Miracle-dz/UniFAR-FTUs huggingface dataset:
A simulation study on some parametric confidence intervals for the difference of means of two skewed populations

Skewed data are common in the Biosciences and in life testing modeling. In this paper, we evaluate several existing techniques and propose some new techniques for estimating the differences of means of two skewed populations. A simulation study has been made to compare the performance of the selected intervals and a real life example has been considered to illustrate the applications of the techniques. We believe the findings of this paper will be helpful for different health researchers those are interested to choose the proper techniques for estimating the differences of means for two skewed populations.
Telomeres, telomerase, and cancer: life on the edge of genomic stability

The presence of telomerase activity in most human tumors, but not in many normal somatic tissues, has raised considerable interest in telomerase as a possible anticancer therapy. Recent advances in the cloning and characterization of mammalian telomerase components have paved the way for a more detailed understanding of the role of telomerase and telomere length maintenance in cell proliferation. Here, we summarize the most recent biochemical and genetic evidence suggesting that telomere length maintenance by telomerase is critical to the proliferative ability of some immortalized mammalian cells in culture and in vivo.
Global financial architechture, legitimacy, and representation: Voice for emerging markets

“Global Financial Architecture” is the term given to the institutional, regulatory, and supervisory framework governing the world’s monetary and financial system. It is largely the creature of the G-7 as opposed to the G-8, although part of it is also based on G-10 and G-20 international co-operation, recognising the growing importance of ‘emerging market’ economies to global financial stability. Efforts to reform the system began with the 1994-95 ‘Tequila’ or Peso Crisis which began in Mexico and spread rapidly on a global scale. The Asian financial crisis beginning in 1997 provided a further shock which stimulated reform. The crucial policy documents were laid out at the Halifax and Birmingham G-7/8 summits, with further minor refinements following (these may be located on the University of Toronto’s G-8 website, www.g8utoronto.ca and www.g8online.org). These summits led to the emergence of what came to be known as the “New International Financial Architecture. ” The aim was a modest adaptation of the ad hoc and essentially market-based financial architecture with limited degrees of international co-operation which predated the summits. In fact little was actually new, and institutional innovation at the global level, despite a range of more radical reform proposals, remained limited.
SMUCKLER/TIM4 is a distinct member of TIM family expressed by stromal cells of secondary lymphoid tissues and associated with lymphotoxin signaling

Lymphotoxin‐α (LTα) was originally linked to delayed‐type hypersensitivity and its production was later attributed to Th1, but not Th2 cells. Studies employing knockout mice demonstrated that LT signaling is essential for the development and functional compartmentalization of lymphoid tissues. Here, using gene expression profiling, we identified a novel gene termed SMUCKLER (spleen, mucin‐containing, knockout of lymphotoxin), that is selectively down‐regulated in spleens of LTα‐ or LTβ‐deficient mice. The encoded transmembrane protein contains immunoglobulin V and mucin domains and is identical to TIM4, a predicted member of recently identified TIM family (T cell immunoglobulin‐ and mucin‐domain‐containing molecule). Unlike TIM1 and TIM3, which were implicatedin T cell‐mediated functions, SMUCKLER lacks tyrosine phosphorylation motif in its intracellular domain and is not expressed by bone marrow‐derived cells. In situ hybridization of spleen sections demonstrated SMUCKLER expression by stromal cells predominantly in the marginal zone and to a lesser extent throughout the white pulp. Similarly to other TIM genes, SMUCKLER maps to a locus associated with predisposition to asthma both in mice and in humans (11.b1 and 5q33, respectively) and shows coding sequence variations between BALB/c and DBA mice. Therefore, SMUCKLER/TIM4 may be considered as a candidate disease‐predisposition gene for asthma.
Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression.

Fifty-two of 175 (30%) survivors of allogeneic marrow transplantation developed chronic graft-versus-hose diseases (GVHD). Five with limited chronic GVHD had an indolent clinical course with involvement of only the skin and liver. Forty-seven with extensive chronic GVHD had an unfavorable multiorgan disorder that resembled several autoimmune diseases. Thirteen patients with extensive disease (group I) were not treated and only 2 survive with Karnofsky scores >- 70%. Mortality resulted from infections and morbidity from sica syndrome, pulmonary and hepatic insufficiency, scleroderma-like skin disease, and contractures. Another 13 (group II) received a median of 8 mo prednisone and/or a brief course of antithymocyte globulin, and 3 survive without disability. The other 21 (group III) were treated with a combination of prednisone (1.0 mg/kg/q.o.d.) and either cyclophosphamide, procarbazine, or azathioprine (all 1.5 mg/kg/day) for a median of 13 mo. Combination therapy was well tolerated with only modest myelotoxicity. Fifteen in group III had a good and 4 a fair response to treatment while 2 with no response died. Azathioprine and prednisone was the most effective regimen. All therapy has been discontinued in 12 group III patients: GVHD returned in 5 (including 2 who died in spite of retreatment) while 7 remain free of GVHD for a median of 11 (range 6-30) mo observation. Only I group III survivor is disabled and 16 of the original 21 are alive 2-4 yr after transplant with Karnofsky scores of 70%-100%. Thus, combination immmunosuppression appears to favorably affect and, in some cases, premanently arrest the adverse natural course of extensive chronic GVHD.
Crucial Role of the Disulfide Bridge between Botulinum Neurotoxin Light and Heavy Chains in Protease Translocation across Membranes*

Clostridial botulinum neurotoxins (BoNTs) exert their neuroparalytic action by arresting synaptic exocytosis. Intoxication requires the disulfide-linked, di-chain protein to undergo conformational changes in response to pH and redox gradients across the endosomal membrane with consequent formation of a protein-conducting channel by the heavy chain (HC) that translocates the light chain (LC) protease into the cytosol. Here, we investigate the role of the disulfide bridge in the dynamics of protein translocation. We utilize a single channel/single molecule assay to characterize in real time the BoNT channel and chaperone activities in Neuro 2A cells under conditions that emulate those prevalent across endosomes. We show that the disulfide bridge must remain intact throughout LC translocation; premature reduction of the disulfide bridge after channel formation arrests translocation. The disulfide bridge must be on the trans compartment to achieve productive translocation of LC; disulfide disruption on the cis compartment or within the bilayer during translocation aborts it. We demonstrate that a peptide linkage between LC and HC in place of a disulfide bridge is insufficient for productive LC translocation. The disulfide linkage, therefore, dictates the outcome of translocation: productive passage of cargo or abortive channel occlusion by cargo. Based on these and previous findings we suggest a sequence of events for BoNT LC translocation to be HC insertion, coupled LC unfolding, and protein conduction through the HC channel in an N to C terminus orientation and ultimate release of the LC from the HC by reduction of the disulfide bridge concomitant with LC refolding in the cytosol.
Pathological and immunohistochemical study of chickens with co-infection of Marek's disease virus and chicken anaemia virus

Chicken anaemia virus (CAV) is the most important confounding pathogen in Marek's disease virus (MDV) infection. The effect of CAV co-infection at 4 weeks of age after inoculation of virulent MDV (vMDV, KS strain) or very virulent MDV (vvMDV, Md/5 strain) in 1-day-old chicks was investigated by pathological and immunohistochemical studies. CAV increased the mortality rates induced by vMDV or vvMDV. The packed cell volume was reduced significantly in vMDV–CAV infection; however, no reduction or non-significant reduction was observed in vMDV infection. Bone marrow hypoplasia was related to CAV co-infection and none of the birds inoculated with vMDV or vvMDV had hypoplasia. Severe atrophy of the thymus and bursa of Fabricius was observed in the vvMDV–CAV and vvMDV groups. Complete regeneration of the thymus cortex and bursa of Fabricius in the vMDV group was noted and was in contrast to sequential lymphoid depletion after CAV inoculation in the vMDV–CAV group. The spleen was either regenerated, lymphoid depleted or had lymphoproliferative lesions. Lymphoid depletion in the spleen was not detected in the vMDV group; however, it was prominent in the vMDV–CAV and vvMDV–CAV groups during the first 2 weeks after CAV inoculation. CAV inclusions and antigens were detected in the thymus cortex and spleen of vMDV–CAV and vvMDV–CAV groups during the experiment. Severe depletion of CD8+ T cells was observed in depleted spleen and thymus. The neoplastic foci appeared around splenic arterioles and venules, and stained mainly by CD4 antibody; however, CD8+ T cells were singly dispersed or were present in clusters. It could be concluded that CAV was responsible for bone marrow hypoplasia, severe anaemia and hindrance of lymphoid organ regeneration in MDV–CAV co-infection.
Excision repair cross‐complementation group 1 predicts progression‐free and overall survival in non‐small cell lung cancer patients treated with platinum‐based chemotherapy

Expression of excision repair cross‐complementation group 1 (ERCC1), p53, or thioredoxin (TRX) is reported to be correlated with resistance to platinum‐based drugs. The authors evaluated whether ERCC1, p53, or TRX expression could predict progression‐free and/or overall survival in relapsed non‐small cell lung cancer (NSCLC) patients treated with platinum‐based chemotherapy. Immunohistochemistry was used to examine the expression of these three proteins in resected lung tumor samples obtained from 67 patients treated with platinum‐based chemotherapy against recurrent tumors after curative resection. Immunostaining for ERCC1, p53, and TRX was positive in 29, 35, and 24 patients, respectively. Patients negative for ERCC1 had a significantly longer median progression‐free (44 vs 26 weeks, P = 0.0075) and overall (73 vs 44 weeks, P = 0.0006) survival than those positive for ERCC1. Patients negative for p53 expression had a significantly longer median overall (70 vs 62 weeks, P = 0.0289), but not progression‐free (37.5 vs 36 weeks, P = 0.2465), survival than those positive for p53 expression. From multivariate analysis, negative ERCC1 expression (hazard ratio [HR] = 1.3740, P = 0.0147) was a significantly favorable factor for progression‐free survival, and negative ERCC1 expression (HR = 1.6533, P = 0.0018) and better performance status (HR = 1.9117, P = 0.0017) were significantly favorable factors for overall survival. This retrospective study indicates that immunostaining for ERCC1 may be useful for predicting survival in NSCLC patients receiving platinum‐based chemotherapy against recurrent tumors after curative resection and can provide critical information for planning personalized chemotherapy. (Cancer Sci 2007; 98: 1336–1343)
Trends in physician-diagnosed osteoarthritis incidence in an administrative database in British Columbia, Canada, 1996-1997 through 2003-2004.

OBJECTIVE Prevalence of osteoarthritis (OA) is expected to increase due to population aging. However, there is little information on the trends in the incidence of OA over time. The purpose of this study was to describe changes in physician-diagnosed OA incidence rates between 1996-1997 and 2003-2004 in British Columbia (BC), Canada. METHODS We used data on all visits to health professionals and hospital admissions covered by the Medical Services Plan of BC (population approximately 4 million) for the fiscal years 1991-1992 through 2003-2004. Rates were standardized to the BC population in 2000. We used 2 definitions of OA: 1) at least 1 visit or hospitalization with a diagnostic code for OA, and 2) at least 2 visits or 1 hospitalization with a code for OA. Incidence rates were calculated with a 5-year run-in period to exclude prevalent cases. RESULTS Between 1996-1997 and 2003-2004, crude incidence rates of OA based on definition 1 increased from 10.5 to 12.2 per 1,000 in men and from 13.9 to 17.4 per 1,000 in women. The age-standardized rates did not change in men and increased from 14.7 to 16.7 per 1,000 in women. Incidence rates based on definition 2 were almost 50% lower, but the trends were similar. CONCLUSION We observed an increase in the incidence of OA in both men and women due to population aging and an additional increase in women beyond the effect of aging. These trends have important implications for public health and provision of health services to this very large group of patients.
Swarm reinforcement learning methods improving certainty of learning for a multi-robot formation problem

In this paper, we treat a multi-robot formation problem. In this problem, multiple robots move from their respective initial positions, and they achieve to make a given target formation by reaching goal positions. The goal positions which the robots reach must be different from each other. They learn their respective goal positions and the shortest routes to the goal positions. For solving the formation problem, we recently proposed a swarm reinforcement learning method. In the method, multiple sets of the robots and environments, which are called learning worlds, are prepared and the robots in each learning world learn not only by performing a usual reinforcement learning method but also by exchanging information among the learning worlds. The method, however, sometimes fails to find not only an optimal policy but also a policy which enables the robots to make the target formation, especially in the case where the target formation is large and complicated. In order to resolve this problem, this paper proposes swarm reinforcement learning methods in which the robots learn through always taking actions according to the current policy in learning by the usual reinforcement learning method. The performance of the proposed methods is evaluated through simulated experiments.
Computational Analysis of Dynamic Logic GMTI Tracker

The major computational challenge of multi-target tracking in clutter is solving the report-to-track association problem that has non-combinatorial complexity. Dynamic logic (DL) tracker performs data association without combinatorial complexity. The algorithm is designed for multi-target high-clutter scenarios in which combinatorial trackers have impractically high complexity. Thus, DL tracker can operate on GMTI data with low detection thresholds and detect very low signal tracks. This paper presents analysis of numerical performance of the dynamic logic tracker on a representative scenario
Prolactin and Autoimmunity

The great asymmetry of autoimmune diseases between genders represents one of the most enigmatic observations among the mosaic of autoimmunity. Sex hormones are believed to play a crucial role on this dimorphism. The higher prevalence of autoimmunity among women at childbearing ages, disease onset/relapses during pregnancy, and post-partum are some of the arguments that support this hypothesis. Certainly, motherhood represents one of the most remarkable challenges for the immune system, which not only has to allow for the conceptus, but also has to deal with complex endocrine alterations. Hormonal homeostasis is known to exert a crucial influence in achieving a competent and healthy immune system. Prolactin (PRL) has a bioactive function acting as a hormone and a cytokine. It interferes with immune system modulation, mainly inhibiting the negative selection of autoreactive B lymphocytes. Likewise, hyperprolactinemia has been described in relation to the pathogenesis and activity of several autoimmune disorders. Dopamine is an effective inhibitor of PRL secretion due to either a direct influence on the hypophysis or stimulation of postsynaptic dopamine receptors in the hypothalamus, arousing the release of the PRL inhibitory factor. Hence, dopamine agonists have proven to offer clinical benefits among autoimmune patients and represent a promising therapy to be explored. In this review, we attempt to provide a critical overview of the link between PRL, autoimmune diseases, and motherhood.
Left atrial mechanical functions in patients with anterior myocardial infarction: a velocity vector imaging-based study.

BACKGROUND The contribution of the left atrium (LA) to left ventricular (LV) function increases in myocardial infarction (MI). AIM To evaluate LA function by using volume measurements and a novel strain imaging method, namely velocity vector imaging (VVI), in patients with acute anterior MI. METHODS Twenty-four patients with previous anterior MI (aged 63.8 ± 4.2 years, 56% men) and 30 healthy controls (aged 60.7 ± 5.3 years, 60% men) were enrolled. LA volume measurements and VVI-derived LA peak systolic strain (S), strain rate (SRs), early diastolic (ESRd) and late diastolic strain rate (LSRd) were measured. LV diastolic function was analysed by pulsed wave-Doppler and tissue velocity ımaging. RESULTS LA maximum volume index was increased in patients compared to controls (28.83 ± 7.2 vs. 19.72 ± 6.27 mL/m²,p = 0.0001). As LA active emptying volume index and fraction were increased (6.16 ± 0.7 vs. 5.46 ± 0.99 mL/m², p = 0.009 and 22.16 ± 3.07 vs. 16.78 ± 2.93%, p = 0.0001, respectively), passive emptying volume index and fraction were decreased in the patient group (6.09 ± 0.57 vs. 7.57 ± 0.61 mL/m², p = 0.0001 and 45.76 ± 6.86 vs. 56.45 ± 5.36%, p = 0.0001, respectively). However, total emptying volume index of the LA was similar between the two groups. VVI-derived LA peak systolic S, SRs and ESRd were impaired in the patient group. LA LSRd was similar between the groups. LA active emptying fraction was positively correlated with LV diastolic dysfunction and negatively correlated with LV systolic dysfunction. CONCLUSIONS We demonstrated increased LA booster function and decreased LA conduit and reservoir functions in patients with prior anterior MI. Improvement in LA booster function correlated with the degree of LV systolic and diastolic dysfunction, suggesting a compensatory response of the LA.
Fear Conditioning to Subliminal Fear Relevant and Non Fear Relevant Stimuli

A growing body of evidence suggests that conscious visual awareness is not a prerequisite for human fear learning. For instance, humans can learn to be fearful of subliminal fear relevant images – images depicting stimuli thought to have been fear relevant in our evolutionary context, such as snakes, spiders, and angry human faces. Such stimuli could have a privileged status in relation to manipulations used to suppress usually salient images from awareness, possibly due to the existence of a designated sub-cortical ‘fear module’. Here we assess this proposition, and find it wanting. We use binocular masking to suppress awareness of images of snakes and wallabies (particularly cute, non-threatening marsupials). We find that subliminal presentations of both classes of image can induce differential fear conditioning. These data show that learning, as indexed by fear conditioning, is neither contingent on conscious visual awareness nor on subliminal conditional stimuli being fear relevant.
Heat shock proteins gp96 as immunogens in cancer patients

Heat shock proteins have been the focus of many experimental studies during the last few years in order to understand their biology and their imunologic features. We conducted pre-clinical experiments showing that gp96 purified from human melanoma lines can represent melanoma antigens and stimulate T cells known to recognize such antigens. Clinical studies of vaccination were then initiated by our group by using heat-shock protein gp96 purified from autologous tumor tissues in patients with melanoma and colorectal carcinoma. The results of these trials in metastatic melanoma patients with measurable disease showed that a melanoma-specific T cell response can be generated or increased in approximately 50% of vaccinated patients. Moreover, signs of clinical responses were obtained consisting of two complete responses and three long-lasting stabilizations. Similar results were obtained in patients with liver metastases of colorectal cancer made disease-free by surgery. In both studies a clear association was found between T cell immune response induced by the vaccine and clinical response both in the trial of melanoma (tumor response) and in that of colorectal cancer patients (disease-free and overall survival at 5 years).
CTCF: insights into insulator function during development

The genome of higher eukaryotes exhibits a patchwork of inactive and active genes. The nuclear protein CCCTC-binding factor (CTCF) when bound to insulator sequences can prevent undesirable crosstalk between active and inactive genomic regions, and it can also shield particular genes from enhancer function, a role that has many applications in development. Exciting recent work has demonstrated roles for CTCF in, for example, embryonic, neuronal and haematopoietic development. Here, we discuss the underlying mechanisms of developmentally regulated CTCF-dependent transcription in relation to model genes, and highlight genome-wide results indicating that CTCF might play a master role in regulating both activating and repressive transcription events at sites throughout the genome.
GPCR Engineering Yields High-Resolution Structural Insights into β2-Adrenergic Receptor Function

The β2-adrenergic receptor (β2AR) is a well-studied prototype for heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) that respond to diffusible hormones and neurotransmitters. To overcome the structural flexibility of the β2AR and to facilitate its crystallization, we engineered a β2AR fusion protein in which T4 lysozyme (T4L) replaces most of the third intracellular loop of the GPCR (“β2AR-T4L”) and showed that this protein retains near-native pharmacologic properties. Analysis of adrenergic receptor ligand-binding mutants within the context of the reported high-resolution structure of β2AR-T4L provides insights into inverse-agonist binding and the structural changes required to accommodate catecholamine agonists. Amino acids known to regulate receptor function are linked through packing interactions and a network of hydrogen bonds, suggesting a conformational pathway from the ligand-binding pocket to regions that interact with G proteins.