLS VIA MODULATION OF INTRACELLULAR ANTIOXIDANT, REDUCED GLUTATHIONE

In the present study, the mechanical basis of a traditional herbal prescription, Debo, on cytotoxic damage of the brain cells including C6 glial and PC12 cells has been studied. Traditionally, Debo has been employed for the purpose of preventing responses to trauma, ischemia, and other diseases in the nervous system. C6 glial cells were exposed to oxidative stress through the imployment of ZnCl2, and generates H2O2 and hydroxyl radicals by fenton reaction. ZnCl2-induced death of C6 glial cells, which was revealed as apoptosis by chromatin condensation as well as DNA fragmentation. Pretreatment of Debo significantly prevented apoptotic death of C6 glial cells via inhibition of H2O2 generation as well as the recovering of an antioxidant, reduced glutathione (GSH). Also, deprivation of serum and glucose, found in ischemia, deceased the viability of PC12 cells up to 60% via generation of H2O2. However, Debo significantly protected cells from ischemic damage through decrease in H2O2 generation. Furthermore, Debo markedly inhibited the transcriptional activation of NF-κB by ZnCl2 in C6 glial cells. These results suggest that Debo may function as an antioxidant system against free radicals and be applicable to protect brain cells against oxidative or ischemic stresses.
Incidence and Risk Factors for Stroke in Type 2 Diabetic Patients: The DAI Study

Background and Purpose— Type 2 diabetes mellitus is a strong predictor of cerebrovascular disease, yet few studies have assessed the incidence of stroke and the role of other risk factors in unselected type 2 diabetes mellitus populations. Methods— We prospectively followed-up 14 432 type 2 diabetes mellitus patients, aged 40 to 97 years, with and without a history of cardiovascular disease at enrollment, and we estimated the incidence of stroke and the hazards ratios with respect to clinical variables. Results— During a 4-year follow-up, 296 incident stroke events were recorded. In persons with no history of cardiovascular disease, the age-standardized incidence of stroke (per 1000 person-years) was 5.5 (95% confidence interval, 4.2 to 6.8) in men and 6.3 (95% confidence interval, 4.5 to 8.2) in women. In persons with a history of cardiovascular disease, it was 13.7 (95% confidence interval, 7.5 to 19.8) in men and 10.8 (95% confidence interval, 7.3 to 14.4) in women. The hazards ratios of stroke incidence varied according to age, sex, and history of cardiovascular disease. Among men with no history, HbA1c and smoking were predictors of stroke. Among patients with a history, the risk factors were, in men, therapy with insulin plus oral agents, treated high total cholesterol and low HDL cholesterol, whereas in women microvascular complications were a risk factor. Previous stroke was a strong predictor of stroke in both sexes. Conclusions— Age and previous stroke are the main predictors of stroke in diabetes. The combined role of Hba1c, microvascular complications, low HDL cholesterol, and treatment with insulin plus oral agents highlights the importance of diabetic history and clinical background in the development of stroke.
How Ongoing Neuronal Oscillations Account for Evoked fMRI Variability

Variability of evoked single-trial responses despite constant input or task is a feature of large-scale brain signals recorded by fMRI. Initial evidence signified relevance of fMRI signal variability for perception and behavior. Yet the underlying intrinsic neuronal sources have not been previously substantiated. Here, we address this issue using simultaneous EEG–fMRI and real-time classification of ongoing alpha-rhythm states triggering visual stimulation in human subjects. We investigated whether spontaneous neuronal oscillations—as reflected in the posterior alpha rhythm—account for variability of evoked fMRI responses. Based on previous work, we specifically hypothesized linear superposition of fMRI activity related to fluctuations of ongoing alpha rhythm and a visually evoked fMRI response. We observed that spontaneous alpha-rhythm power fluctuations largely explain evoked fMRI response variance in extrastriate, thalamic, and cerebellar areas. For extrastriate areas, we confirmed the linear superposition hypothesis. We hence linked evoked fMRI response variability to an intrinsic rhythm's power fluctuations. These findings contribute to our conceptual understanding of how brain rhythms can account for trial-by-trial variability in stimulus processing.
Protection of Plasminogen Activator Inhibitor-1-Deficient Mice from Nasal Allergy1

This study was performed to clarify the relationship between fibrinolytic components and the pathology of allergy, particularly that during the development of nasal allergy and nasal tissue changes. Intranasal OVA challenge after sensitization by i.p. administration of OVA induced a higher level of excess subepithelial collagen deposition in wild-type (WT) C57BL/6J mice than in plasminogen activator inhibitor (PAI)-1-deficient (PAI-1−/−) mice. The excess PAI-1 induction in the nasal mucosa and higher level of active PAI-1 in the nasal lavage fluid of WT-OVA mice compared with those in WT-control mice suggested that the decrease of proteolytic activity inhibits the removal of subepithelial collagen. The frequency of sneezing, nasal rubbing, nasal hyperresponsiveness, production of specific IgG1 and IgE in the serum, and production of IL-4 and IL-5 in splenocyte culture supernatant increased significantly in WT-OVA mice. In PAI-1−/− mice, these reactions were absent, and specific IgG2a in serum and IFN-γ in splenocyte culture medium increased significantly. Histopathologically, there were marked goblet cell hyperplasia and eosinophil infiltration into the nasal mucosa in WT-OVA mice, but these were absent in PAI-1−/− mice. These results indicate that the immune response in WT-OVA mice can be classified as a dominant Th2 response, which would promote collagen deposition. In contrast, the Th2 response in PAI-1−/− mice was down-regulated, and the immune response shifted from Th2-dominant reaction to a Th1-dominant one. Taken together, these findings suggest that PAI-1 plays an important role not only in thrombolysis but also in immune response.
A novel splicing isoform of protein arginine methyltransferase 1 (PRMT1) that lacks the dimerization arm and correlates with cellular malignancy

Methylation of arginine residues is an important modulator of protein function that is involved in epigenetic gene regulation, DNA damage response and RNA maturation, as well as in cellular signaling. The enzymes that catalyze this post‐translational modification are called protein arginine methyltransferases (PRMTs), of which PRMT1 is the predominant enzyme. Human PRMT1 has previously been shown to occur in seven splicing isoforms, which are differentially abundant in different tissues, and have distinct substrate specificity and intracellular localization. Here we characterize a novel splicing isoform which does not affect the amino‐terminus of the protein like the seven known isoforms, but rather lacks exons 8 and 9 which encode the dimerization arm of the enzyme that is essential for enzymatic activity. Consequently, the isoform does not form catalytically active oligomers with the other endogenous PRMT1 isoforms. Photobleaching experiments reveal an immobile fraction of the enzyme in the nucleus, in accordance with earlier results from our laboratory that had shown a tight association of inhibited or inactivated PRMT1 with chromatin and the nuclear scaffold. Thus, it apparently is able to bind to the same substrates as catalytically active PRMT1. This isoform is found in a variety of cell lines, but is increased in those of cancer origin or after expression of the EMT‐inducing transcriptional repressor Snail1. We discuss that the novel isoform could act as a modulator of PRMT1 activity in cancer cells by acting as a competitive inhibitor that shields substrates from access to active PRMT1 oligomers.
The Prosurvival Activity of p53 Protects Cells from UV-Induced Apoptosis by Inhibiting c-Jun NH2-terminal Kinase Activity and Mitochondrial Death Signaling

The cytoprotective function of p53 recently has been exploited as a therapeutic advantage for cancer prevention; agents activating the prosurvival activity of p53 are shown to prevent UV-induced damages. To explore the mechanisms of p53-mediated protection from UV-induced apoptosis, we have established stable clones of H1299 lung carcinoma cells expressing a temperature-sensitive p53 mutant, tsp53V143A. At the permissive temperature of 32°C, the tsp53V143A-expressing cells were arrested in G1 phase without the occurrence of apoptosis; consistent with this is the preferential induction of genes related to growth arrest and DNA damage repair. Previous expression of functional tsp53V143A for ≥18 hours inhibited the release of proapoptotic molecules from mitochondria and protected the cells from UV-induced apoptosis; moreover, it suppressed the activation of c-Jun NH2-terminal kinase (JNK) signaling and relieved the effect of UV on p53 target gene activation. p53 associated with JNK and inhibited its kinase activity. Using the p53-null H1299 cells, we showed that inhibition of JNK blocked the UV-elicited mitochondrial death signaling and caspase activation. Our results suggest that the ability of p53 to bind and inactivate JNK, together with the activation of the p53 target genes related to cell cycle arrest and DNA damage repair, is responsible for its protection of cells against UV-induced apoptosis.
Regulation of Prostate Cancer Cell Survival by Protein Kinase Cϵ Involves Bad Phosphorylation and Modulation of the TNFα/JNK Pathway*

Protein kinase Cϵ (PKCϵ), a diacyglycerol- and phorbol ester-responsive serine-threonine kinase, has been implicated in mitogenic and survival control, and it is markedly overexpressed in human tumors, including in prostate cancer. Although prostate cancer cells undergo apoptosis in response to phorbol ester stimulation via PKCδ-mediated release of death factors, the involvement of PKCϵ in this response is not known. PKCϵ depletion by RNAi or expression of a dominant negative kinase-dead PKCϵ mutant potentiated the apoptotic response of PMA and sensitized LNCaP cells to the death receptor ligand TNFα. On the other hand, overexpression of PKCϵ by adenoviral means protected LNCaP cells against apoptotic stimuli. Interestingly, PKCϵ RNAi depletion significantly enhanced the release of TNFα in response to PMA and greatly potentiated JNK activation by this cytokine. Further mechanistic analysis revealed that PMA fails to promote phosphorylation of Bad in Ser112 in PKCϵ-depleted LNCaP cells, whereas PKCϵ overexpression greatly enhanced Bad phosphorylation. This effect was independent of Akt, ERK, or p90Rsk, well established kinases for Ser112 in Bad. Moreover, expression of a S112A-Bad mutant potentiated PMA-induced apoptosis. Finally, we found that upon activation PKCϵ accumulated in mitochondrial fractions in LNCaP cells and that Bad was a substrate of PKCϵ in vitro. Our results established that PKCϵ modulates survival in prostate cancer cells via multiple pathways.