Miracle-dz/UniFAR-FTUs huggingface dataset:
Computational Methods for Predicting and Validating the Causes of Mendelian Disease

Computational methods for predicting and validating the causes of Mendelian disease Orion J. Buske Doctor of Philosophy Graduate Department of Computer Science University of Toronto 2016 We still do not know the genetic basis of roughly half of the estimated 7,000 Mendelian diseases. For some diseases, the responsible variants will not be discovered with standard genetic sequencing. If the variant falls outside of the exome, occurs in a repetitive region, or is a larger structural change, it is unlikely to be found by whole exome sequencing. For other diseases, the variant might be found, but the association with the disease has not yet been discovered. In these cases, making such a discovery requires several steps. Computational approaches are necessary to accurately prioritize harmful variants based on available knowledge. Then, additional information is needed to substantiate the association, such as functional tests, animal models, or identifying unrelated families with the same variant. This thesis presents several contributions to help researchers determine the genetic basis of unsolved Mendelian diseases: First, a method was developed that improves variant prioritization for a class of variants that are usually ignored by analysis pipelines: synonymous variants. After curating known examples from the literature, machine learning methods were trained to prioritize these variants based on a set of designed features. Second, finding additional families is a substantial hurdle in rare disease research. By collecting detailed phenotype information, computational methods can be used to find patients with a similar presentation. This leads to improved variant prioritization by combining sequencing data from several similar patients, without ever needing to explicitly define cohorts. The power of matchmaking methods grows exponentially with the size of the database, but simulations suggest that several hundred thousand cases are needed to identify the genetic basis of most Mendelian diseases. Finally, these matchmaking algorithms are implemented in a web portal, PhenomeCentral, which is used by several consortia and hundreds of clinicians and researchers. While this platform is a repository of several thousand undiagnosed cases, matchmaking between platforms is critical to achieve the numbers of cases predicted to be necessary. Towards this end, the Matchmaker Exchange (MME) was established and an API developed. Case profiles are exchanged within a secure federated network to reduce the time for researchers to validate genetic hypotheses.
Cognitive Dysfunction in Drug-induced Parkinsonism Caused by Prokinetics and Antiemetics

The use of prokinetics/antiemetics is one of the leading causes of drug-induced parkinsonism (DIP) observed in neurology clinics. Cognitive dysfunction in DIP has recently been recognized, but pathologies related with cognitive dysfunction is unknown. Among our retrospective cohort of 385 consecutive parkinsonian patients enrolled in our parkinsonism registry, 14 patients were identified who satisfied our inclusion criteria: parkinsonism caused by prokinetics/antiemetics, existing T1-weighted 3D volumetric MR images, and normal [18F]-N-3-fluoropropyl-2-β-carboxymethoxy-3-β-(4-iodophenyl) nortropane PET scan images. For the comparison of volumetric MR data, 30 age- and sex-matched healthy individuals were included in this study. Among 14 patients with DIP, 4 patients were diagnosed with dementia, and all other patients had mild cognitive impairment (MCI). Comparisons of MR volumetric data between DIP patients with MCI and controls show that cortical gray matter volumes are reduced bilaterally in DIP (P=0.041) without changes in either total white matter volume or total intracranial volume. Among subcortical structures, the volume of the right hippocampus is reduced in DIP patients compared with controls (P=0.011, uncorrected). In DIP, cortical thickness is reduced in the bilateral lingual (P=0.002), right fusiform (P=0.032) and part of the left lateral occipital gyri (P=0.007). Our results suggests that cognitive dysfunction in DIP caused by prokinetics/antiemetics is common. Structural changes in the brain by 3D MRI may be associated with cognitive decline in DIP. Graphical Abstract
ON EATING ANIMALS

Abstract This essay is a critical response to Loren Lomasky's essay in this volume: “Is It Wrong to Eat Animals? ” The essay argues that Lomasky both overestimates the value of eating meat and underestimates the harms to animals of practices surrounding meat eating. While Lomasky takes the fact that an animal would not have lived at all if it were not being raised for food to constitute a benefit for animals being so raised, this essay argues that it would be better for animals raised on factory farms to have never been born. It also contends that Lomasky overstates his case regarding the benefits of meat eating for human well-being. While gastronomic experiences can enrich our lives, it would be a mistake to think that meat eating is indispensable to the enrichment of our lives; one can experience the flourishing of eating well without eating animals.
The estimation of age-related rates of infection from case notifications and serological data

SUMMARY The paper describes a maximum-likelihood method for the estimation of age-related changes in the per capita rate of infection, from case notification records or serological data. The methods are applied to records of measles incidence in the UK and USA, for which the estimated rates of infection tend to rise to a maximum value at around 10 years of age and then to decline in the older age-classes. Longer-term and seasonal trends are analysed by reference to changes in the estimated average age at infection; a statistic derived from a knowledge of the age-specific rates of infection. Future data needs in the epidemiological study of directly transmitted viral and bacterial diseases are discussed with reference to the detection and interpretation of age-dependent rates of disease transmission.
Synchrony upon repetition : One or multiple neural mechanisms ?

Gotts, Chow and Martin provide a very nice review of repetition priming and suppression that reaches a compelling conclusion—we need to look more closely at synchronization in learning and priming. Indeed, current modeling work focuses on this issue—namely, the dynamic causal modeling of electrophysiological responses to address the role of synchrony in Bayesian explaining away. This commentary revisits the nature and relationships among the four theories in Gotts et al. and nuances some of their empirical predictions. In particular, I emphasize precision or uncertainty in predictive coding as a unifying consideration. I think that we are closer to understanding the computational anatomy of repetition and priming than might be thought. This optimism rests upon casting the theories reviewed in Gotts et al. as complementary perspectives on the same problem: Facilitation and sharpening are phenomena that are fully consistent with Bayesian explaining away, which is mediated by synchronization. In other words, explaining away is a theory about what the brain is doing and synchronization is a proposal about how the brain does it. In one sense, the Bayesian brain hypothesis is almost certainly correct—in the sense that our capacity for near-optimal perceptual inference means that we must be performing some form of approximate Bayesian (probabilistic) inference. The real question is how this approximate inference is implemented neuronally. At present, the most popular implementation is predictive coding that involves reciprocal message-passing between hierarchically deployed cortical areas (Mumford, 1992; Rao & Ballard, 1999). There is a vast amount of neurobiological evidence in support of this scheme, which can be derived—in a fairly straightforward way— from (approximate) Bayesian optimality principles (Friston, 2008). So, can predictive coding explain the phenomena of facilitation and sharpening; and does it admit a role for synchrony?
PCE implementation and testing by using virtual machines

In this paper, we describe the way to implement and test a PCE on the virtualized environment. The PCE is a special computational entity that will corporate with similar entities to compute the best possible path through single or multiple domains. Generally, in real network, the testing and implementation of network-related works are very difficult and complex but those works are much easier on the virtualized environment using virtual machines and networks. In this paper, we introduce the result of PCE implementation and test environment by using virtual machines and networks of VMware hypervisor, VMware ESX Server.
Supporting Real-Time Video in SCTP Networks

In this paper, we present adaptation strategies for realtime video streams over stream control transmission protocol (SCTP), where we switch among several versions of the coded video to match the available network bandwidth accurately, and meet client delay constraints. By monitoring the application buffer at the server, we estimate the current and future server buffer drain delay, and derive the transmission rate to minimize client buffer starvation. We also show that the adaptation accuracy can be significantly improved by a simple scaling to SCTP send-buffer size. The proposed mechanisms were evaluated through simulation and real Internet traces. Performance results show that the adaptation mechanism is responsive to bandwidth fluctuations, while ensuring that the client buffer does not underflow, and that the quality adaptation is smooth so that the impact on the perceptual quality at the client is minimal
Carbohydrate and LPG expression in Leishmania viannia subgenus.

Glycosylated molecules expressed on the cell surface of Leishmania promastigotes contribute to the outcome of contact between the parasite and its invertebrate and vertebrate hosts. The expression of several such molecules is growth phase dependent. Information on the expression of carbohydrates by Leishmania of the Viannia subgenus (braziliensis complex), a widespread cause of morbidity in the Americas, is fragmentary. We have examined the relationship between growth phase and the expression of glycosylated surface structures in WHO reference strains of 3 species of the Viannia subgenus, i.e., L. panamensis, L. guyanensis, and L. braziliensis. Agglutination with lectins and the monoclonal antibody specific for the repeat unit of L. donovani lipophosphoglycan, CA7AE, distinguished logarithmic and stationary-phase promastigotes of all 3 species. Flow cytometry revealed increased heterogeneity and disparity in the expression of the repeat unit epitope in stationary-as compared to logarithmic-phase promastigotes. Biochemical analyses showed the LPG repeat unit of all 3 species reference strains to be constituted by mannose and galactose with little or no substitution and, hence, to be similar to the LPG of L. donovani. Initial quantitative analyses of L. braziliensis LPG indicated a 10-fold lower quantity of LPG in this species than L. donovani and an increase in the size of LPG in the stationary phase. These findings provide bases for isolating and biologically characterizing phenotypically distinct populations of promastigotes and for identifying molecular determinants of the host parasite-relationship among Leishmania Viannia.
Suppression of arthritis-induced bone erosion by a CRAC channel antagonist

Objective We have shown in vitro and in vivo that osteoclast maturation requires calcium-release activated calcium (CRAC) channels. In inflammatory arthritis, osteoclasts mediate severe and debilitating bone erosion. In the current study, we assess the value of CRAC channels as a therapeutic target to suppress bone erosion in acute inflammatory arthritis. Methods Collagen-induced arthritis (CIA) was induced in mice. The CRAC channel inhibitor 3,4-dichloropropionaniline (DCPA) and a placebo was administered 1 day prior to collagen II booster to induce arthritis. Effects on swelling, inflammatory cell invasion in joints, serum cytokines and bone erosion were measured. Results Assays, by blinded observers, of arthritis severity showed that DCPA, 21 mg/kg/day, suppressed arthritis development over 3 weeks. Bone and cartilage damage in sections of animal feet was reduced approximately 50%; overall swelling of joints was reduced by a similar amount. Effects on bone density by µCT showed clear separation in DCPA-treated CIA animals from CIA without treatment, while differences between controls without CIA and CIA treated with DCPA differed by small amounts and in most cases were not statistically different. Response was not related to anticollagen titres. There were no adverse effects in the treated group on animal weight or activity, consistent with low toxicity. The effect was maximal 12–17 days after collagen booster, during the rapid appearance of arthritis in untreated CIA. At 20 days after treatment (day 40), differences in arthritis score were reduced and tumour necrosis factor α, interleukin (IL)-1, or IL-6 in the serum of the animals were similar in treated and untreated animals. Conclusions DCPA, a novel inhibitor of CRAC channels, suppresses bone erosion associated with acute arthritis in mice and might represent a new treatment modality for acute arthrits.
The influence of global self-heating on the Yarkovsky and YORP effects

In addition to collisions and gravitational forces, there is a growing amount of evidence that photon recoil forces from the asymmetric reflection and thermal re-radiation of absorbed sunlight are primary mechanisms that are fundamental to the physical and dynamical evolution of small asteroids. The Yarkovsky effect causes orbital drift, and the Yarkovsky–O’Keefe–Radzievskii–Paddack (YORP) effect causes changes in the rotation rate and pole orientation. We present an adaptation of the Advanced Thermophysical Model to simultaneously predict the Yarkovsky and YORP effects in the presence of global self-heating that occurs within the large concavities of irregularly shaped asteroids, which has been neglected or dismissed in all previous models. It is also combined with rough surface thermal-infrared beaming effects, which have been previously shown to enhance the Yarkovsky orbital drift and dampen on average the YORP rotational acceleration by orders of several tens of per cent. Tests on all published concave shape models of near-Earth asteroids, and also on 100 Gaussian random spheres, show that the Yarkovsky effect is sensitive to shadowing and global self-heating effects at the few per cent level or less. For simplicity, Yarkovsky models can neglect these effects if the level of accuracy desired is of this order. Unlike the Yarkovsky effect, the YORP effect can be very sensitive to shadowing and global self-heating effects. Its sensitivity increases with decreasing relative strength of the YORP rotational acceleration, and does not appear to depend greatly on the degree of asteroid concavity. Global self-heating tends to produce a vertical offset in an asteroid's YORP-rotational-acceleration versus obliquity curve which is in opposite direction to that produced by shadowing effects. It also ensures that at least one critical obliquity angle exists at which zero YORP rotational acceleration occurs. Global self-heating must be included for accurate predictions of the YORP effect if an asteroid exhibits a large shadowing effect. If global self-heating effects are not included, then it is found in ~75 per cent of cases that better predictions are produced when shadowing is also not included. Furthermore, global self-heating has implications for reducing the sensitivity of the YORP effect predictions to detailed variations in an asteroid's shape model.
Leading Public Service Organizations: How to obtain employees with high self-efficacy

Public management literature has often debated the usefulness of transactional leadership. Some scholars are concerned that transactional leadership strategies will harm public employees’ perceived competence (i.e. their self-efficacy), but in fact there are also arguments for the opposite result - that feelings of competence are strengthened by conditional rewards, because they provide feedback about performance. We study how 91 high school principals’ reported use of rewards and sanctions affect perceived professional competence among their 1,921 teachers. The results show that the use of rewards strengthens self-efficacy, and that the use of sanctions does not seem to have negative effects. Furthermore, the teachers’ self-efficacy can be linked positively to organizational performance. This suggests that rewards can be an important tool for managers in the public sector.
Stability and optimality of coalition formation game for resource allocation in device-to-device underlaying cellular networks

This paper considers the problem of joint channel allocation and power control in the uplink scenario of device-to-device communications underlaying cellular networks. The problem is formulated as a coalition formation game, then a merge-split algorithm for that game is investigated. We analyze the conditions for which an merge-split algorithm will always converge to the Dc-stable coalitional structure and optimal solution. Since those conditions are shown not to hold in most practical scenarios of users' position distribution, that idealized algorithm is not applicable. We propose a merge-split based algorithm that can be applied to practical systems. The analytical results are confirmed by the numerical simulations through multiple users' position scenarios. The simulation results also show that our approach achieves high individual and system performance compared with others.
How We See Our Culture: Photographic Self-Representations from the Cape Flats, South Africa

This article presents visual imaginations of culture on the periphery of Cape Town. Auto-photography was engaged to investigate popular understandings of culture and the processes, discourses and practices of negotiating culture in contemporary South Africa. Some township residents were provided with inexpensive cameras to represent visually what they see as their culture. This auto-photography was complemented with studies of visual culture in post-apartheid townships and with extended interviews with the research collaborators that explored life histories, everyday practices and their reflections on culture. A selection of the images was presented in an exhibition in a township cultural center.
Consequences of reduced intracellular coenzyme A content in Escherichia coli

Escherichia coli beta-alanine auxotrophs (panD2) were used to manipulate the specific cellular content of coenzyme A (CoA) and assess the associated physiological effects. Growth-limiting concentrations of CoA resulted in an increase in phospholipid/protein ratio in relA1 mutants, but not in their rel+ counterparts, indicating that protein biosynthesis was more severely affected by CoA deprivation than phospholipid biosynthesis. Acetyl-CoA was the dominant component (79.8%) of the CoA pool in cells exponentially growing in glucose-minimal medium, with significant concentrations of CoA (13.8%) and succinyl-CoA (5.9%) also detected. Malonyl-CoA was a minor species (0.5%), and the mixed disulfide of CoA and glutathione was not present. Acetyl-CoA was also the major constituent in cells depleted of CoA. On the other hand, succinyl-CoA was absent, suggesting that the protein synthesis defect may be due to the inability to generate sufficient quantities of precursors via the tricarboxylic acid cycle to support amino acid biosynthesis. Production of acyl carrier protein was controlled in part by the availability of CoA, and the lower concentration of acyl carrier protein in CoA-depleted cells was associated with a concomitant decrease in the saturated/unsaturated fatty acid ratio.
A comparative study of solvers in Amazons endgames

The game of Amazons is a fairly young member of the class of territory-games. The best Amazons programs play now at a high level, but can still be defeated by humans expert of the game. Our focus here is on the solving of endgames, with the goal of improving the general playing level of Amazons programs. Our comparative study of four solvers, DFPN, WPNS, Alpha/Beta and Monte-Carlo Tree-Search, shows that usual game-playing methods used for Amazons, namely Alpha-Beta and Monte-Carlo Tree-Search, are best suited for this task. This result also emphasizes the need of an evaluation function for the game of Amazons.
Analyse Economique des Pratiques Liées a l'Externalisation

Depuis maintenant plus d’une decennie sous l’influence de nouvelles modes manageriales, de l’intensification de la concurrence, de l’emergence de nouvelles techniques de coordination interentreprises (en partie assises sur les capacites des technologies de l’information et de la communication), de l’emergence de multiples prestataires specialises exploitants des « niches » dans tous les domaines des services aux entreprises, du renforcement du pouvoir d’actionnaires devenus plus « court-termistes », (etc.) les entreprises ont entrepris un vaste mouvement de recentrage sur leur « metier ». Il s’agit de simplifier la gestion des entreprises en en diminuant la taille et en limitant la diversite de leurs activites tout en beneficiant d’une division accrue du travail qui, selon les principes de l’analyse economique, permet d’augmenter la productivite.
ARMOUR: Large-scale experiments for IoT security & trust

The IoT is composed of a global network of heterogeneous devices that exchange information with each other. In this kind of scenarios, the number of smart objects is increasingly high, which enhances the possibility of attacks that compromise security, privacy and trust of the exchanged information. Thus, the need to provide duly tested, benchmarked and certified security and trust solutions for large-scale IoT arises in order to solve these risks. In this direction, this paper presents ARMOUR, a research project in which a methodology to experiment, validate and certify different technological solutions in large-scale conditions is defined. Additionally, a set of bootstrapping, group sharing and software programming experiments is proposed, on which different tests will be executed with the purpose to verify their security and trust in IoT scenarios.
Meta-analysis Reveals No Association of DNMT3B -149 C>T Gene Polymorphism With Overall Cancer Risk

Background: DNA methyltransferase-3B (DNMT3B) plays a key role in establishment and maintenance of genomic methylation patterns. Polymorphism in promoter region -149 C>T (C46359T) of DNMT3B gene may alter DNMT3B activity which leads to increased susceptibility to cancer. Inconsistent results regarding this have been reported in a number of studies. Objective: To carry out a meta-analysis of the studies reported to assess the precise relationship between the DNMT3B -149 C>T polymorphism and the overall cancer risk. Method: PubMed (MEDLINE) web database was searched for the studies concerning DNMT3B -149 C>T polymorphism and its association with cancer risk. The pooled odds ratios (ORs) along with 95% confidence intervals (95% CIs) were calculated for all the genetic models, from the selected case-control studies, by meta-analysis. Results: Overall eighteen studies containing 5583 cancer cases and 7618 controls were analyzed. No significant risk was observed overall for T allele carrier (T vs. C: p=0.303; OR=1.032, 95% CI=0.972-1.097), homozygous (TT vs. CC: p=0.336; OR=1.063, 95% CI=0.939–1.204), heterozygous (CT vs. CC: p=0.802; OR=1.022, 95% CI=0.860-1.216), dominant (TT vs. CC+CT: p=0.298; OR=1.101, 95% CI=0.919-1.319) and recessive (TT+CT vs. CC: p=0.656; OR=1.021, 95% CI=0.931-1.121) genetic models. Subgroup analysis of Asian and Caucasian populations also did not demonstrate any cancer risk in all the genetic models studied. Conclusion: Our meta-analysis proposes that the DNMT3B -149 C>T polymorphism may not be an independent predisposing factor for the risk of cancer. However, larger sample size and expression studies are required to confirm the observation.