Miracle-dz/UniFAR-FTUs huggingface dataset:
Stress Augments Insulin Resistance and Prothrombotic State

Stressors contribute to thrombosis and insulin resistance. Since obesity-related adipose inflammation is also involved in these pathological states, we assumed that stress correlates with adipose inflammation. Male mice were subjected to 2-week intermittent restraint stress. Expression of plasma lipids, monocyte/macrophage markers (CD11b, CD68, and F4/80), proinflammatory cytokines (monocyte chemoattractant protein-1 [MCP-1], tumor necrosis factor-α, and interleukin-6), adiponectin, heat shock protein 70.1 (HSP70.1), and coagulation factors (plasminogen activation inhibitor-1 [PAI-1] and tissue factor [TF]) in blood and inguinal white adipose tissue (WAT) was determined using immunohistochemistry, enzyme-linked immunosorbent assay, and RT-PCR, respectively. Glucose metabolism was assessed by glucose tolerance tests (GTTs) and insulin tolerance tests, and expression of insulin receptor substrate-1 (IRS-1) and glucose transporter 4 (GLUT4) in WAT. To examine effects of MCP-1 blockade, animals were treated with control or neutralizing antibody, or transplanted with control or 7ND (dominant-negative form of MCP-1)-overexpressing adipose-derived stromal cells (ADSCs). Stress increased monocyte accumulation, free fatty acids, proinflammatory cytokine, and HSP70.1 and reduced adiponectin. Adipose stromal cells highly expressed MCP-1. The stress-induced adipose inflammation increased PAI-1 and TF but did not give rise to thrombus formation. Without any changes in GTT, stress worsened insulin sensitivity and decreased IRS-1 and GLUT4 in WAT. Neutralizing antibody and 7ND-ADSCs reversed stress-induced adipose inflammation, procoagulant state, and insulin resistance. Stress evoked adipose inflammation to increase coagulation factors and impair insulin sensitivity through adipose-derived MCP-1.
A New Approach for Modeling Darrieus-Type Vertical Axis Wind Turbine Rotors Using Electrical Equivalent Circuit Analogy: Basis of Theoretical Formulations and Model Development

Models are crucial in the engineering design process because they can be used for both the optimization of design parameters and the prediction of performance. Thus, models can significantly reduce design, development and optimization costs. This paper proposes a novel equivalent electrical model for Darrieus-type vertical axis wind turbines (DTVAWTs). The proposed model was built from the mechanical description given by the Paraschivoiu double-multiple streamtube model and is based on the analogy between mechanical and electrical circuits. This work addresses the physical concepts and theoretical formulations underpinning the development of the model. After highlighting the working principle of the DTVAWT, the step-by-step development of the model is presented. For assessment purposes, simulations of aerodynamic characteristics and those of corresponding electrical components are performed and compared.
Definition of the hypothalamic GnRH pulse generator in mice

Significance Neural networks located in the hypothalamus are responsible for generating ultradian patterns of hormone secretion that control a wide variety of functions. How these neural networks generate pulsatile hormone secretion remains unknown. We report here that a population of hypothalamic kisspeptin neurons represents the gonadotropin-releasing hormone (GnRH) pulse generator. These cells have the remarkable ability to generate synchronized GnRH secretion every 9 min to drive pulsatile gonadotropin hormone secretion in the blood. These observations indicate the arcuate kisspeptin neurons as the origin of reproductive hormone pulsatility in mice and offer the prospect of better understanding and manipulating fertility in the clinic. The pulsatile release of luteinizing hormone (LH) is critical for mammalian fertility. However, despite several decades of investigation, the identity of the neuronal network generating pulsatile reproductive hormone secretion remains unproven. We use here a variety of optogenetic approaches in freely behaving mice to evaluate the role of the arcuate nucleus kisspeptin (ARNKISS) neurons in LH pulse generation. Using GCaMP6 fiber photometry, we find that the ARNKISS neuron population exhibits brief (∼1 min) synchronized episodes of calcium activity occurring as frequently as every 9 min in gonadectomized mice. These ARNKISS population events were found to be near-perfectly correlated with pulsatile LH secretion. The selective optogenetic activation of ARNKISS neurons for 1 min generated pulses of LH in freely behaving mice, whereas inhibition with archaerhodopsin for 30 min suppressed LH pulsatility. Experiments aimed at resetting the activity of the ARNKISS neuron population with halorhodopsin were found to reset ongoing LH pulsatility. These observations indicate the ARNKISS neurons as the long-elusive hypothalamic pulse generator driving fertility.
Analysis of HLA association among North Indian HIV-positive individuals co-infected with Mycobacterium tuberculosis

Background: Genetic variation in HLA genes influence the immune response and may thus contribute to differential development of tuberculosis (TB) in HIV-infected individuals. The study was designed to determine whether HLA polymorphisms influence the development of Mycobacterium tuberculosis infection in HIV-infected individuals. Materials and Methods: Fifty HIV-positive individuals without TB (HIV+TB−), 50 HIV patients co-infected with TB (HIV+TB+) and 50 control subjects (HIV-TB-) were analyzed for HLA Class I and II polymorphisms. Results: In HLA Class II, frequency of occurrence of DRB1*13 (OR 3.165, CI 1.176–8.518, P value 0.019), DRB5 (OR 2.253, CI 1.011–5.019, P value 0.045) and DQB1*06 (OR 2.705, CI 1.197–6.113, P value 0.016) were increased in HIV+TB+compared to HIV+TB−. HLA DQB1*02 (OR 0.436, CI 0.185–1.029, P value 0.05) on the other hand conferred a protective role. In HLA Class I, frequency of B*15 (OR 2.705, CI 1.040–7.036, P value 0.038) was increased, whereas B*51 (OR 0.148, CI 0.031–0.706, P value 0.007) was decreased in HIV+TB+group compared to HIV+TB−. These differences however were not significant when compared with healthy controls. Conclusion: HLA polymorphisms independently did not account for the susceptibility to either of the disease mostly, although they seem to play a role once the infection(s) has established in a particular individual. Further studies are needed on a larger sample size to confirm these observations.
Can Laparoscopic Hernia Repair Alter Function and Volume of Testis?: Randomized Clinical Trial

Testicular atrophy is a sequela of inguinal hernioplasty. The purpose of this study was to evaluate the effects of Lichtenstein (LHR) and laparoscopic totally extraperitoneal (TEP) hernia repair techniques on testicular function and volume. This study is a randomized prospective clinical trial with the blind assessment of outcome. A total of 26 patients who underwent elective herniorrhaphy for groin hernia were included in the study. Each patient was randomly assigned into one of two groups: either TEP or LHR (n = 13 for each). Six of the patients had bilateral hernia (n = 3 for each group). Luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone levels, and testicular volume by Doppler ultrasonography were detected just before and 3 months after the operation. LH, FSH levels did not change, when compared preoperative and postoperatively in both groups. Testicular volume and testosterone levels were observed to be significantly decreased after TEP when compared with LHR while no significant preoperative changes were observed between those groups. This affected the testicular volume in normal limits. TEP or LHR could not affect LH, FSH, testosterone values, but TEP could lead a decreasing effect on volume of testis in normal limits.
Calcium‐sensing mechanism in TRPC5 channels contributing to retardation of neurite outgrowth

The calcium‐ and sodium‐permeable transient receptor potential channel TRPC5 has an inhibitory role in neuronal outgrowth but the mechanisms governing its activity are poorly understood. Here we propose a mechanism involving the neuronal calcium sensor‐1 (NCS‐1) protein. Inhibitory mutants of TRPC5 and NCS‐1 enhance neurite outgrowth similarly. Mutant NCS‐1 does not inhibit surface‐expression of TRPC5 but generally suppresses channel activity, irrespective of whether it is evoked by carbachol, store depletion, lanthanides or elevated intracellular calcium. NCS‐1 and TRPC5 are in the same protein complex in rat brain and NCS‐1 directly binds to the TRPC5 C‐terminus. The data suggest protein–protein interaction between NCS‐1 and TRPC5, and involvement of this protein complex in retardation of neurite outgrowth.
Common cerebral networks associated with distinct deep brain stimulation targets for cluster headache

Background Several centers have reported efficacious cluster headache suppression with deep brain stimulation (DBS) of the hypothalamic region using a variety of targets. While the connectivity of some of these targets has individually been studied, commonalities across these targets, especially with respect to network-level connectivity, have not previously been explored. Methods We examined the anatomic connectivity of the four distinct DBS targets reported in the literature using probabilistic diffusion tensor tractography in normal subjects. Results Despite being described as hypothalamic, the DBS targets localized in the midbrain tegmentum posterior to the hypothalamus. Common tracts across DBS targets and subjects included projections to the ipsilateral hypothalamus, reticular formation, and cerebellum. Discussion Although DBS target coordinates are not located within the hypothalamus, a strong connection between DBS targets and the hypothalamus likely exists. Moreover, a common projection to the medial ipsilateral cerebellum was identified. Understanding the common connectivity of DBS-targeted regions may elucidate anatomic pathways that are involved in modulating cluster headache attacks and facilitate more precise patient-specific targeting of DBS.
Mortality attributable to obesity among middle-aged adults in the united states

Obesity is considered a major cause of premature mortality and a potential threat to the longstanding secular decline in mortality in the United States. We measure relative and attributable risks associated with obesity among middle-aged adults using data from the Health and Retirement Study (1992–2004). Although class II/III obesity (BMI _ 35.0 kg/m2) increases mortality by 40% in females and 62% in males compared with normal BMI (BMI = 18.5-24.9), class I obesity (BMI = 30.0-34.9) and being overweight (BMI = 25.0-29.9) are not associated with excess mortality. With respect to attributable mortality, class II/III obesity (BMI _ 35.0) is responsible for approximately 4% of deaths among females and 3% of deaths among males. Obesity is often compared with cigarette smoking as a major source of avoidable mortality. Smoking-attributable mortality is much larger in this cohort: about 36% in females and 50% in males. Results are robust to confounding by preexisting diseases, multiple dimensions of socioeconomic status (SES), smoking, and other correlates. These findings challenge the viewpoint that obesity will stem the long-term secular decline in U.S. mortality.
Extracting edge centrality from social networks using heat diffusion algorithm

Social networks are generally sets of individuals or organizations that are connected with one or more links. Usually, social networks are presented by undirected graphs, where the set of vertices V and the set of edges E state the individuals and relation between them respectively. One of the most applicable problems in these networks is the centrality values allocation problem to the vertices and edges. Recently, a new evaluation criterion for the edge centrality so called centrality index of k paths has been proposed which is based on intranet issuing the messages along with random paths composed of k edges. From the other side, it has been vivid the importance of computing the edges centrality through these years. In this study, by referring to message propagation along random paths, a new diffusion model was reached by applying heat diffusion algorithm. This model was based such that the vertex on the way of heat diffusion of most of vertices could be considered as an important node and it could obtain centrality edges by scoring the edges on the heat diffusion path. The proposed technique was compared with centrality drawing method by means of random paths of length k and the results of analyzing the algorithm performance on online large social networks’ data set show a remarkable efficacy of the proposed method to the mentioned method. Utilizing known large social networks in evaluation proves the efficiency of the proposed method for analyzing the large scale network.
Responses of Hydrological Processes to Climate Change in the Zhujiang River Basin in the 21st Century

Abstract In this study, discharge at the outlet of Xijiang River, the biggest sub-basin of the Zhujiang River, was simulated and projected from 1961 to 2099 using the hydrological model HBV-D. The model uses precipitation and temperature data from CISRO/MK3–5, MPI/ECHAM5, and NCAR/CCSM3 under three greenhouse gas emission scenarios (SRES A2, A1B, B1). The results in water resources and flood frequency suggest that annual precipitation and annual runoff would increase after 2050 relative to the reference period of 1961–1990. In addition, increasing trends have been projected in area averaged monthly precipitation and runoff from May to October, while decreasing trends in those from December to February. More often and larger floods would occur in future. Potential increase in runoff during the low-flow season could ease the pressure of water demand until 2030, but the increase in runoff in the high-flow season, with more often and larger floods, more pressure on flood control after 2050 is expected. Citation LIU, L. -L. , T. JIANG, J.-G. XU, et al., 2012: Responses of hydrological processes to climate change in the Zhujiang River Basin in the 21st century. Adv. Clim. Change Res. , 3 (2), doi: 10.3724/SP.J.1248.2012. 00084.
Herpes Simplex Virus Type 1 and Other Pathogens are Key Causative Factors in Sporadic Alzheimer’s Disease

Abstract This review focuses on research in epidemiology, neuropathology, molecular biology, and genetics regarding the hypothesis that pathogens interact with susceptibility genes and are causative in sporadic Alzheimer’s disease (AD). Sporadic AD is a complex multifactorial neurodegenerative disease with evidence indicating coexisting multi-pathogen and inflammatory etiologies. There are significant associations between AD and various pathogens, including Herpes simplex virus type 1 (HSV-1), Cytomegalovirus, and other Herpesviridae, Chlamydophila pneumoniae, spirochetes, Helicobacter pylori, and various periodontal pathogens. These pathogens are able to evade destruction by the host immune system, leading to persistent infection. Bacterial and viral DNA and RNA and bacterial ligands increase the expression of pro-inflammatory molecules and activate the innate and adaptive immune systems. Evidence demonstrates that pathogens directly and indirectly induce AD pathology, including amyloid-β (Aβ) accumulation, phosphorylation of tau protein, neuronal injury, and apoptosis. Chronic brain infection with HSV-1, Chlamydophila pneumoniae, and spirochetes results in complex processes that interact to cause a vicious cycle of uncontrolled neuroinflammation and neurodegeneration. Infections such as Cytomegalovirus, Helicobacter pylori, and periodontal pathogens induce production of systemic pro-inflammatory cytokines that may cross the blood-brain barrier to promote neurodegeneration. Pathogen-induced inflammation and central nervous system accumulation of Aβ damages the blood-brain barrier, which contributes to the pathophysiology of AD. Apolipoprotein E4 (ApoE4) enhances brain infiltration by pathogens including HSV-1 and Chlamydophila pneumoniae. ApoE4 is also associated with an increased pro-inflammatory response by the immune system. Potential antimicrobial treatments for AD are discussed, including the rationale for antiviral and antibiotic clinical trials.
Pilot Dose-Escalation Study of Caffeine Plus Ethanol (Caffeinol) in Acute Ischemic Stroke

Background and Purpose— In animal models, the combination of caffeine and ethanol (caffeinol) provides robust neuroprotection at blood levels that should be easily and safely achieved in humans. This study was designed to determine the safety and tolerability of ascending doses of this combination in stroke patients. Methods— This Food and Drug Administration–approved open-label, single-arm, dose-escalation study had 3 original dose groups: group 1, caffeine 6 mg/kg plus ethanol 0.2 g/kg; groups 2 and 3, incremental increases of caffeine and ethanol by 2 mg/kg and 0.2 g/kg, respectively. Intravenous thrombolysis was encouraged if patients qualified. Drug was started within 6 hours of stroke onset, and blood levels of caffeine and ethanol were drawn at baseline and end of infusion. The target blood caffeine and ethanol ranges were 8 to 10 &mgr;g/mL and 30 to 50 mg/dL, respectively. Clinical outcome measurements included the National Institutes of Health Stroke Scale at the end of infusion, at 24 hours, and at discharge. Potential complications from caffeine and ethanol were recorded. Cases were reviewed by an independent stroke neurologist for safety. Results— A total of 23 patients were recruited. Target blood caffeine and ethanol levels were reached in 0 of the 4 patients in the first group. The second dose group (caffeine 8 mg/kg plus ethanol 0.4 g/kg) included 8 patients. The median end-of-infusion caffeine and ethanol levels were within the desired target ranges. Two days after infusion, 1 patient in this group with preexisting cardiac disease and end-of-infusion caffeine and ethanol levels of 10.7 &mgr;g/mL and 69 mg/dL developed reversible congestive heart failure and required transfer to an intensive care unit. The original third dose group was canceled given achievement of target blood caffeine and ethanol levels in group 2. However, 3 new dose groups were created in an attempt to minimize the dose of ethanol. Although blood levels were proportional to dose, none of these new dose groups provided optimal blood levels. Congestive heart failure occurred in 1 other patient with previously asymptomatic cardiomyopathy. No other side effects were noted. Concomitant thrombolytic therapy was given in 8 patients, 1 of whom died of intracerebral hemorrhage. Conclusions— Caffeinol alone or combined with intravenous tissue plasminogen activator can be administered safely. Caffeine 8 mg/kg plus ethanol 0.4 g/kg produces target caffeine and ethanol levels of 8 to 10 &mgr;g/mL and 30 to 50 mg/dL, respectively. A randomized, placebo-controlled trial is needed to determine the neuroprotective effect of this combination.
Determination of ketotifen and its conjugated metabolite in human plasma by liquid chromatography/tandem mass spectrometry: application to a pharmacokinetic study.

A sensitive and specific liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed for the investigation of the pharmacokinetics of ketotifen and its major metabolite, ketotifen N-glucuronide, in human plasma. The plasma samples were treated by liquid-liquid extraction and analyzed using LC/MS/MS with an electrospray ionization interface. Diphenhydramine was used as the internal standard. The method had a lower limit of quantitation of 10 pg/mL for ketotifen, which offered increased sensitivity, selectivity and speed of analysis, compared with existing methods. The intra- and inter-day precision were measured to be below 8.2% and accuracy between -2.4% and 3.4% for all QC samples. Incubation of the plasma samples with beta-glucuronidase allowed the quantitation of ketotifen N-glucuronide. This quantitation method was successfully applied to a pharmacokinetic study of ketotifen and its major metabolite after oral administration of 2 mg ketotifen fumarate to 16 healthy volunteers.
Olig2-Targeted G-Protein-Coupled Receptor Gpr17 Regulates Oligodendrocyte Survival in Response to Lysolecithin-Induced Demyelination

Demyelinating diseases, such as multiple sclerosis, are known to result from acute or chronic injury to the myelin sheath and inadequate remyelination; however, the underlying molecular mechanisms remain unclear. Here, we performed genome occupancy analysis by chromatin immunoprecipitation sequencing in oligodendrocytes in response to lysolecithin-induced injury and found that Olig2 and its downstream target Gpr17 are critical factors in regulating oligodendrocyte survival. After injury to oligodendrocytes, Olig2 was significantly upregulated and transcriptionally targeted the Gpr17 locus. Gpr17 activation inhibited oligodendrocyte survival by reducing the intracellular cAMP level and inducing expression of the pro-apoptotic gene Xaf1. The protein kinase A signaling pathway and the transcription factor c-Fos mediated the regulatory effects of Gpr17 in oligodendrocytes. We showed that Gpr17 inhibition elevated Epac1 expression and promoted oligodendrocyte differentiation. The loss of Gpr17, either globally or specifically in oligodendrocytes, led to an earlier onset of remyelination after myelin injury in mice. Similarly, pharmacological inhibition of Gpr17 with pranlukast promoted remyelination. Our findings indicate that Gpr17, an Olig2 transcriptional target, is activated after injury to oligodendrocytes and that targeted inhibition of Gpr17 promotes oligodendrocyte remyelination. SIGNIFICANCE STATEMENT Genome occupancy analysis of oligodendrocytes in response to lysolecithin-mediated demyelination injury revealed that Olig2 and its downstream target Gpr17 are part of regulatory circuitry critical for oligodendrocyte survival. Gpr17 inhibits oligodendrocyte survival through activation of Xaf1 and cell differentiation by reducing Epac1 expression. The loss of Gpr17 in mice led to precocious myelination and an earlier onset of remyelination after demyelination. Pharmacological inhibition of Gpr17 promoted remyelination, highlighting the potential for Gpr17-targeted therapeutic approaches in demyelination diseases.