Miracle-dz/UniFAR-FTUs huggingface dataset:
Structure and Function of Heterotrimeric G Protein-Regulated Rho Guanine Nucleotide Exchange Factors

Activation of certain classes of G protein-coupled receptors (GPCRs) can lead to alterations in the actin cytoskeleton, gene transcription, cell transformation, and other processes that are known to be regulated by Rho family small-molecular-weight GTPases. Although these responses can occur indirectly via cross-talk from canonical heterotrimeric G protein cascades, it has recently been demonstrated that Dbl family Rho guanine nucleotide exchange factors (RhoGEFs) can serve as the direct downstream effectors of heterotrimeric G proteins. Heterotrimeric Gα12/13, Gαq, and Gβγ subunits are each now known to directly bind and regulate RhoGEFs. Atomic structures have recently been determined for several of these RhoGEFs and their G protein complexes, providing fresh insight into the molecular mechanisms of signal transduction between GPCRs and small molecular weight G proteins. This review covers what is currently known about the structure, function, and regulation of these recently recognized effectors of heterotrimeric G proteins.
Angiotensin II Type 1 Receptor-Mediated Electrical Remodeling in Mouse Cardiac Myocytes

We recently characterized an autocrine renin angiotensin system (RAS) in canine heart. Activation of Angiotensin II Type 1 Receptors (AT1Rs) induced electrical remodeling, including inhibition of the transient outward potassium current Ito, prolongation of the action potential (AP), increased calcium entry and increased contractility. Electrical properties of the mouse heart are very different from those of dog heart, but if a similar system existed in mouse, it could be uniquely studied through genetic manipulations. To investigate the presence of a RAS in mouse, we measured APs and Ito in isolated myocytes. Application of angiotensin II (A2) for 2 or more hours reduced Ito magnitude, without affecting voltage dependence, and prolonged APs in a dose-dependent manner. Based on dose-inhibition curves, the fast and slow components of Ito (Ito,fast and IK,slow) appeared to be coherently regulated by [A2], with 50% inhibition at an A2 concentration of about 400 nM. This very high K0.5 is inconsistent with systemic A2 effects, but is consistent with an autocrine RAS in mouse heart. Pre-application of the microtubule destabilizing agent colchicine eliminated A2 effects on Ito and AP duration, suggesting these effects depend on intracellular trafficking. Application of the biased agonist SII ([Sar1-Ile4-Ile8]A2), which stimulates receptor internalization without G protein activation, caused Ito reduction and AP prolongation similar to A2-induced changes. These data demonstrate AT1R mediated regulation of Ito in mouse heart. Moreover, all measured properties parallel those measured in dog heart, suggesting an autocrine RAS may be a fundamental feedback system that is present across species.
Maintenance of respiratory chain function in mouse hearts with severely impaired mtDNA transcription

The basal mitochondrial transcription machinery is essential for biogenesis of the respiratory chain and consists of mitochondrial RNA polymerase, mitochondrial transcription factor A (TFAM) and mitochondrial transcription factor B2. This triad of proteins is sufficient and necessary for mtDNA transcription initiation. Abolished mtDNA transcription caused by tissue-specific knockout of TFAM in the mouse heart leads to early onset of a severe mitochondrial cardiomyopathy with lethality within the first post-natal weeks. Here, we describe a mouse model expressing human TFAM instead of the endogenous mouse TFAM in heart. These rescue mice have severe reduction in mtDNA transcription initiation, but, surprisingly, are healthy at the age of 52 weeks with near-normal steady-state levels of transcripts. In addition, we demonstrate that heavy-strand mtDNA transcription normally terminates at the termination-associated sequence in the control region. This termination is abolished in rescue animals resulting in heavy (H)-strand transcription of the entire control region. In conclusion, we demonstrate here the existence of an unexpected mtDNA transcript stabilization mechanism that almost completely compensates for the severely reduced transcription initiation in rescue hearts. Future elucidation of the underlying molecular mechanism may provide a novel pathway to treat mitochondrial dysfunction in human pathology.
Heterosexual Women’s Anal Sex Attitudes and Motivations: A Focus Group Study

Focus group methods were used to explore heterosexual women’s receptive anal sex attitudes and motivations. Behaviors under investigation included penile–anal intercourse (PAI), manual–anal stimulation, oral–anal contact, and the use of sex toys. A total of 33 self-identified heterosexual women ages 18 to 30 recruited from two metropolitan areas in the Midwestern United States participated in one of six focus groups. The findings suggest that women viewed heterosexual anal sex as an emerging norm. Attitudes and motivations were complex and varied by behavior. Dominant themes included curiosity, pain, pleasure, and stigma. Relational factors, including acquiescence, coercion, and consent, were also salient among participants. Factors that influence anal sexual behaviors may not be entirely distinct from those that influence other sexual behaviors; however, factors that influence anal intercourse may be distinct from those that influence nonintercourse anal sex. Improved understanding will allow scientists to better understand the integration of anal sex behaviors into the broader sexual repertoire.
Health care transition in Germany – standardization of procedures and improvement actions

Previous studies have assessed an increase in the number of people in need and emphasized the advantages of structured discharge management and health care transition. Therefore, our study evaluated the status quo of transition in a major German city after standardization of procedures and implementation of standard forms. Satisfaction with handling of standard forms and improvement of procedures was evaluated. Additionally, patients who had recently been hospitalized were asked about the hospital discharge process. The results show that the recent efforts of standardization helped to improve interface management for health care workers and patients and showed further improvement options.
The role of selective estrogen receptor modulators in the treatment of schizophrenia.

BACKGROUND Gender differences in schizophrenia have been recognized for a long time and it has been widely accepted that sex steroid hormones, especially estradiol, are strongly attributed to this fact. Two hypotheses regarding estradiol action in psychoses gained special research attention - the estrogen protection hypothesis and hypoestrogenism hypothesis. A growing number of studies have shown benefits in augmenting antipsychotic treatment with estrogens or selective estrogen receptor modulators (SERM). METHODS This review is focused on the role of selective estrogen receptor modulators in the treatment of schizophrenic patients. In order to achieve this result PubMed was searched using the following terms: schizophrenia, raloxifene, humans. We reviewed only randomized, placebo-controlled studies. RESULTS Raloxifene, a selective estrogen receptor modulator was identified as useful to improve negative, positive, and general psychopathological symptoms, and also cognitive functions. All reviewed studies indicated improvement in at least one studied domain. Augmentation with raloxifene was found to be a beneficial treatment strategy for chronic schizophrenia both in female and male patients, however potential side effects (a small increase in the risk of venous thromboembolism and endometrial cancer) should be carefully considered. CONCLUSIONS SERMs could be an effective augmentation strategy in the treatment of both men women with schizophrenia, although further research efforts are needed to study potential long-term side effects.
Alternating direction optimization for image segmentation using hidden Markov measure field models

Image segmentation is fundamentally a discrete problem. It consists of finding a partition of the image domain such that the pixels in each element of the partition exhibit some kind of similarity. The solution is often obtained by minimizing an objective function containing terms measuring the consistency of the candidate partition with respect to the observed image, and regularization terms promoting solutions with desired properties. This formulation ends up being an integer optimization problem that, apart from a few exceptions, is NP-hard and thus impossible to solve exactly. This roadblock has stimulated active research aimed at computing “good” approximations to the solutions of those integer optimization problems. Relevant lines of attack have focused on the representation of the regions (i.e., the partition elements) in terms of functions, instead of subsets, and on convex relaxations which can be solved in polynomial time. In this paper, inspired by the “hidden Markov measure field” introduced by Marroquin et al. in 2003, we sidestep the discrete nature of image segmentation by formulating the problem in the Bayesian framework and introducing a hidden set of real-valued random fields determining the probability of a given partition. Armed with this model, the original discrete optimization is converted into a convex program. To infer the hidden fields, we introduce the Segmentation via the Constrained Split Augmented Lagrangian Shrinkage Algorithm (SegSALSA). The effectiveness of the proposed methodology is illustrated with simulated and real hyperspectral and medical images.
Early life stress and macaque amygdala hypertrophy: preliminary evidence for a role for the serotonin transporter gene

Background: Children exposed to early life stress (ELS) exhibit enlarged amygdala volume in comparison to controls. The primary goal of this study was to examine amygdala volumes in bonnet macaques subjected to maternal variable foraging demand (VFD) rearing, a well-established model of ELS. Preliminary analyses examined the interaction of ELS and the serotonin transporter gene on amygdala volume. Secondary analyses were conducted to examine the association between amygdala volume and other stress-related variables previously found to distinguish VFD and non-VFD reared animals. Methods: Twelve VFD-reared and nine normally reared monkeys completed MRI scans on a 3T system (mean age = 5.2 years). Results: Left amygdala volume was larger in VFD vs. control macaques. Larger amygdala volume was associated with: “high” cerebrospinal fluid concentrations of corticotropin releasing-factor (CRF) determined when the animals were in adolescence (mean age = 2.7 years); reduced fractional anisotropy (FA) of the anterior limb of the internal capsule (ALIC) during young adulthood (mean age = 5.2 years) and timid anxiety-like responses to an intruder during full adulthood (mean age = 8.4 years). Right amygdala volume varied inversely with left hippocampal neurogenesis assessed in late adulthood (mean age = 8.7 years). Exploratory analyses also showed a gene-by-environment effect, with VFD-reared macaques with a single short allele of the serotonin transporter gene exhibiting larger amygdala volume compared to VFD-reared subjects with only the long allele and normally reared controls. Conclusion: These data suggest that the left amygdala exhibits hypertrophy after ELS, particularly in association with the serotonin transporter gene, and that amygdala volume variation occurs in concert with other key stress-related behavioral and neurobiological parameters observed across the lifecycle. Future research is required to understand the mechanisms underlying these diverse and persistent changes associated with ELS and amygdala volume.
Suppression of Autoimmune Diabetes by Soluble Galectin-11

Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that targets the β-cells of the pancreas. We investigated the ability of soluble galectin-1 (gal-1), an endogenous lectin that promotes T cell apoptosis, to down-regulate the T cell response that destroys the pancreatic β-cells. We demonstrated that in nonobese diabetic (NOD) mice, gal-1 therapy reduces significantly the amount of Th1 cells, augments the number of T cells secreting IL-4 or IL-10 specific for islet cell Ag, and causes peripheral deletion of β-cell-reactive T cells. Administration of gal-1 prevented the onset of hyperglycemia in NOD mice at early and subclinical stages of T1D. Preventive gal-1 therapy shifted the composition of the insulitis into an infiltrate that did not invade the islets and that contained a significantly reduced number of Th1 cells and a higher percentage of CD4+ T cells with content of IL-4, IL-5, or IL-10. The beneficial effects of gal-1 correlated with the ability of the lectin to trigger apoptosis of the T cell subsets that cause β-cell damage while sparing naive T cells, Th2 lymphocytes, and regulatory T cells in NOD mice. Importantly, gal-1 reversed β-cell autoimmunity and hyperglycemia in NOD mice with ongoing T1D. Because gal-1 therapy did not cause major side effects or β-cell toxicity in NOD mice, the use of gal-1 to control β-cell autoimmunity represents a novel alternative for treatment of subclinical or ongoing T1D.
The Social Engineering Personality Framework

We explore Information and Communication Technology (ICT) security in a socio-technical world and focus in particular on the susceptibility to social engineering attacks. We pursue the question if and how personality traits influence this susceptibility. We use Cialdini's principles of influence to categorise social engineering attacks. First we show with a comprehensive literature review how existent research approaches social engineering susceptibility. Based on this review we construct suggestions for plausible relations between personality traits of the Five-Factor Model (Big 5) and the principles of influence. We propose our - at this stage theory-based - "Social Engineering Personality Framework" (SEPF) which we will evaluate in future empiric research. The characteristics of victims' personality traits in the SEPF will support and guide security researchers and practitioners in developing detection, mitigation, and prevention strategies while dealing with human factors in social engineering attacks.
Morphology, activity area, and movement patterns of the frugivorous monitor lizard Varanus Bitatawa

The newly described Varanus bitatawa is a large, frugivorous, monitor lizard endemic to the northern Sierra Madre mountain range in Luzon, Philippines. This study presents the first description of its ecology from tracking and camera trapping. We captured five adult lizards weighing 1.0-5.1 kg with snout-vent lengths (SVL) from 40-66 cm and total lengths from 100-164 cm. Activity areas were non-overlapping with a mean of 12,400 m(2); males (23,300 m(2)) had larger activity areas than females (5,200 m(2)). Capture and camera trap records indicate that lizards move most frequently between 1000 and 1500. Movements were characterized by straight line distances between trees with a mean distance travelled between trees of 79 m. Mean daily distance covered was 176 m with larger distances covered by males (228 m vs 142 m for females).
Compliance through Informed Consent: Semantic Based Consent Permission and Data Management Model

The General Data Protection Regulations (GDPR) imposes greater restrictions on obtaining valid user consents involving the use of personal data. A semantic model of consent can make the concepts of consent explicit, estab-lish a common understanding and enable re-use of consent. Therefore, forming a semantic model of consent will satisfy the GDPR requirements of specificity and unambiguity and is an important step towards ensuring compliance. In this paper, we discuss obtaining an open vocabulary of expressing consent leveraging existing semantic models of provenance, processes, permission and obligations. We also present a reference architecture for the management of data processing according to consent permission. This data management model utilizes the open vocabulary of consent and incorporates the change of context into the data processing activity. By identifying and incorporating changes to the rela-tional context between data controllers and data subjects into the data processing model, it aims to improve the integration of data management across different information systems specifically adhering to the GDPR and helping controllers to demonstrate compliance.
Gene and Gene-Set Analysis for Genome-Wide Association Studies

Genome-wide association studies (GWAS) have identified hundreds of loci at very stringent levels of statistical significance across many different human traits. However, it is now clear that very large samples (n~10^4-10^5) are needed to find the majority of genetic variants underlying risk for most human diseases. Therefore, the field has engaged itself in a race to increase study sample sizes with some studies yielding very successful results but also studies which provide little or no new insights. This project started early on in this new wave of studies and I decided to use an alternative approach that uses prior biological knowledge to improve both interpretation and power of GWAS. The project aimed to a) implement and develop new gene-based methods to derive gene-level statistics to use GWAS in well established system biology tools; b) use of these gene-level statistics in networks and gene-set analyses of GWAS data; c) mine GWAS of neuropsychiatric disorders using gene, gene-sets and integrative biology analyses with gene-expression studies; and d) explore the ability of these methods to improve the analysis GWAS on disease sub-phenotypes which usually suffer of very small sample sizes.
Sigma factor mimicry involved in regulation of general stress response

Bacteria have evolved regulatory traits to rapidly adapt to changing conditions. Two principal regulatory mechanisms to modulate gene expression consist of regulation via alternative sigma factors and phosphorylation-dependent response regulators. PhyR represents a recently discovered protein family combining parts of both systems: a sigma factor-like domain of the extracytoplasmic function (ECF) subfamily linked to a receiver domain of a response regulator. Here we investigated the mode of action of this key regulator of general stress response in Methylobacterium extorquens. Our results indicate that PhyR does not act as a genuine sigma factor but instead controls gene expression indirectly through protein-protein interactions. This is evident from the analysis of additional proteins involved in PhyR-dependent gene regulation. We demonstrated that the ECF sigma factor-like domain of PhyR interacts with a protein, designated NepR, upon phosphorylation of the PhyR receiver domain. Using transcriptome analysis and phenotypic assays, we showed that NepR is a negative regulator of PhyR response. Furthermore, we provide biochemical and genetic evidence that NepR exerts this inhibitory effect through sequestration of the ECF sigma factor σEcfG1. Our data support an unprecedented model according to which PhyR acts as a mimicry protein triggering a partner-switching mechanism. Such a regulation of general stress response clearly differs from the two known models operating via σS and σB. Given the absence of these master regulators and the concomitant conservation of PhyR in Alphaproteobacteria, the novel mechanism presented here is most likely central to the control of general stress response in this large subclass of Proteobacteria.
Enhanced linear precoding in coordinated multicell broadcast systems

Communication quality in interference-limited cellular networks depends heavily on the coordination among base stations (BSs) for mitigating the interference. In this paper we present a novel linear precoding technique based on phase alignment in coordinated networks to provide spectrally efficient communications in cellular downlink systems employing M-ary phase-shift keying (M-PSK) modulation. We consider a wireless interference network consisting of K BS where each BS transmitting d independent data streams which can be shared among mobile units. We also assume zero-forcing coordination among all BSs. To evaluate the performance of the proposed network configuration, we compare it with interference alignment (IA). Simulation results show that for the fixed number of degrees of freedom per cell, the proposed scheme achieves much better sum rate as well as symbol error rate performance than zero-forcing IA (ZFIA) while requiring much less number of transmit and receive antennas.
Induction of conjugation by chemical agents in Paramecium.

Induction of conjugation by chemical agents was studied in nine species of Paramecium. KCl + acriflavine + Ca-poor conditions were effective in inducing conjugation in P. caudatum, P. multimicronucleatum, P. aurelia, P. jenningsi and probably in P. trichium. KCL + Ca-poor conditions were effective in P. caudatum, P. traunsteineri and probably in P. trichium. KCl + acriflavine + Ca-poor conditions were also effective in inducing interspecific conjugation. Interaction between complementary mating types is not involved in the chemical induction of conjugation, but otherwise chemically-induced conjugation is, in at least some pairs, essentially identical to normal conjugation induced by the interaction between complementary mating types. The mechanism of induction of conjugation and applications of chemical induction of conjugation to genetic studies are discussed.
Mitochondrial release of apoptosis-inducing factor occurs downstream of cytochrome c release in response to several proapoptotic stimuli

Mitochondrial outer membrane permeabilization by proapoptotic Bcl-2 family proteins, such as Bax, plays a crucial role in apoptosis induction. However, whether this only causes the intracytosolic release of inducers of caspase-dependent death, such as cytochrome c, or also of caspase-independent death, such as apoptosis-inducing factor (AIF) remains unknown. Here, we show that on isolated mitochondria, Bax causes the release of cytochrome c, but not of AIF, and the association of AIF with the mitochondrial inner membrane provides a simple explanation for its lack of release upon Bax-mediated outer membrane permeabilization. In cells overexpressing Bax or treated either with the Bax- or Bak-dependent proapoptotic drugs staurosporine or actinomycin D, or with hydrogen peroxide, caspase inhibitors did not affect the intracytosolic translocation of cytochrome c, but prevented that of AIF. These results provide a paradigm for mitochondria-dependent death pathways in which AIF cannot substitute for caspase executioners because its intracytosolic release occurs downstream of that of cytochrome c.
Maximum Norm a Posteriori Error Estimation For a Time-dependent Reaction-diffusion Problem

Abstract A semilinear second-order singularly perturbed parabolic equation in one space dimension is considered. For this equation, we give computable a posteriori error estimates in the maximum norm for a difference scheme that uses Backward-Euler in time and central differencing in space. Sharp L¹-norm bounds for the Green's function of the parabolic operator and its derivatives are derived that form the basis of the a posteriori error analysis. Numerical results are presented.