Miracle-dz/UniFAR-FTUs huggingface dataset:
Consideration of plausible genetic architectures for schizophrenia and implications for analytic approaches in the era of next generation sequencing

The results of linkage and association studies imply that there are no common, dominantly active variants which have a substantial effect on the risk of schizophrenia. However, there are rare structural variants with a major effect and it is argued that results to date are not incompatible with the existence of large numbers of individually rare sequence variants with major effect, since these would not have been detected by the methods used to date. It is also argued that the epidemiology is consistent with a contribution from recessively acting variants and that likewise these might have gone undetected. It is shown that methods of analysis specifically designed to detect recessive variants through testing departure from Hardy–Weinberg equilibrium offer substantial increases of power over conventional methods. It is recommended that analytic approaches aim to detect very rare variants with major effect and that specific attempts are made to detect recessively acting loci.
Yeast telomere capping protein Stn1 overrides DNA replication control through the S phase checkpoint

Telomere integrity is maintained through end-protection proteins that block nuclease degradation and prevent telomeres from being recognized as DNA breaks. Although less well understood, end protection proteins may also play a role in facilitating telomere replication. Here, we show that overproduction (OP) of the yeast telomere capping protein Stn1 makes cells highly sensitive to the replication inhibitors hydroxyurea (HU) and methyl-methane sulfonate (MMS). Unexpectedly, this sensitivity corresponds with Stn1 OP blocking most, if not all, aspects of the S phase checkpoint. The checkpoint kinase Rad53 is phosphorylated with normal timing in Stn1 OP cells, indicating Stn1 does not interfere with signaling steps involved in activating the checkpoint. Part of the role of Stn1 in telomere integrity is mediated through the Pol12 subunit of DNA polymerase α (Polα). We show that overproduced Stn1 generally associates with chromosomes in HU treated and untreated cells, and, remarkably, Stn1 chromosome binding and OP checkpoint defects are rescued in pol12 mutants. We propose Stn1 normally promotes Polα activity at telomeres but can be recruited through Pol12 to nontelomeric sites when overproduced. During replication stress, the mislocalized Stn1 may inappropriately promote Polα in a manner that interferes with Rad53 effector mechanisms controlling replication fork integrity.
Recent Advances on the Role of Cytokines in Atherosclerosis

Atherosclerosis is a chronic inflammatory disease of the arterial wall driven by innate and adaptive immune responses. Inflammation controls the development and the destabilization of arterial plaque. Cells involved in the atherosclerotic process secrete and are activated by soluble factors, known as cytokines. Important recent advances in the comprehension of the mechanisms of atherosclerosis have provided evidence for a dual role of cytokines: proinflammatory and T helper-1-related cytokines promote the development and progression of the disease, whereas antiinflammatory and regulatory T cell–related cytokines exert clear antiatherogenic activities. This review focuses on recent advances regarding the role of cytokines, with the exception of chemokines, in the development, progression, and complications of atherosclerosis.
The MAPK Signaling Cascade is a Central Hub in the Regulation of Cell Cycle, Apoptosis and Cytoskeleton Remodeling by Tripeptidyl-Peptidase II

Tripeptidyl-peptidase II (TPPII) is a serine peptidase highly expressed in malignant Burkitt’s lymphoma cells (BL). We have previously shown that overexpression of TPPII correlates with chromosomal instability, centrosomal and mitotic spindle abnormalities and resistance to apoptosis induced by spindle poisons. Furthermore, TPPII knockdown by RNAi was associated with endoreplication and the accumulation of polynucleated cells that failed to complete cell division, indicating a role of TPPII in the cell cycle. Here we have applied a global approach of gene expression analysis to gain insights on the mechanism by which TPPII regulates this phenotype. mRNA profiling of control and TPPII knockdown BL cells identified one hundred and eighty five differentially expressed genes. Functional categorization of these genes highlighted major physiological functions such as apoptosis, cell cycle progression, cytoskeleton remodeling, proteolysis, and signal transduction. Pathways and protein interactome analysis revealed a significant enrichment in components of MAP kinases signaling. These findings suggest that TPPII influences a wide network of signaling pathways that are regulated by MAPKs and exerts thereby a pleiotropic effect on biological processes associated with cell survival, proliferation and genomic instability.
Maternal Infection with Trypanosoma cruzi and Congenital Chagas Disease Induce a Trend to a Type 1 Polarization of Infant Immune Responses to Vaccines

Background We previously showed that newborns congenitally infected with Trypanosoma cruzi (M+B+) display a strong type 1 parasite-specific T cell immune response, whereas uninfected newborns from T. cruzi-infected mothers (M+B−) are prone to produce higher levels of proinflammatory cytokines than control neonates (M−B−). The purpose of the present study was to determine if such fetal/neonatal immunological environments could alter the response to standard vaccines administered in early life. Methodology Infants (6–7 months old) living in Bolivia, an area highly endemic for T. cruzi infection, and having received Bacillus Calmette Guerin (BCG), hepatitis B virus (HBV), diphtheria and tetanus vaccines, were enrolled into the M+B+, M+B−, M−B− groups mentioned above. The production of IFN-γ and IL-13, as markers of Th1 and Th2 responses respectively, by peripherical blood mononuclear cells stimulated with tuberculin purified protein derivative of Mycobacterium tuberculosis (PPD) or the vaccinal antigens HBs, diphtheria toxoid (DT) or tetanus toxoid (TT), as well as circulating levels of IgG antibodies against HBsAg, DT and TT were analyzed in infants. Cellular responses to the superantigen SEB were also monitored in M+B+, M+B−, M−B−infants and newborns. Principal Findings M+B+ infants developed a stronger IFN-γ response to hepatitis B, diphtheria and tetanus vaccines than did M+B− and M−B− groups. They also displayed an enhanced antibody production to HBsAg. This was associated with a type 1-biased immune environment at birth, since cells of M+B+ newborns produced higher IFN-γ levels in response to SEB. M+B− infants produced more IFN-γ in response to PPD than the other groups. IL-13 production remained low and similar in all the three groups, whatever the subject's ages or vaccine status. Conclusion These results show that: i) both maternal infection with T. cruzi and congenital Chagas disease do not interfere with responses to BCG, hepatitis B, diphtheria and tetanus vaccines in the neonatal period, and ii) the overcoming of immunological immaturity by T. cruzi infection in early life is not limited to the development of parasite-specific immune responses, but also tends to favour type 1 immune responses to vaccinal antigens.
Periodontal mechanoreceptor input reduces synchronous discharge of voluntarily activated masseter motor units in man

The control exerted by inputs from periodontal mechanoreceptors (PMRs) on the tonic activity of 35 pairs of single motor units in the left masseter muscle was investigated with and without the presence of continuous pressure on the upper left central incisor tooth. Crosscorrelograms were computed to assess the temporal coupling between the discharges of the motor unit pairs. In the absence of continuous pressure, central peaks in the cross-correlograms revealed the presence of significant synchronous discharge in 16 out of the 35 pairs tested. In contrast, during PMR stimulation only nine pairs were found to discharge with a significant amount of synchronization. It is concluded that short-term synchronization due to common, partially common and synchronized inputs shared by the motoneurons was reduced whenever extraneous periodontal inputs were superimposed on the voluntary command. This indicates that the interneurons which mediate the periodontal inputs arising from one single tooth are not distributed widely throughout the masseter motoneuron pool. In contrast, it appears that periodontal inputs are liable to reduce the efficiency of common inputs distributed to the masseter motoneurons during voluntary contraction ("desynchronization").
A close examination of performance and power characteristics of 4G LTE networks

With the recent advent of 4G LTE networks, there has been increasing interest to better understand the performance and power characteristics, compared with 3G/WiFi networks. In this paper, we take one of the first steps in this direction. Using a publicly deployed tool we designed for Android called 4GTest attracting more than 3000 users within 2 months and extensive local experiments, we study the network performance of LTE networks and compare with other types of mobile networks. We observe LTE generally has significantly higher downlink and uplink throughput than 3G and even WiFi, with a median value of 13Mbps and 6Mbps, respectively. We develop the first empirically derived comprehensive power model of a commercial LTE network with less than 6% error rate and state transitions matching the specifications. Using a comprehensive data set consisting of 5-month traces of 20 smartphone users, we carefully investigate the energy usage in 3G, LTE, and WiFi networks and evaluate the impact of configuring LTE-related parameters. Despite several new power saving improvements, we find that LTE is as much as 23 times less power efficient compared with WiFi, and even less power efficient than 3G, based on the user traces and the long high power tail is found to be a key contributor. In addition, we perform case studies of several popular applications on Android in LTE and identify that the performance bottleneck for web-based applications lies less in the network, compared to our previous study in 3G [24]. Instead, the device's processing power, despite the significant improvement compared to our analysis two years ago, becomes more of a bottleneck.
Seasonal variation in suicides re‐examined: no sex difference in Hong Kong and Taiwan

The seasonal variation in suicides in Hong Kong and Taiwan during the period 1981 to 1993 was examined using harmonic analysis. A single cycle per year with lowest incidence in the winter months was found in both locations and for both sexes. Despite the regional differences in ascertainment procedures and preferred suicide methods, the absence of a biseasonal distribution of female suicides was consistently observed. This finding was contrary to that reported in many Western countries. A non‐shared psychosocial process underlying the cross‐cultural difference in the seasonality of female suicide is suggested.
Monte Carlo simulated corrections for beam commissioning measurements with circular and MLC shaped fields on the CyberKnife M6 System: a study including diode, microchamber, point scintillator, and synthetic microdiamond detectors

Monte Carlo simulation was used to calculate correction factors for output factor (OF), percentage depth-dose (PDD), and off-axis ratio (OAR) measurements with the CyberKnife M6 System. These include the first such data for the InCise MLC. Simulated detectors include diodes, air-filled microchambers, a synthetic microdiamond detector, and point scintillator. Individual perturbation factors were also evaluated. OF corrections show similar trends to previous studies. With a 5 mm fixed collimator the diode correction to convert a measured OF to the corresponding point dose ratio varies between −6.1% and −3.5% for the diode models evaluated, while in a 7.6 mm × 7.7 mm MLC field these are −4.5% to −1.8%. The corresponding microchamber corrections are +9.9% to +10.7% and +3.5% to +4.0%. The microdiamond corrections have a maximum of −1.4% for the 7.5 mm and 10 mm collimators. The scintillator corrections are <1% in all beams. Measured OF showed uncorrected inter-detector differences >15%, reducing to <3% after correction. PDD corrections at d > dmax were <2% for all detectors except IBA Razor where a maximum 4% correction was observed at 300 mm depth. OAR corrections were smaller inside the field than outside. At the beam edge microchamber OAR corrections were up to 15%, mainly caused by density perturbations, which blurs the measured penumbra. With larger beams and depths, PTW and IBA diode corrections outside the beam were up to 20% while the Edge detector needed smaller corrections although these did vary with orientation. These effects are most noticeable for large field size and depth, where they are dominated by fluence and stopping power perturbations. The microdiamond OAR corrections were <3% outside the beam. This paper provides OF corrections that can be used for commissioning new CyberKnife M6 Systems and retrospectively checking estimated corrections used previously. We recommend the PDD and OAR corrections are used to guide detector selection and inform the evaluation of results rather than to explicitly correct measurements.
Analysis of the electrical excitation of CNS neurons

The artificial excitation process of neurons of the central nervous system depends on the applied extracellular field, on the geometry of the neuron and on the electrical properties of the neural subunits. Results of computer simulations are based on a compartment model of the neuron and its equivalent electrical network. Furthermore, a theory is presented which generalizes the activating function concept known from peripheral nerve stimulation. The theory predicts the influence of electrical and geometrical parameters on the excitation threshold. Generally, the myelinated axon is the part of a neuron which is most excitable to a given applied field. An example demonstrates that for a target neuron the quotient (anodic threshold current)/(cathodic threshold current) essentially depends on the position and orientation of the neuron relative to the electrode.
Targeting Dendritic Cell Function during Systemic Autoimmunity to Restore Tolerance

Systemic autoimmune diseases can damage nearly every tissue or cell type of the body. Although a great deal of progress has been made in understanding the pathogenesis of autoimmune diseases, current therapies have not been improved, remain unspecific and are associated with significant side effects. Because dendritic cells (DCs) play a major role in promoting immune tolerance against self-antigens (self-Ags), current efforts are focusing at generating new therapies based on the transfer of tolerogenic DCs (tolDCs) during autoimmunity. However, the feasibility of this approach during systemic autoimmunity has yet to be evaluated. TolDCs may ameliorate autoimmunity mainly by restoring T cell tolerance and, thus, indirectly modulating autoantibody development. In vitro induction of tolDCs loaded with immunodominant self-Ags and subsequent cell transfer to patients would be a specific new therapy that will avoid systemic immunosuppression. Herein, we review recent approaches evaluating the potential of tolDCs for the treatment of systemic autoimmune disorders.
Replication restart in UV‐irradiated Escherichia coli involving pols II, III, V, PriA, RecA and RecFOR proteins

In Escherichia coli, UV‐irradiated cells resume DNA synthesis after a transient inhibition by a process called replication restart. To elucidate the role of several key proteins involved in this process, we have analysed the time dependence of replication restart in strains carrying a combination of mutations in lexA, recA, polB (pol II), umuDC (pol V), priA, dnaC, recF, recO or recR. We find that both pol II and the origin‐independent primosome‐assembling function of PriA are essential for the immediate recovery of DNA synthesis after UV irradiation. In their absence, translesion replication or ‘replication readthrough’ occurs ≈ 50 min after UV and is pol V‐dependent. In a wild‐type, lexA+ background, mutations in recF, recO or recR block both pathways. Similar results were obtained with a lexA(Def) recF strain. However, lexA(Def) recO or lexA(Def) recR strains, although unable to facilitate PriA‐pol II‐dependent restart, were able to perform pol V‐dependent readthrough. The defects in restart attributed to mutations in recF, recO or recR were suppressed in a recA730 lexA(Def) strain expressing constitutively activated RecA (RecA*). Our data suggest that in a wild‐type background, RecF, O and R are important for the induction of the SOS response and the formation of RecA*‐dependent recombination intermediates necessary for PriA/Pol II‐dependent replication restart. In con‐trast, only RecF is required for the activation of RecA that leads to the formation of pol V (UmuD′2C) and facilitates replication readthrough.
A capability-based access control architecture for multi-domain publish/subscribe systems

Publish/subscribe has emerged as an attractive communication paradigm for building Internet-wide distributed systems by decoupling message senders from receivers. So far most of the research on publish/subscribe has focused on efficient event routing, event filtering, and composite event detection. Very little research has been published regarding securing publish/subscribe systems. In this paper, we present a capability-based access control architecture that enables multiple domains to co-operate in order to build a shared, wide-scale publish/subscribe system. Our architecture employs SPKI authorisation certificates for delegating access control responsibilities to access control services within independent domains in order to balance security and scalability. The architecture supports controlling access both for new event brokers joining the broker network as well as for clients accessing the publish/subscribe API
Activity-dependent coordination of presynaptic release probability and postsynaptic GluR2 abundance at single synapses

The strength of an excitatory synapse depends on both the presynaptic release probability (pr) and the abundance of functional postsynaptic AMPA receptors. How these parameters are related or balanced at a single synapse remains unknown. By taking advantage of live fluorescence imaging in cultured hippocampal neurons where individual synapses are readily resolved, we estimate pr by labeling presynaptic vesicles with a styryl dye, FM1-43, while concurrently measuring postsynaptic AMPA receptor abundance at the same synapse by immunolabeling surface GluR2. We find no appreciable correlation between pr and the level of surface synaptic GluR2 under basal condition, and blocking basal neural activity has no effect on the observed lack of correlation. However, elevating network activity drives their correlation, which accompanies a decrease in mean GluR2 level. These findings provide the direct evidence that the coordination of pre- and postsynaptic parameters of synaptic strength is not intrinsically fixed but that the balance is tuned by synaptic use at individual synapses.
Overview of Venous Thrombosis in Inflammatory Bowel Disease

Abstract:Thrombosis in inflammatory bowel disease (IBD) is an increasingly noted extraintestinal manifestation with high morbidity and mortality. While controlling the activity of the disease with the appropriate therapy, thromboembolism prophylaxis should be applied to all patients. All common risk factors for thromboembolism are also valid for patients with IBD; however, it is clear that uncontrolled disease and hospitalization are major disease-specific risk factors for venous thromboembolism in patients with IBD. Pharmacological thromboprophylaxis with currently available anticoagulants does not increase the risk of further bleeding in patients with IBD with mild-to-moderate bleeding. In severe bleeding or with increased risk of further bleeding due to other comorbid conditions, thromboprophylaxy with mechanical methods should be the treatment option. Whether thrombosis is the cause or the result of intestinal inflammation remains to be elucidated, and other issues in the etiology, such as the role of intestinal flora in thrombosis pathogenesis, will be the subject of future studies.
A linear iteration time layout algorithm for visualising high-dimensional data

A technique is presented for the layout of high dimensional data in a low dimensional space. This technique builds upon the force based methods that have been used previously to make visualisations of various types of data such as bibliographies and sets of software modules. The canonical force based model, related to solutions of the N body problem, has a computational complexity of O(N/sup 2/) per iteration. The paper presents a stochastically based algorithm of linear complexity per iteration which produces good layouts, has low overhead, and is easy to implement. Its performance and accuracy are discussed, in particular with regard to the data to which it is applied. Experience with application to bibliographic and time series data, which may have a dimensionality in the tens of thousands, is described.
The role of climate variability and riverine pulsing in the community dynamics of estuarine nekton in Breton Sound, Louisiana

xv CHAPTER 1. GENERAL INTRODUCTION . 1 BACKGROUND . 1 RESEARCH OBJECTIVE . 5 STUDY AREA . 6 SYNOPSIS OF CHAPTERS . 6 LITERATURE CITED.8 CHAPTER 2. RELATING LARGE-SCALE CLIMATE VARIABILITY TO LOCAL SPECIES ABUNDANCE: ENSO FORCING AND BROWN SHRIMP (FARFANTEPENAEUS AZTECUS) IN BRETON SOUND, LOUISIANA, USA. 1
Differences in symptoms, first medical contact and pre-hospital delay times between patients with ST- and non-ST-elevation myocardial infarction

Aim: In ST-elevation myocardial infarction, time to reperfusion is crucial for the prognosis. Symptom presentation in myocardial infarction influences pre-hospital delay times but studies about differences in symptoms between patients with ST-elevation myocardial infarction and non-ST-elevation myocardial infarction are sparse and inconclusive. The aim was to compare symptoms, first medical contact and pre-hospital delay times in patients with ST-elevation myocardial infarction and non-ST-elevation myocardial infarction. Methods and results: This multicentre, observational study included 694 myocardial infarction patients from five hospitals. The patients filled in a questionnaire about their pre-hospital experiences within 24 h of hospital admittance. Chest pain was the most common symptom in ST-elevation myocardial infarction and non-ST-elevation myocardial infarction (88.7 vs 87.0%, p=0.56). Patients with cold sweat (odds ratio 3.61, 95% confidence interval 2.29–5.70), jaw pain (odds ratio 2.41, 95% confidence interval 1.04–5.58), and nausea (odds ratio 1.70, 95% confidence interval 1.01–2.87) were more likely to present with ST-elevation myocardial infarction, whereas the opposite was true for symptoms that come and go (odds ratio 0.58, 95% confidence interval 0.38-0.90) or anxiety (odds ratio 0.52, 95% confidence interval 0.29–0.92). Use of emergency medical services was higher among patients admitted with ST-elevation myocardial infarction. The pre-hospital delay time from symptom onset to first medical contact was significantly longer in non-ST-elevation myocardial infarction (2:05 h vs 1:10 h, p=0.001). Conclusion: Patients with ST-elevation myocardial infarction differed from those with non-ST-elevation myocardial infarction regarding symptom presentation, ambulance utilisation and pre-hospital delay times. This knowledge is important to be aware of for all healthcare personnel and the general public especially in order to recognise symptoms suggestive of ST-elevation myocardial infarction and when to decide if there is a need for an ambulance.