Miracle-dz/UniFAR-FTUs huggingface dataset:
Autosomal loci associated with a sex‐related difference in the development of autoimmune phenotypes in a lupus model

Sex‐related differences (SrD) are a general characteristic of human autoimmune diseases. There is an increasing body of evidence that suggests a link between sex‐related hormones and autoimmune onsets. Here, through a genetic approach using a lupus mouse model, we attempted to show the involvement of genetic factors in the development of SrD in autoimmune diseases. Using MRL/lpr × (MRL/lpr × C57BL/6.Faslpr)F1 (MBN2) mice, the whole genome was searched to identify linkage loci to autoimmune phenotypes inherited from a lupus MRL/Mp.Faslpr (MRL/lpr) strain of mice, which exhibits glomerulonephritis, splenomegaly and antinuclear autoantibody. The genome‐wide association study confirmed four linkage loci on chromosomes 4, 7, 13, and 17. Furthermore, differential analyses performed using male and female groups of MBN2 mice revealed that two loci located on chromosomes 4 (41–72 cM, MRL/lpr allele) and 7 (4–21 cM, B6/lpr allele) were male specific and suppressed autoimmune phenotypes. Notably, the sum effect of the two loci adequately explained a range of SrD developed in the MBN2 mice. Our present findings suggest the presence of a male‐predominant mechanism underlying the development of SrD in autoimmunity, depending on the effects of autosomal loci under an undefined male‐specific condition.
Arrhythmogenesis in the short-QT syndrome associated with combined HERG channel gating defects: a simulation study.

BACKGROUND This study aimed to show the mechanism how the HERG channel gating defects causes life-threatening arrhythmia in the short-QT syndrome, using a simulation model of ventricular action potentials (APs). METHODS AND RESULTS To evaluate the electrophysiological consequences of the short-QT syndrome at the level of the cardiac AP, the Markov model of wild-type (WT) KCNH2 channel was modified to obtain a model of the KCNH2 channel with the N588K mutation associated with the short-QT syndrome. Two parameters (betai and betabeta) were changed to reconstruct the N588K mutant Markov model, which successfully reproduced the experimental results of voltage-clamp recordings. The WT and mutant models were then integrated into the Luo-Rudy theoretical model of the cardiac ventricular AP. Unexpectedly, 1 parameter change alone, which caused gain of function, could shorten the AP duration (APD) but failed to induce early after-depolarizations (EADs). Only the condition with the combined gating defects could lead to EAD. CONCLUSIONS Although the gain of function for KCNH2 shortened APD in the short-QT syndrome, this simulation study suggested that arrhythmogenesis was associated not only with gain of function, but also with accelerated deactivation of KCNH2.
Clinical effect of irinotecan in advanced and metastatic breast cancer patients previously treated with doxorubicin- and docetaxel-containing regimens.

BACKGROUND Previous phase II trials in Japan suggested that irinotecan was a promising agent for advanced or metastatic breast cancer pretreated with anthracycline. However, irinotecan has not yet been evaluated in the salvage setting for breast cancer pretreated with both anthracycline and taxane, which are two active agents for breast cancer. METHODS The efficacy and safety of irinotecan were retrospectively evaluated in patients with breast cancer who had previously been treated with both doxorubicin and docetaxel. From 1996 to 1999, irinotecan was administered to 20 patients, all with a performance status of <2. Irinotecan treatment was repeated in approximately 6 week cycles consisting of the administration of irinotecan once weekly for 4 weeks followed by a 2 week rest. The median dose of irinotecan administered was 100 mg/m(2) weekly. The median number of irinotecan cycles given was 1 (range: 1-8 cycles). The median total dose was 388 mg/m(2) (range: 50-2400 mg/m(2)). RESULTS Performance status declined to >3 after treatment with irinotecan in four patients. Two patients had grade 3 leukopenia; three had grade 3 anemia and one had a creatinine elevation of grade 4. The objective response rate for all patients was 5.0% (95% CI: 0-15.5%). The median time to progression and overall survival were 35 days (range: 17-285 days) and 124 days (range: 17-667 days), respectively, since the start of the administration of irinotecan. CONCLUSIONS Salvage chemotherapy with irinotecan may be inactive against advanced and metastatic breast cancer pretreated with doxorubicin and docetaxel. We will evaluate irinotecan for advanced and metastatic breast cancer patients as first- or second-line chemotherapy combined with anthracycline or taxane.
Low Temperature Copper-Copper Thermocompression Bonding

Successful direct copper thermocompression bonding was demonstrated at room temperature under ambient environment, yielding shear strength of 21 MPa. Studies on the effect of bonding temperature on the copper joint shear strength revealed a unique phenomenon at the low temperature regime (~80degC -140degC) whereby bond integrity degrades with increasing temperature. Beyond 140degC, direct relationship between temperature and joint shear strength was observed. A hypothesis on the bonding mechanism between copper surfaces is proposed to explain the anomalous bonding behaviour with temperature.
Causal attribution across cultures: Variation and universality.

Growing cross-cultural evidence suggests that East Asians are less likely to show the correspondence bias, or a preference for explanations of behavior in terms of traits, dispositions, or other internal attributes of the target. The scope of this evidence spans several research paradigms and diverse methodologies. The cultural difference, however, appears not to be caused by an absence of dispositional thinking in East Asian cultures. Indeed, extensive ethnographic and psychological data indicate that "dispositionism" is a cross-culturally widespread mode of thinking, although East Asians believe dispositions to be more malleable and have a more holistic conception of the person as being situated in a broad social context. The East-West split in attribution thus originates primarily from a stronger "situationism" or belief in the importance of the context of behavior in East Asia. Consequently, East Asians are more likely than Westerners to avoid the correspondence bias as long as situational constraints are salient.
Cortical demyelination in PML and MS

Objective: To characterize pathologic changes in the cerebral cortex of patients with multiple sclerosis (MS) and progressive multifocal leukoencephalopathy (PML). Methods: Autopsy brain tissue was obtained from 13 patients with PML, 4 patients with MS, 2 patients with HIV encephalopathy, and 1 subject without neurologic pathology. Immunohistochemistry for myelin proteins, inflammatory cells, and neurofilaments was performed to evaluate the distribution of cortical lesions, their inflammatory activity, and neuritic pathology. Confocal microscopy was applied to examine pathologic changes in neurites in PML cortex. Results: Leukocortical, intracortical, and subpial patterns of cortical demyelination were represented in MS brain tissue. In PML brain tissue intracortical and leukocortical but not subpial lesions were observed. Cortical lesions in PML and MS contained fewer inflammatory cells than demyelinated areas in the white matter. Neuritic pathology in cortical PML lesions was represented by dystrophic and transected neurites. Pathologic modifications in neuritic processes in PML were more evident in highly inflamed white matter than in gray matter areas of demyelination, reminiscent of previous reports of neuritic pathology in MS. JC virus-infected cells were associated with PML white matter, leukocortical and intracortical lesions. Conclusions: Cortical pathology represents a distinct feature of progressive multifocal leukoencephalopathy. Similarities and differences with regard to multiple sclerosis cortical pathology were noted and may be informative regarding the pathogenesis of both disorders. GLOSSARY: AP = alkaline phosphatase; DAB = diaminobenzidine; HAART = highly active antiretroviral therapy; HIVE = HIV encephalopathy; MBP = myelin basic protein; MS = multiple sclerosis; NNTC = NeuroAIDS Tissue Consortium; PLP = proteolipid protein; PML = progressive multifocal leukoencephalopathy; SPMS = secondary progressive multiple sclerosis; X-ALD = X-linked adrenoleukodystrophy.
Role of insulin autoantibody affinity as a predictive marker for type 1 diabetes in young children with HLA‐conferred disease susceptibility

Insulin autoantibodies (IAA) are early markers of prediabetic autoimmunity. As transient and fluctuating IAA positivity are common among young children, distinguishing non‐progressive IAA from destruction‐related IAA is essential when preventive measures are considered. We tested whether children progressing rapidly to type 1 diabetes (progressors) are characterized by a higher prediabetic IAA affinity than IAA‐positive children remaining unaffected or progressing more slowly to diabetes (non‐progressors), and whether IAA affinity increases towards diagnosis.
Glycosylation Affects Rat Kv1.1 Potassium Channel Gating by a Combined Surface Potential and Cooperative Subunit Interaction Mechanism

The effect of glycosylation on Kv1.1 potassium channel function was investigated in mammalian cells stably transfected with Kv1.1 or Kv1.1N207Q. Macroscopic current analysis showed that both channels were expressed but Kv1.1N207Q, which was not glycosylated, displayed functional differences compared with wild‐type, including slowed activation kinetics, a positively shifted V1/2, a shallower slope for the conductance versus voltage relationship, slowed C‐type inactivation kinetics, and a reduced extent of and recovery from C‐type inactivation. Kv1.1N207Q activation properties were also less sensitive to divalent cations compared with those of Kv1.1. These effects were largely due to the lack of trans‐Golgi added sugars, such as galactose and sialic acid, to the N207 carbohydrate tree. No apparent change in ionic current deactivation kinetics was detected in Kv1.1N207Q compared with wild‐type. Our data, coupled with modelling, suggested that removal of the N207 carbohydrate tree had two major effects. The first effect slowed the concerted channel transition from the last closed state to the open state without changing the voltage dependence of its kinetics. This effect contributed to the G‐V curve depolarization shift and together with the lower sensitivity to divalent cations suggested that the carbohydrate tree and its negatively charged sialic acids affected the negative surface charge density on the channel's extracellular face that was sensed by the activation gating machinery. The second effect reduced a cooperativity factor that slowed the transition from the open state to the closed state without changing its voltage dependence. This effect accounted for the shallower G‐V slope, and contributed to the depolarized G‐V shift, and together with the inactivation changes it suggested that the carbohydrate tree also affected channel conformations. Thus N‐glycosylation, and particularly terminal sialylation, affected Kv1.1 gating properties both by altering the surface potential sensed by the channel's activation gating machinery and by modifying conformational changes regulating cooperative subunit interactions during activation and inactivation. Differences in glycosylation pattern among closely related channels may contribute to their functional differences and affect their physiological roles.
PLACEBO-DRIVEN CLINICAL TRIALS OF TRANSFER POINT GLUCAN #300 IN CHILDREN WITH CHRONIC RESPIRATORY PROBLEMS: ANTIBODY PRODUCTION

The role of glucan in stimulation of immune reactio ns has been well-established. In this report, we fo cused on the antibody production in glucan-supplemented children with chronic respiratory problems. We measured the levels of salivary IgA, IgM and IgG in 40 children aged 8-12 years and evaluated the effe cts of 100 mg d -1 oral dose of glucan. We found a significant increa se in production of all tested antibodies in the glucan-stimulated group, but a decrease of anti body production in the control group. A thirty-day oral application of yeast-based natural immunomodulator β-glucan strongly stimulated the mucosal immunity of children with chronic respiratory problems.
Heterogeneous Cellular Networks: From Resource Allocation To User Association

Heterogeneous networking paradigm addresses the ever growing need for capacity and coverage in wireless networks by deploying numerous low power base stations overlaying the existing macro cellular coverage. Heterogeneous cellular networks encompass many deployment scenarios, with different backhauling techniques (wired versus wireless backhauling), different transmission coordination mechanisms and resource allocation schemes, different types of links operating at different bands and air-interface technologies, and different user association schemes. Studying these deployment scenarios and configurations, and understanding the interplay between different processes is challenging. In the first part of the thesis, we present a flowbased optimization framework that allows us to obtain the throughput performance of a heterogeneous network when the network processes are optimized jointly. This is done under a given system “snapshot”, where the system parameters like the channel gains and the number of users are fixed and assumed known. Our framework allows us to configure the network parameters to allocate optimal throughputs to these flows in a fair manner. This is an offline-static model and thus is intended to be used at the engineering and planning phase to compare many potential configurations and decide which ones to study further. Using the above-mentioned formulation, we have been able to study a large set of deployment scenarios and different choices of resource allocation, transmission coordination, and user association schemes. This has allowed us to provide a number of important engineering insights on the throughput performance of different scenarios and their configurations. The second part of our thesis focuses on understanding the impact of backhaul infrastructure’s capacity limitation on the radio resource management algorithms like user scheduling and user association. Most existing studies assume an ideal backhaul. This assumption, however, needs to be revisited as backhaul considerations are critical in heterogeneous networks due to the economic considerations. In this study, we formulate a global α-fair user scheduling problem under backhaul limitations, and show how this limitation has a fundamental impact on user scheduling. Using results from convex optimization, we characterize the solution of optimal backhaul-aware user scheduling and show that simple heuristics can be used to obtain good throughput performance with relatively
Thyroid Hormone Receptor α1 Downregulation in Postischemic Heart Failure Progression: The Potential Role of Tissue Hypothyroidism

Thyroid hormone (TH) signaling is altered in response to various stresses including myocardial ischemia. The present study investigated potential implication of TH signaling in the pathophysiology of postischemic remodeling. Acute myocardial infarction was induced in rats by coronary artery ligation (AMI). After 34 weeks, 6 animals were on congestive heart failure (CHF) as indicated by measurements in lung and right ventricular weight. 7 animals were in compensated state (Non-CHF) and 8 sham-operated animals (SHAM) served as controls. Progression to congestive heart failure was characterized by marked decrease in EF% and all other functional echocardiographic parameters. Furthermore, beta-MHC expression was significantly increased in CHF. A distinct pattern of thyroid hormone receptor (TR) expression was observed in the course of postischemic remodeling; TR alpha 1 was upregulated and TR beta 1 was downregulated in Non-CHF, and TR alpha 1 expression was markedly decreased during the transition from Non-CHF to CHF resulting in tissue hypothyroidism. Circulating T3 and T4 remained unchanged. This response was associated with marked decrease in mTOR activation. A potential link between mTOR and TR alpha 1 expression was shown in a neonatal cardiomyocytes model of PE (phenylephrine)-induced pathological growth. Phenylephrine increased the expression of TR alpha 1 in nucleus and this response was abrogated in the case of mTOR inhibition by rapamycin. In conclusion, progression to congestive heart failure after myocardial infarction is associated with suppressed expression of TR alpha 1 and results in tissue hypothyroidism. This process may, at least in part, be mTOR dependent.
Mass spectrometry analysis of HIV‐1 Vif reveals an increase in ordered structure upon oligomerization in regions necessary for viral infectivity

HIV‐1 Vif, an accessory protein in the viral genome, performs an important role in viral pathogenesis by facilitating the degradation of APOBEC3G, an endogenous cellular inhibitor of HIV‐1 replication. In this study, intrinsically disordered regions are predicted in HIV‐1 Vif using sequence‐based algorithms. Intrinsic disorder may explain why traditional structure determination of HIV‐1 Vif has been elusive, making structure‐based drug design impossible. To characterize HIV‐1 Vif's structural topology and to map the domains involved in oligomerization we used chemical cross‐linking, proteolysis, and mass spectrometry. Cross‐linking showed evidence of monomer, dimer, and trimer species via denaturing gel analysis and an additional tetramer via western blot analysis. We identified 47 unique linear peptides and 24 (13 intramolecular; 11 intermolecular) noncontiguous, cross‐linked peptides, among the noncross‐linked monomer, cross‐linked monomer, cross‐linked dimer, and cross‐linked trimer samples. Almost complete peptide coverage of the N‐terminus is observed in all samples analyzed, however reduced peptide coverage in the C‐terminal region is observed in the dimer and trimer samples. These differences in peptide coverage or “protections” between dimer and trimer indicate specific differences in packing between the two oligomeric forms. Intramolecular cross‐links within the monomer suggest that the N‐terminus is likely folded into a compact domain, while the C‐terminus remains intrinsically disordered. Upon oligomerization, as evidenced by the intermolecular cross‐links, the C‐terminus of one Vif protein becomes ordered by wrapping back on the N‐terminal domain of another. In addition, the majority of the intramolecular cross‐links map to regions that have been previously reported to be necessary for viral infectivity. Thus, this data suggests HIV‐1 Vif is in a dynamic equilibrium between the various oligomers potentially allowing it to interact with other binding partners. Proteins 2007. © 2007 Wiley‐Liss, Inc.
Treatment of prostate cancer with intermittent versus continuous androgen deprivation: a systematic review of randomized trials.

PURPOSE Uncertainty exists regarding benefits of intermittent androgen deprivation (IAD) compared with continuous androgen deprivation (CAD) for treatment of prostate cancer. On the basis of a systematic review of evidence, our aim was to formulate a recommendation for either IAD or CAD to treat relapsing, locally advanced, or metastatic prostate cancer. METHODS We searched literature published up to September 2012 from MEDLINE, EMBASE, the Cochrane Library, and major conference proceedings. We included randomized controlled trials comparing IAD and CAD if they reported overall survival (OS) or biochemical/radiologic time to disease progression. RESULTS Nine studies with 5,508 patients met our criteria. There were no significant differences in time-to-event outcomes between the groups in any studies. The pooled hazard ratio (HR) for OS was 1.02 (95% CI, 0.94 to 1.11) for IAD compared with CAD, and the HR for progression-free survival was 0.96 (95% CI, 0.76 to 1.20). More prostate cancer-related deaths with IAD tended to be balanced by more deaths not related to prostate cancer with CAD. Superiority of IAD for sexual function, physical activity, and general well-being was observed in some trials. Median cost savings with IAD was estimated to be 48%. CONCLUSION There is fair evidence to recommend use of IAD instead of CAD for the treatment of men with relapsing, locally advanced, or metastatic prostate cancer who achieve a good initial response to androgen deprivation. This recommendation is based on evidence against superiority of either strategy for time-to-event outcomes and substantial decrease with IAD in exposure to androgen deprivation, resulting in less cost, inconvenience, and potential toxicity.
Intratympanic Dexamethasone Is an Effective Method as a Salvage Treatment in Refractory Sudden Hearing Loss

Objectives This study aimed to investigate the therapeutic efficacy of intratympanic dexamethasone (ITD) as a salvage treatment in sudden hearing loss (SHL) patients who had no response to initial systemic combination steroid therapy. Patients and Methods From May 2007 to June 2010, 415 SHL patients visited 3 tertiary referral centers within 7 days of disease onset. They were all treated with an identical protocol, a 10-day scheduled hospitalization and oral steroid treatment. Of these, 151 patients were totally unresponsive 2 weeks after treatment initiation according to Siegel’s criteria. We divided these 151 refractory patients into 3 groups: those receiving no further treatment (control group, n = 59), those receiving one more 10-day cycle of oral steroids (systemic reapplication group, n = 26), and those receiving ITD therapy (ITD group, n = 66). Final assessment of hearing was conducted approximately 3 months after the onset of SHL. Hearing improvement was defined as demonstrating “any” improvement according to Siegel’s criteria. Results The initial average hearing thresholds of all groups were similar. Overall hearing improvement was observed in 10 of 59 patients in the control group, in 4 of 26 in the systemic reapplication group, and in 32 of 66 in the ITD group. No serious complications were observed. Analyzing by frequency, paradoxically, hearing of the low and mid frequencies was more significantly improved than high frequencies in the ITD group. Conclusion Intratympanic dexamethasone administration after failure of an initial treatment is effective, and this should be used as a salvage treatment in cases of refractory SHL.
The Aging Process of Human Neonatal Erythrocytes

ABSTRACT: The red blood cell population of the human newborn is more heterogeneous than that of adults. To characterize this heterogeneity, red cells were separated on Stractan gradients into populations according to their density and, therefore, generally according to their age. Lipid content, phospholipid asymmetry, osmotic fragility, and deformability were measured. With increasing density, osmotic resistance and deformability decreased to a greater extent in the neonatal than the adult red cell. There was a marked loss of surface area throughout the life span of the neonatal red cell which was not accompanied by a parallel loss of membrane lipid. This apparent discrepancy could be explained at least in part by internalization of membrane lipid as a result of endocytosis, a process shown to be present in even the densest neonatal red cells.
Directed Graph Embeddings

Definitions of graph embeddings and graph minors for directed graphs are introduced. For the class of 2-terminal directed acyclic graphs (TDAGs) the definitions coincide, and the class is closed under both operations. The usefulness of the directed embedding operation is demonstrated be characterizing all TDAGs with parallel-width at most $k$, which generalizes earlier characterizations of series-parallel graphs.