Miracle-dz/UniFAR-FTUs huggingface dataset:
Synaptic remodelling and elimination as integral processes of synaptogenesis.

It has become increasingly clear that the development and maintenance of synaptic connectivity patterns in the central and peripheral nervous system are not only based on the formation of synapses but include the selective elimination of synaptic subpopulations. Synaptic remodeling and elimination apparently also play a key role in the specification of neuronal connections during ontogenesis of the neocortex in various species. At least three types of synapse elimination have been demonstrated until now, i.e. physiological cell death of synaptically connected neurons, synaptic disconnection and lysosomal degradation, predominantly of presynaptic elements. Occurrence of different elimination types appears to depend on (1) whether the presynaptic or postsynaptic element induces the synaptic reorganization and (2) whether or not the neuron inducing the synapse elimination survives. The same type of synapse elimination may be seen during normal development and under pathological conditions. Factors inducing mental retardation may then either retard synapse formation or interfere with the process of synapse removal. In order to undergo plastic changes in synaptic connections, neurons may respond to exogenous factors such as lack of trophic factors or sensitivity for them (e.g. NGF), long-lasting changes in neuronal activity (e.g. due to drug application or sensory deprivation), hormonal influences (e.g. thyroxin or sexual hormones), learning conditions, or lesions (partial deafferentation and axotomy). The neurons, in turn, may change their responsiveness to exogenous stimuli by inducing synaptic reorganisation.
Nonbiased Molecular Screening Identifies Novel Molecular Regulators of Fibrogenic and Proliferative Signaling in Myxomatous Mitral Valve Disease

Background—Pathological processes underlying myxomatous mitral valve degeneration (MMVD) remain poorly understood. We sought to identify novel mechanisms contributing to the development of this condition. Methods and Results—Microarrays were used to measure gene expression in 11 myxomatous and 11 nonmyxomatous human mitral valves. Differential gene expression (thresholds P<0.05; fold-change >1.5) and pathway activation (Ingenuity) were confirmed using quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Contributions of bone morphogenetic protein 4 and transforming growth factor (TGF)-&bgr;2 to differential gene expression were evaluated in vitro. Contributions of angiotensin II to differential pathway activation were examined in mice in vivo. A total of 2602 genes were differentially expressed between myxomatous and nonmyxomatous valves. Canonical TGF-&bgr; signaling was increased in MMVD because of increased ligand expression and derepression of SMA mothers against decapentaplegic 2/3 signaling and was confirmed with quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Myxomatous valves demonstrated activation of canonical bone morphogenetic protein and Wnt/&bgr;-catenin signaling and upregulation of their common target runt-related transcription factor 2. Our data set provided transcriptional and immunohistochemical evidence for activated immune cell infiltration. In vitro treatment of mitral valve interstitial cells with TGF-&bgr;2 increased &bgr;-catenin signaling at mRNA and protein levels, suggesting interactions between TGF-&bgr;2 and Wnt signaling. In vivo infusion of mice with angiotensin II recaptured several changes in signaling pathways characteristic of human MMVD. Conclusions—These data support a new disease framework whereby activation of TGF-&bgr;2, bone morphogenetic protein 4, Wnt/&bgr;-catenin, or immune signaling plays major roles in the pathogenesis of MMVD. We propose these pathways act in a context-dependent manner to drive phenotypic changes that fundamentally differ from those observed in aortic valve disease and open novel avenues guiding future research into the pathogenesis of MMVD.
Whole exome sequencing identifies a KCNJ12 mutation as a cause of familial dilated cardiomyopathy

Abstract Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation, and is associated with systolic dysfunction and increased action potential duration. Approximately 50% of DCM cases are caused by inherited gene mutations with genetic and phenotypic heterogeneity. Next generation sequencing may be useful in screening unknown mutations in such cases. A family was identified with DCM, in which the affected family members developed heart failure, arrhythmia, and sudden death. Probands and 4 affected family members underwent whole exome sequencing (WES), bioinformatics methods, and gene annotation to identify potentially causative variants. The Sanger sequencing method was used to verify the candidate mutation. WES yielded 2,238,831 variations. KCNJ12 (p.Glu334del) was identified as a candidate mutation, and the heterozygous mutation was verified by Sanger sequencing. Our study emphasizes the application of WES in identifying causative mutations in DCM. This report is the first to describe the KCNJ12 gene as a cause of DCM in patients.
Oxidative damage to DNA related to survivorship and carotenoid-based sexual ornamentation in the common yellowthroat

Carotenoid-based sexual ornaments are hypothesized to be reliable signals of male quality, based on an allocation trade-off between the use of carotenoids as pigments and their use in antioxidant defence against reactive oxygen species. Carotenoids appear to be poor antioxidants in vivo, however, and it is not clear whether variation in ornament expression is correlated with measures of oxidative stress (OXS) under natural conditions. We used single-cell gel electrophoresis to assay oxidative damage to erythrocyte DNA in the common yellowthroat (Geothlypis trichas), a sexually dichromatic warbler in which sexual selection favours components of the males' yellow ‘bib’. We found that the level of DNA damage sustained by males predicted their overwinter survivorship and was reflected in the quality of their plumage. Males with brighter yellow bibs showed lower levels of DNA damage, both during the year the plumage was sampled (such that yellow brightness signalled current OXS) and during the previous year (such that yellow brightness signalled past OXS). We suggest that carotenoid-based ornaments can convey information about OXS to prospective mates and that further work exploring the proximate mechanism(s) linking OXS to coloration is warranted.
Observation of coronal loop torsional oscillation

We suggest that the global torsional oscillation of solar coronal loop may be observed by the periodical variation of a spectral line width. The amplitude of the variation must be maximal at the velocity antinodes and minimal at the nodes of the torsional oscillation. Then the spectroscopic observation as a time series at different heights above the active region at the solar limb may allow to determine the period and wavelength of global torsional oscillation and consequently the Alfven speed in corona. From the analysis of early observation (Egan & Schneeberger [CITE]) we suggest the value of coronal Alfven speed as ~500 km s -1 .
ExPERT: Pareto-Efficient Task Replication on Grids and a Cloud

Many scientists perform extensive computations by executing large bags of similar tasks (BoTs) in mixtures of computational environments, such as grids and clouds. Although the reliability and cost may vary considerably across these environments, no tool exists to assist scientists in the selection of environments that can both fulfill deadlines and fit budgets. To address this situation, we introduce the Expert BoT scheduling framework. Our framework systematically selects from a large search space the Pareto-efficient scheduling strategies, that is, the strategies that deliver the best results for both make span and cost. Expert chooses from them the best strategy according to a general, user-specified utility function. Through simulations and experiments in real production environments, we demonstrate that Expert can substantially reduce both make span and cost in comparison to common scheduling strategies. For bioinformatics BoTs executed in a real mixed grid + cloud environment, we show how the scheduling strategy selected by Expert reduces both make span and cost by 30%-70%, in comparison to commonly-used scheduling strategies.
Estrogen-Induced Developmental Disorders of the Rat Penis Involve Both Estrogen Receptor (ESR)- and Androgen Receptor (AR)-Mediated Pathways1

This study tested the hypothesis that the estrogen receptor (ESR) pathway, androgen receptor (AR) pathway, or both mediate estrogen-induced developmental penile disorders. Rat pups received diethylstilbestrol (DES), with or without the ESR antagonist ICI 182,780 (ICI) or the AR agonist dihydrotestosterone (DHT) or testosterone (T), from Postnatal Days 1 to 6. Testicular T concentration, penile morphology and morphometry, and/or fertility was determined at age 7, 28, or 150 days. DES treatment alone caused 90% reduction in the neonatal intratesticular T surge; this reduction was prevented by ICI coadministration, but not by DHT or T coadministration. Unlike the T surge, coadministration of ICI and coadministration of DHT or T mitigated penile deformities and loss of fertility. Generally, ICI, DHT, or T treatment alone did not alter penile morphology; however, fertility was 20% that of controls in ICI-treated rats vs. 70%–90% in DHT- or T-treated rats. The lower fertility in the rats treated with ICI alone could be due to altered sexual behavior, as these males did not deposit vaginal plugs. In conclusion, observations that both an ESR antagonist and AR agonists prevent penile deformities and infertility suggest that both pathways are involved in estrogen-induced penile disorders. Observations that coadministration of ICI, but not DHT or T, prevents the DES-induced reduction in the neonatal T surge suggest that, although ICI exerts its mitigating effect both at the level of Leydig cells and penile stromal cells, DHT and T do so only at the level of stromal cells.
On Combining Quota-Share and Excess of Loss

Abstract This paper considers reinsurance retention limits in cases where the cedent has a choice between a pure quota-share treaty, a pure excess of loss treaty or a combination of the two. Our primary aim is to find the combination of retention limits which minimizes the skewness coefficient of the insurer's retained risk subject to constraints on the variance and the expected value of his retained risk. The results are given without specifying precisely how the excess of loss reinsurance premium is calculated. It is also shown that, depending to some extent on the constraint on the variance, the solution to the problem is a pure excess of loss treaty if the excess of loss premium is calculated using the expected value or standard deviation principle but that this need not be true if the variance principle is used.
Multi-scale Feature Spaces for Shape Processing and Analysis

In digital geometry processing and shape modeling, the Laplace-Beltrami and the heat diffusion operator, together with the corresponding Laplacian eigenmaps, harmonic and geometry-aware functions, have been used in several applications, which range from surface parameterization, deformation, and compression to segmentation, clustering, and comparison. Using the linear FEM approximation of the Laplace-Beltrami operator, we derive a discrete heat kernel that is linear, stable to an irregular sampling density of the input surface, and scale covariant. With respect to previous work, this last property makes the kernel particularly suitable for shape analysis and comparison; in fact, local and global changes of the surface correspond to a re-scaling of the time parameter without affecting its spectral component. Finally, we study the scale spaces that are induced by the proposed heat kernel and exploited to provide a multi-scale approximation of scalar functions defined on 3D shapes.
Anaplasmataceae agents among wild mammals and ectoparasites in Brazil

SUMMARY Anaplasmataceae agents comprise obligate intracellular bacteria that can cause disease in humans and animals. Between August 2013 and March 2015, 31 Nasua nasua (coati), 78 Cerdocyon thous (crab-eating fox), seven Leopardus pardalis (ocelot), 110 wild rodents, 30 marsupials, and 42 dogs were sampled in the Pantanal wetland, Brazil. In addition, ectoparasites found parasitizing the animals were collected and identified. The present work aimed to investigate the occurrence of Anaplasmataceae agents in wild mammals, domestic dogs and ectoparasites, by molecular and serological techniques. Overall, 14 (17·9%) C. thous, seven (16·6%) dogs and one (3·2%) N. nasua were seroreactive to Ehrlichia canis. Nine dogs, two C. thous, one N. nasua, eight wild rodents, five marsupials, eight Amblyomma sculptum, four Amblyomma parvum, 13 A. sculptum nymphal pools, two Amblyomma larvae pools and one Polygenis (Polygenis) bohlsi bohlsi flea pool were positive for Ehrlichia spp. closely related to E. canis. Seven N. nasua, two dogs, one C. thous, one L. pardalis, four wild rodents, three marsupials, 15 A. sculptum, two Amblyomma ovale, two A. parvum and one Amblyomma spp. larval pools were positive for Anaplasma spp. closely related to A. phagocytophilum or A. bovis. The present study provided evidence that wild animals from Brazilian Pantanal are exposed to Anaplasmataceae agents.
Intonational Prominence of "SHI...(DE)" Construction in Standard Chinese

The present study mainly deals with the phonetic realization of the intonational prominence in the shi. (de) construction in standard Chinese. Results of acoustic and perceptual experiments demonstrate that the prominence placement bears corresponding relationship with the focused constituents marked by shi. (de) structure, specifically, the appearance of intonational prominence is symbolized by the focus marker shi. The phonetic realization of the intonational prominence lies in the expansion of the pitch range of the focus-bearing constituent and the compression of the pitch registers of the successive syllables.
On-line multi-modal speaker diarization

This paper presents a novel framework that utilizes multi-modal information to achieve speaker diarization. We use dynamic Bayesian networks to achieve on-line results. We progress from a simple observation model to a complex multi-modal one as more data becomes available. We present an efficient way to guide the learning procedure of the complex model using the early results achieved with the simple model. We present the results achieved in various real-world situations, including videos coming from webcameras, human computer interaction and video conferences.
Hierarchical mechanics of functional amyloid protein based materials

Amyloid and amyloid-like proteins are a broad class of misfolded protein structures known for their their roles in a variety of neurodegenerative diseases, but also for their impressive mechanical properties and their propensity to self-assemble at diverse length scales. These properties make amyloid and amyloid-like proteins excellent candidate materials for the design of engineered functional biomaterials. However, many of the fundamental structure-property relationships which could guide the design of amyloid-based functional materials for various applications are not well understood. In this thesis, a multiscale modeling and simulation approach is used to investigate these structure-property relationships at multiple length scales. Full atomistic simulations are used to study the tensile and bending response of single fibrils, as well as the inter-fibril interaction strength. It is found that in tension, the specific geometry of the fibrils does not significantly influence the deformation behavior, but the mechanical properties, most notably the tensile strength, depends strongly on the areal density of hydrogen bonds in the fibril cross-section. The mechanical response at the molecular scale is used to guide the development of a coarse-grained description of amyloid and amyloid-like fibrils. Next, the adhesive behavior of amorphous polymers is studied to identify design principles which enhance adhesive performance and could be applied to aid in the design of amyloid-based adhesives, an exciting potential functional role for amyloid-based biomaterials. Finally, mesoscale structures are investigated including a nanowire-like geometry and adhesive films. These studies demonstrate that the mechanics of larger scale amyloid based structures are largely determined by the inter-fibril interactions; the specific intra-fibril properties become less significant at larger scales. The results presented in this thesis form the foundation for the development of basic materials selection criteria to aid in the design of functional amyloid-based biomaterials for diverse applications. Thesis Supervisor: Markus J. Buehler Title: Professor of Civil and Environmental Engineering
Characterization of Non-Trivial Neighborhood Fold Constraints from Protein Sequences using Generalized Topohydrophobicity

Prediction of key features of protein structures, such as secondary structure, solvent accessibility and number of contacts between residues, provides useful structural constraints for comparative modeling, fold recognition, ab-initio fold prediction and detection of remote relationships. In this study, we aim at characterizing the number of non-trivial close neighbors, or long-range contacts of a residue, as a function of its “topohydrophobic” index deduced from multiple sequence alignments and of the secondary structure in which it is embedded. The “topohydrophobic” index is calculated using a two-class distribution of amino acids, based on their mean atom depths. From a large set of structural alignments processed from the FSSP database, we selected 1485 structural sub-families including at least 8 members, with accurate alignments and limited redundancy. We show that residues within helices, even when deeply buried, have few non-trivial neighbors (0–2), whereas β-strand residues clearly exhibit a multimodal behavior, dominated by the local geometry of the tetrahedron (3 non-trivial close neighbors associated with one tetrahedron; 6 with two tetrahedra). This observed behavior allows the distinction, from sequence profiles, between edge and central β-strands within β-sheets. Useful topological constraints on the immediate neighborhood of an amino acid, but also on its correlated solvent accessibility, can thus be derived using this approach, from the simple knowledge of multiple sequence alignments.
Taurine and Osmoregulation. IV. Cerebral Taurine Transport Is Increased in Rats with Hypernatremic Dehydration

ABSTRACT: Taurine is an organic osmolyte in brain cells. We studied whether cerebral taurine transport is enhanced as part of the cell volume regulatory adaptation to hypernatremia. Hypernatremic dehydration was induced for 48 h. Synaptosomes, metabolically active nerve terminal vesicles, were isolated by homogenization of brain and purification on a discontinuous Ficoll gradient. Taurine transport was evaluated in vitro using a rapid filtration assay. After 48 h of hypernatremia, there was a 22.4% increment in Na+-specific taurine transport from 2.99 ± 0.16 to 3.66 ± 0.13 μmol/mg protein/30 min (p < 0.001). Dehydration for 48 h without hypertonic saline loading had no effect on taurine uptake. Glycine transport was unaltered by hypernatremia. The adaptation in taurine uptake resulted from an enhanced Vmax of the high affinity-low capacity transport system [265 ±17, control versus 337 ±19 nmol/min/ mg protein, experimental (p < 0.03)] without a change in the Km (≈60 μM). Under both control and hypernatremic conditions, Na+ and Cl− were required for maximal total Na+-mediated taurine uptake. Oubain (1 mM) decreased taurine uptake by 25%, whereas addition of β-alanine or hypotaurine (500 μM) to the external media reduced taurine transport by 45–65% in both control and experimental conditions (p < 0.01). Synaptosomal taurine uptake in hypernatremic rats was inhibited by 15–20% (p < 0.01) after addition of 4-acetamido-4′-isothiocyanostilbene-2,2′-disulfonic acid (0.1 mM) or 4,4′-diisothiocyanostiIbene-2,2′-disulfonic acid (0.1 mM) to the external medium. We conclude that hypernatremic dehydration of moderate severity and duration results in stimulation of brain taurine uptake, mediated by increased activity of the β-amino acid carrier. An intact anionic binding site is required for maximal taurine uptake during hypernatremia.
Site-directed Mutagenesis of CC Chemokine Receptor 1 Reveals the Mechanism of Action of UCB 35625, a Small Molecule Chemokine Receptor Antagonist*

The chemokine receptor CCR1 and its principal ligand, CCL3/MIP-1α, have been implicated in the pathology of several inflammatory diseases including rheumatoid arthritis, multiple sclerosis, and asthma. As such, these molecules are the focus of much research with the ultimate aim of developing novel therapies. We have described previously a non-competitive small molecule antagonist of CCR1 (UCB 35625), which we hypothesized interacted with amino acids located within the receptor transmembrane (TM) helices (Sabroe, I., Peck, M. J., Jan Van Keulen, B., Jorritsma, A., Simmons, G., Clapham, P. R., Williams, T. J., and Pease, J. E. (2000) J. Biol. Chem. 275, 25985-25992). Here we describe an approach to identifying the mechanism by which the molecule antagonizes CCR1. Thirty-three point mutants of CCR1 were expressed transiently in L1.2 cells, and the cells were assessed for their capacity to migrate in response to CCL3 in the presence or absence of UCB 35625. Cells expressing the mutant constructs Y41A (TM helix 1, or TM1), Y113A (TM3), and E287A (TM7) were responsive to CCL3 but resistant to the antagonist, consistent with a role for the TM helices in CCR1 interactions with UCB 35625. Subsequent molecular modeling successfully docked the compound with CCR1 and suggests that the antagonist ligates TM1, 2, and 7 of CCR1 and severely impedes access to TM2 and TM3, a region thought to be perturbed by the chemokine amino terminus during the process of receptor activation. Insights into the mechanism of action of these compounds may facilitate the development of more potent antagonists that show promise as future therapeutic agents in the treatment of inflammatory disease.
Fetal overgrowth in the Cdkn1c mouse model of Beckwith-Wiedemann syndrome

SUMMARY Mutations in the imprinted CDKN1C gene are associated with the childhood developmental disorder Beckwith-Wiedemann syndrome (BWS). Multiple mouse models with deficiency of Cdkn1c recapitulate some aspects of BWS but do not exhibit overgrowth of the newborn, a cardinal feature of patients with BWS. In this study, we found that Cdkn1c mutants attained a 20% increase in weight during gestation but experienced a rapid reversal of this positive growth trajectory very late in gestation. We observed a marked effect on placental development concurrently with this loss of growth potential, with the appearance of large thrombotic lesions in the labyrinth zone. The trilaminar trophoblast layer that separates the maternal blood sinusoids from fetal capillaries was disordered with a loss of sinusoidal giant cells, suggesting a role for Cdkn1c in maintaining the integrity of the maternal-fetal interface. Furthermore, the overgrowth of mutant pups decreased in the face of increasing intrauterine competition, identifying a role for Cdkn1c in the allocation of the maternal resources via the placenta. This work explains one difficulty in precisely replicating BWS in this animal model: the differences in reproductive strategies between the multiparous mouse, in which intrauterine competition is high, and humans, in which singleton pregnancies are more common.