Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel Allosteric Agonists of M1 Muscarinic Acetylcholine Receptors Induce Brain Region-Specific Responses That Correspond with Behavioral Effects in Animal Models

M1 muscarinic acetylcholine receptors (mAChRs) represent a viable target for treatment of multiple disorders of the central nervous system (CNS) including Alzheimer's disease and schizophrenia. The recent discovery of highly selective allosteric agonists of M1 receptors has provided a major breakthrough in developing a viable approach for the discovery of novel therapeutic agents that target these receptors. Here we describe the characterization of two novel M1 allosteric agonists, VU0357017 and VU0364572, that display profound differences in their efficacy in activating M1 coupling to different signaling pathways including Ca2+ and β-arrestin responses. Interestingly, the ability of these agents to differentially activate coupling of M1 to specific signaling pathways leads to selective actions on some but not all M1-mediated responses in brain circuits. These novel M1 allosteric agonists induced robust electrophysiological effects in rat hippocampal slices, but showed lower efficacy in striatum and no measureable effects on M1-mediated responses in medial prefrontal cortical pyramidal cells in mice. Consistent with these actions, both M1 agonists enhanced acquisition of hippocampal-dependent cognitive function but did not reverse amphetamine-induced hyperlocomotion in rats. Together, these data reveal that M1 allosteric agonists can differentially regulate coupling of M1 to different signaling pathways, and this can dramatically alter the actions of these compounds on specific brain circuits important for learning and memory and psychosis.
Interaction of Mean and Pulse Pressures in the Circulation of the Isolated Dog Tongue

In the isolated, perfused dog's tongue, alterations of pulse pressure, at constant mean pressure, can produce parallel or oppositely directed changes in blood flow or can leave the flow unaffected. Parallel changes occur when the vascular bed is passively distensible; opposite changes occur when active contraction of smooth muscle overcomes the effects of passive distensibility, and no change is found when the two effects balance. The first is seen at mean pressures below 80 mm Hg or peak pressures above 155 to 165 mm Hg. The other reactions are produced in the mean pressure range in which autoregulatory reactions occur, viz. opposite changes when the pulse pressure is low and no change under conditions close to in situ mean and pulse pressure. Even when pulse pressure has no observable influence on flow, therefore, it modifies vascular tone. The active response of vascular smooth muscle to pulse pressure persists in part after the removal of the stimulus, opposing stress-relaxation of resistance vessels. Tissue weight changes reflect alterations in capacitance vessel volume which may vary in direction from the volume changes occurring in resistance vessels.
Viral hepatitis, type B.

INTRODUCTION Hepatitis B virus (HBV) is a DNA virus which is highly host and organ specific; to date it has only been found to infect hepatocytes of man and of a few nonhuman primate species. Despite the continuing failure of virologists to find an in vitro system for propagating HBV, it has been possible to gain a great deal of information about the agent and about viral hepatitis, type B, as a result of the discovery of the Australia antigen, now termed hepatitis B surface antigen (HB,Ag), and the recognition of its significance (1-4). The presumptive infectious form of HBV is a 40-42-nm particle, known as the Dane particle (5), which consists of an inner nucleocapsid core, termed hepatitis B core antigen (HBCAg) (6), and an outer lipoprotein coat composed of HB,Ag. The respective antibodies for the inner and outer components of HBV are called anti-HB, and anti-HB,. In the last several years a number of tests have been developed for detecting these antigens and antibodies (7). The most sensitive methods are radioimmunoassays (RIA), which use solid phase or double antibody techniques for separating specifically bound from free radiolabeled proteins. Almost as sensitive and avoiding the requirements for working with radioactive isotopes are the following hemagglutination techniques: passive hemagglutination (PHA) for anti-HB, detection, reversed passive hemagglutination (RPHA) for HB,Ag detection, and immune adherence hemagglutination (IAHA) for anti-HB, detection. A number of less sensitive methods, including agar gel diffusion, counterelectrophoresis, complement fixation, and reversed passive latex agglutination, are valuable for certain specific applications, but the more sensitive methods have vastly increased our understanding of the clinical disease, epidemiology, and approaches to prevention of type B hepatitis.
Morphological and topographical anatomy of nutrient foramina in the lower limb long bones and its clinical importance.

BACKGROUND Knowledge regarding nutrient foramina of bones is useful in surgical procedures such as microvascular bone transfer in order to preserve the circulation. The objective of the present study was to study the morphology and topography of nutrient foramina and to determine the foraminal index of the lower limb long bones to provide detailed data on such features. METHOD The study comprised examination of 206 lower limb long bones which included femora, tibiae and fibulae. The nutrient foramina were identified analysed macroscopically and the foramen index calculated. Each bone was divided into five parts and topographical analysis was performed on each section. RESULTS Femora had single nutrient foramen in 47.7% of the cases, double foramen in 44.2% of the cases, triple in 3.5% of the cases and an absence of foramen in 4.6%. In the case of tibiae, 98.6% showed single foramen and in 1.4% of the cases, the foramen was absent. With respect to fibulae, 90.2% had single foramen and foramen was absent in 9.8%. The mean foraminal index was 38.9 for the femora, 32.5 for tibiae and 49.2 for fibulae. The majority (51.3%) of the foramina in the femora were located at the 2/5(th) part, 98.3% of the tibiae foramina at the 2/5(th) part and 60% of the fibulae at the 3/5(th) part. CONCLUSION The study provides information on the morphology and topography of nutrient foramina in lower limb long bones. The double foramina were more common in femur and rare in the tibia and fibula. The foramina of the femur and tibia were commonly observed at their upper part, whereas in the fibula they were present on the lower part. This knowledge of the nutrient foramina has to be kept in mind during surgical procedures.
Prediction, filtering and smoothing using LSCR: State estimation algorithms with guaranteed confidence sets

In this paper we present a new approach to state estimation based on the Leave-out Sign-dominant Correlation Regions (LSCR) principle from system identification. The LSCR approach constructs a confidence set for the state which has the property that, regardless of the value of the true state, the constructed confidence set will contain it with a guaranteed user chosen probability. This property makes the approach potentially very useful in monitoring and detection applications. The proposed approach is illustrated in simulation examples.
Matrix Learning in Learning Vector Quantization

We propose a new matrix learning scheme to extend Generalized Relevance Learning Vector Quantization (GRLVQ), an efficient prototype-based classification algorithm. By introducing a full matrix of relevance factors in the distance measure, correlations between different features and their importance for the classification scheme can be taken into account and automated, general metric adaptation takes place during training. In comparison to the weighted euclidean metric used for GRLVQ, a full matrix is more powerful to represent the internal structure of the data appropriately. Interestingly, large margin generalization bounds can be transfered to the case of a full matrix such that bounds which are independent of the input dimensionality and the number of parameters arise. This also holds for local metrics attached to each prototype. The algorithm is tested and compared to GLVQ without metric adaptation and GRLVQ with diagonal relevance factors using an artificial dataset and the image segmentation data from the UCI repository.
Arsenic Induces Functional Re-Expression of Estrogen Receptor α by Demethylation of DNA in Estrogen Receptor-Negative Human Breast Cancer

Estrogen receptor α (ERα) is a marker predictive for response of breast cancers to endocrine therapy. About 30% of breast cancers, however, are hormone- independent because of lack of ERα expression. New strategies are needed for re-expression of ERα and sensitization of ER-negative breast cancer cells to selective ER modulators. The present report shows that arsenic trioxide induces reactivated ERα, providing a target for therapy with ER antagonists. Exposure of ER-negative breast cancer cells to arsenic trioxide leads to re-expression of ERα mRNA and functional ERα protein in in vitro and in vivo. Luciferase reporter gene assays and 3-(4,5-dimethylthiazol-2-yl)- 5-(3-carboxymethoxyphenyl)- 2-(4-sulfophenyl)- 2H-tetrazolium (MTS) assays show that, upon exposure to arsenic trioxide, formerly unresponsive, ER-negative MDA-MB-231 breast cancer cells become responsive to ER antagonists, 4-hydroxytamoxifen and ICI 182,780. Furthermore, methylation- specific PCR and bisulfite-sequencing PCR assays show that arsenic trioxide induces partial demethylation of the ERα promoter. A methyl donor, S-adenosylmethionine (SAM), reduces the degree of arsenic trioxide-induced re-expression of ERα and demethylation. Moreover, Western blot and ChIP assays show that arsenic trioxide represses expression of DNMT1 and DNMT3a along with partial dissociation of DNMT1 from the ERα promoter. Thus, arsenic trioxide exhibits a previously undefined function which induces re-expression ERα in ER-negative breast cancer cells through demethylation of the ERα promoter. These findings could provide important information regarding the application of therapeutic agents targeting epigenetic changes in breast cancers and potential implication of arsenic trioxide as a new drug for the treatment of ER–negative human breast cancer.
Streptococcus pneumoniae Resistance to Complement-Mediated Immunity Is Dependent on the Capsular Serotype

ABSTRACT Streptococcus pneumoniae strains vary considerably in the ability to cause invasive disease in humans, and this is partially associated with the capsular serotype. The S. pneumoniae capsule inhibits complement- and phagocyte-mediated immunity, and differences between serotypes in these effects on host immunity may cause some of the variation in virulence between strains. However, the considerable genetic differences between S. pneumoniae strains independent of the capsular serotype prevent an unambiguous assessment of the effects of the capsular serotype on immunity using clinical isolates. We have therefore used capsular serotype-switched TIGR4 mutant strains to investigate the effects of the capsular serotype on S. pneumoniae interactions with complement. Flow cytometry assays demonstrated large differences in C3b/iC3b deposition on opaque-phase variants of TIGR4(−)+4, +6A, +7F, and +23F strains even though the thicknesses of the capsule layers were similar. There was increased C3b/iC3b deposition on TIGR4(−)+6A and +23F strains compared to +7F and +4 strains, and these differences persisted even in serum depleted of immunoglobulin G. Neutrophil phagocytosis of the TIGR4(−)+6A and +23F strains was also increased, but only in the presence of complement, showing that the effects of the capsular serotype on C3b/iC3b deposition are functionally significant. In addition, the virulence of the TIGR4(−)+6A and +23F strains was reduced in a mouse model of sepsis. These data demonstrate that resistance to complement-mediated immunity can vary with the capsular serotype independently of antibody and of other genetic differences between strains. This might be one mechanism by which the capsular serotype can affect the relative invasiveness of different S. pneumoniae strains.
Toward a Knowledge Base for School Learning

The purpose of this article is to identify and estimate the influence of educational, psychological, and social factors on learning. Using evidence accumulated from 61 research experts, 91 meta-analyses, and 179 handbook chapters and narrative reviews, the data for analysis represent over 11,000 relationships. Three methods—content analyses, expert ratings, and results from meta-analyses—are used to quantify the importance and consistency of variables that influence learning. Regardless of which method is employed, there is moderate to substantial agreement on the categories exerting the greatest influence on school learning as well as those that have less influence. The results suggest an emergent knowledge base for school learning. Generally, proximal variables (e.g., psychological, instructional, and home environment) exert more influence than distal variables (e.g., demographic, policy, and organizational). The robustness and consistency of the findings suggest they can be used to inform educational policies and practices.
Formation of a pterin radical in the reaction of the heme domain of inducible nitric oxide synthase with oxygen.

The heme domain (iNOS(heme)) of inducible nitric oxide synthase (NOS) was expressed in Escherichia coli and purified to homogeneity. Rapid freeze-quench (RFQ) EPR was used to monitor the reaction of the reduced iNOS(heme) with oxygen in the presence and absence of substrate. In these reactions, heme oxidation occurs at a rate of approximately 15 s(-)(1) at 4 degrees C. A transient species with a g = 2.0 EPR signal is also observed under these conditions. The spectral properties of the g = 2.0 signal are those of an anisotropic organic radical with S = (1)/(2). Comparison of the EPR spectra obtained when iNOS(heme) is reconstituted with N5-(14)N- and (15)N-substituted tetrahydrobiopterin (H(4)B) shows a hyperfine interaction with the pterin N5 nitrogen and identifies the radical as the one-electron oxidized form (H(3)B. ) of the bound H(4)B. Substitution of D(2)O for H(2)O reveals the presence of hyperfine-coupled exchangeable protons in the H(4)B radical. This radical forms at a rate of 15-20 s(-)(1), with a slower decay rate that varies (0.12-0.7 s(-)(1)) depending on the substrate. At 127 ms, H(3)B. accumulates to a maximum of 80% of the total iNOS(heme) concentration in the presence of arginine but only to approximately 2.8% in the presence of NHA. Double-mixing RFQ experiments, where NHA is added after the formation of H(3)B. , show that NHA does not react rapidly with H(3)B. and suggest that NHA instead prevents the formation of the H(4)B radical. These data constitute the first direct evidence for an NOS-bound H(3)B. and are most consistent with a role for H(4)B in electron transfer in the NOS reaction.
Time-invariant measurement of time-varying bioimpedance using vector impedance analysis

When stepped-sine impedance spectroscopy measurements are carried out on (periodically) time-varying bio-systems, the inherent time-variant (time-periodic) parts are traditionally ignored or mitigated by filtering. The latter, however, lacks theoretical foundation and, in this paper, it is shown that it only works under certain specific conditions. Besides, we propose an alternative method, based on multisine signals, that exploits the non-stationary nature in time-varying bio-systems with a dominant periodic character, such as cardiovascular and respiratory systems, or measurements interfered with by their physiological activities. The novel method extracts the best—in a mean square sense—linear time-invariant (BLTI) impedance approximation ZBLTI(jω) of a periodically time-varying (PTV) impedance ZPTV(jω, t) as well as its time-periodic part. Relying on the geometrical interpretation of the BLTI concept, a new impedance analysis tool, called vector impedance analysis (VIA), is also presented. The theoretical and practical aspects are validated through measurements performed on a PTV dummy circuit and on an in vivo myocardial tissue.
Optimizing Burrows-Wheeler Transform-Based Sequence Alignment on Multicore Architectures

Computational biology sequence alignment tools using the Burrows-Wheeler Transform (BWT) are widely used in next-generation sequencing (NGS) analysis. However, despite extensive optimization efforts, the performance of these tools still cannot keep up with the explosive growth of sequencing data. Through an in-depth performance analysis of BWA, a popular BWT-based aligner on multicore architectures, we demonstrate that such tools are limited by memory bandwidth due to their irregular memory access patterns. We then propose a locality-aware implementation of BWA that aims at optimizing its performance by better exploiting the caching mechanisms of modern multicore processors. Experimental results show that our improved BWA implementation can reduce last-level cache (LLC) misses by 30% and translation look aside buffer (TLB) misses by 20%, resulting in up to 2.6-fold speedup over the original BWA implementation.
Study to Explore the Impact of Personality Traits on Employee Turnover in Public and Private Sector

The motive of conducting this research was to investigate the relationship between personality traits of employees and their turnover in public and private Organizations. This study also highlights the numerous definitions and description of personality and its traits in contemporary literature. The purpose of this research was to explore what kinds of personality traits are more dominant in those employees who have high turnover intensions or having high job quitting probability. This study highlights that Personality traits like Extraversion, Emotional Stability, Conscientiousness and Agreeableness were found negatively associated to individuals' intents to quit, while Openness to experience were observed to be positively related with intention to quit.
Web-based Recruiting for a Survey on Knowledge and Awareness of Cervical Cancer Prevention Among Young Women Living in Kanagawa Prefecture, Japan

Objectives Cervical cancer (CC) incidence and mortality among young women have been increasing in Japan. To develop effective measures to combat this, we assessed the feasibility of using a social networking site (SNS) to recruit a representative sample of young women to conduct a knowledge and attitude study about CC prevention via an internet-based questionnaire. Methods From July 2012 to March 2013, advertising banners targeting women aged 16 to 35 years in Kanagawa Prefecture were placed on Facebook in a similar manner as an Australian (AUS) study conducted in 16- to 25-year-olds in 2010 and on a homepage to advertise our CC advocacy activities. Eligible participants were emailed instructions for accessing our secure Web site where they completed an online survey including demographics, awareness, and knowledge of human papillomavirus (HPV) and CC. Data for the study population were compared with the general Japanese population and the AUS study. Results Among 394 women who expressed interest, 243 (62%) completed the survey, with 52% completing it via Facebook. Women aged 26 to 35 years, living in Yokohama City, with an education beyond high school, were overrepresented. Participants had high awareness and knowledge of HPV and CC, comparable with the AUS study participants. However, the self-reported HPV vaccination rate (22% among participants aged 16–25 years) and the recognition rate of the link between smoking and CC (31%) were significantly lower than in the AUS study (58% and 43%, respectively) (P < 0.05). Significant predictors of high knowledge scores about HPV included awareness of HPV vaccine (P < 0.001) and self-reported HPV vaccination (P < 0.05). Conclusions The SNS and homepage are efficient methods to recruit young women into health surveys, which can effectively be performed online. A nationwide survey using SNSs would be an appropriate next step to better understand the current lack of uptake of the national HPV vaccine program by young women in Japan.
The cell biology of the plasminogen system

The plasminogen system plays a pivotal role in maintaining vascular patency and in cell migration. Binding of plasminogen to surfaces (i.e., fibrin or cells) is of crucial importance in regulating the function of this system. Plasmin(ogen) binds to cells with low affinity and high capacity via its lysine binding sites, which are associated with its kringle domains and recognize carboxy‐terminal lysines of cell surface proteins. Upon binding to cellular receptors, plasminogen is more readily activated; bound plasinin has increased enzymatic activity and is protected from inactivation by inhibitors. Plasminogen receptors are modulated by numerous factors, including proteases, steroid hormones, cytokines and the adhesive state of the cells. The apoprotein(a) moiety of lipoprotein(a) is remarkably similar in amino acid secpience to plasminogen. Shared binding sites for lipoprotein(a) and plasmin(ogen) on cell surfaces and in the sub endothelial matrix may contribute to the pathogenetic risks associated with elevated levels of lipoprotein(a). —Plow, E. F. , Herren, T. , Redlitz, A. , Miles, L. A. , Hoover‐PLOW, J. L. The cell biology of the plasminogen system. FASEB J., 9, 939‐945 (1995)
Symptoms, stigma, or secondary social disruption: Three mechanisms of network dynamics in severe mental illness

Research has documented social network instability among people with serious mental illness focusing on (1) psychiatric symptoms that interfere with social skills and interaction and (2) stigma, discrimination, and social rejection. However, the social network consequences of disruptive events that often accompany onset of serious mental illness (e.g., divorce, job loss, and residential instability) are seldom considered. In this study, the relative impact of symptoms, stigma, and secondary disruptive events on membership turnover was examined using data from 100 people experiencing first contact with the mental health treatment system. Findings indicated that disruptive events and, to a lesser degree, psychiatric symptoms predicted membership turnover. A theory of relationship and network dynamics in mental illness integrating insights from the psychiatric, labeling, and social network perspectives is proposed.
Self-Esteem and its Sources: Stability and Change in Later Life

ABSTRACT Stability and change in self-esteem and its reported sources were investigated in a sample of older people re-interviewed 10 and 13 years after initial study. Most indicated a continuing high to medium-high level of self-esteem, and apart from an increase in mention of interest activities their pattern of illustrations also remained consistent. Variables in the initial study which predicted a maintained high level of self-esteem included number of hobbies, number of types of outings, self perceived activity level, and mention of people other than family members as sources of self-esteem. The usefulness of collecting data on expressed sources is exemplified in two case histories. Consideration is given to the implications of these findings for conceptualising identity processes in later life.