Miracle-dz/UniFAR-FTUs huggingface dataset:
Pre-equilibrium competitive library screening for tuning inhibitor association rate and specificity toward serine proteases.

High structural and sequence similarity within protein families can pose significant challenges to the development of selective inhibitors, especially toward proteolytic enzymes. Such enzymes usually belong to large families of closely similar proteases and may also hydrolyze, with different rates, protein- or peptide-based inhibitors. To address this challenge, we employed a combinatorial yeast surface display library approach complemented with a novel pre-equilibrium, competitive screening strategy for facile assessment of the effects of multiple mutations on inhibitor association rates and binding specificity. As a proof of principle for this combined approach, we utilized this strategy to alter inhibitor/protease association rates and to tailor the selectivity of the amyloid β-protein precursor Kunitz protease inhibitor domain (APPI) for inhibition of the oncogenic protease mesotrypsin, in the presence of three competing serine proteases, anionic trypsin, cationic trypsin and kallikrein-6. We generated a variant, designated APPIP13W/M17G/I18F/F34V, with up to 30-fold greater specificity relative to the parental APPIM17G/I18F/F34V protein, and 6500- to 230 000-fold improved specificity relative to the wild-type APPI protein in the presence of the other proteases tested. A series of molecular docking simulations suggested a mechanism of interaction that supported the biochemical results. These simulations predicted that the selectivity and specificity are affected by the interaction of the mutated APPI residues with nonconserved enzyme residues located in or near the binding site. Our strategy will facilitate a better understanding of the binding landscape of multispecific proteins and will pave the way for design of new drugs and diagnostic tools targeting proteases and other proteins.
Functional Redundancy and Ecological Innovation Shape the Circulation of Tick-Transmitted Pathogens

Ticks are vectors of pathogens affecting human and animal health worldwide. Nevertheless, the ecological and evolutionary interactions between ticks, hosts, and pathogens are largely unknown. Here, we integrated a framework to evaluate the associations of the tick Ixodes ricinus with its hosts and environmental niches that impact pathogen circulation. The analysis of tick-hosts association suggested that mammals and lizards were the ancestral hosts of this tick species, and that a leap to Aves occurred around 120 M years ago. The signature of the environmental variables over the host's phylogeny revealed the existence of two clades of vertebrates diverging along a temperature and vegetation split. This is a robust proof that the tick probably experienced a colonization of new niches by adapting to a large set of new hosts, Aves. Interestingly, the colonization of Aves as hosts did not increase significantly the ecological niche of I. ricinus, but remarkably Aves are super-spreaders of pathogens. The disparate contribution of Aves to the tick-host-pathogen networks revealed that I. ricinus evolved to maximize habitat overlap with some hosts that are super-spreaders of pathogens. These results supported the hypothesis that large host networks are not a requirement of tick survival but pathogen circulation. The biological cost of tick adaptation to non-optimal environmental conditions might be balanced by molecular mechanisms triggered by the pathogens that we have only begun to understand.
Effect of satiety on brain activation during chocolate tasting in men and women.

BACKGROUND The brain plays a crucial role in the decision to eat, integrating multiple hormonal and neural signals. A key factor controlling food intake is selective satiety, ie, the phenomenon that the motivation to eat more of a food decreases more than does the motivation to eat foods not eaten. OBJECTIVE We investigated the effect of satiation with chocolate on the brain activation associated with chocolate taste in men and women. DESIGN Twelve men and 12 women participated. Subjects fasted overnight and were scanned by use of functional magnetic resonance imaging while tasting chocolate milk, before and after eating chocolate until they were satiated. RESULTS In men, chocolate satiation was associated with increased taste activation in the ventral striatum, insula, and orbitofrontal and medial orbitofrontal cortex and with decreased taste activation in somatosensory areas. Women showed increased taste activation in the precentral gyrus, superior temporal gyrus, and putamen and decreased taste activation in the hypothalamus and amygdala. Sex differences in the effect of chocolate satiation were found in the hypothalamus, ventral striatum, and medial prefrontal cortex (all P < 0.005). CONCLUSIONS Our results indicate that men and women differ in their response to satiation and suggest that the regulation of food intake by the brain may vary between the sexes. Therefore, sex differences are a covariate of interest in studies of the brain's responses to food.
Probabilistic and Regularized Graph Convolutional Networks

This paper explores the recently proposed Graph Convolutional Network architecture proposed in (Kipf & Welling, 2016) The key points of their work is summarized and their results are reproduced. Graph regularization and alternative graph convolution approaches are explored. I find that explicit graph regularization was correctly rejected by (Kipf & Welling, 2016). I attempt to improve the performance of GCN by approximating a k-step transition matrix in place of the normalized graph laplacian, but I fail to find positive results. Nonetheless, the performance of several configurations of this GCN variation is shown for the Cora, Citeseer, and Pubmed datasets.
Functional status and physical impairments of adult patients infected with the human immunodeficiency virus admitted to hospital: a scoping review protocol.

RESEARCH QUESTION/OBJECTIVE The objectives of this scoping review are to describe the physical impairments and subsequent level of function of adult individuals infected with the human immunodeficiency virus (HIV) admitted to an acute care hospital, determine the outcome measures used by rehabilitation professionals when evaluating said impairments and level of function in the population of interest, and identify the rehabilitation interventions offered to individuals while in hospital as a means of addressing these physical impairments and individuals' functional status.Specifically, the research questions are:The current scoping review will comprehensively identify the physical impairments of people living with HIV when admitted to an acute care hospital and highlight the subsequent influence on their level of function as a means of emphasizing the disability present. Findings regarding the rehabilitation interventions offered could inform clinical practice as a means of mapping which interventions are offered to address the related physical impairments and thus highlight areas for future research.
Macrophages with a deletion of the phosphoenolpyruvate carboxykinase 1 (Pck1) gene have a more proinflammatory phenotype

Phosphoenolpyruvate carboxykinase (Pck1) is a metabolic enzyme that is integral to the gluconeogenic and glyceroneogenic pathways. However, Pck1's role in macrophage metabolism and function is unknown. Using stable isotopomer MS analysis in a mouse model with a myeloid cell–specific Pck1 deletion, we show here that this deletion increases the proinflammatory phenotype in macrophages. Incubation of LPS-stimulated bone marrow–derived macrophages (BMDM) with [U-13C]glucose revealed reduced 13C labeling of citrate and malate and increased 13C labeling of lactate in Pck1-deleted bone marrow–derived macrophages. We also found that the Pck1 deletion in the myeloid cells increases reactive oxygen species (ROS). Of note, this altered macrophage metabolism increased expression of the M1 cytokines TNFα, IL-1β, and IL-6. We therefore conclude that Pck1 contributes to M1 polarization in macrophages. Our findings provide important insights into the factors determining the macrophage inflammatory response and indicate that Pck1 activity contributes to metabolic reprogramming and polarization in macrophages.
Morphology in Statistical Machine Translation from English to a Highly Inflectional Language ITC 1 / 47

In this paper, we investigate the role of morphology in phrase-based statistical machine translation (SMT) from English to the highly inflectional Slovenian language. Translation to an inflectional language is a challenging task because of its morphological complexity. Rich morphology increases data sparsity and worsens the quality of statistical machine translation. The idea of the paper is to find the SMT configuration, based on morpho-syntactic information, with the best translation results, when translating from English to the highly inflectional Slovenian language. To address this issue, we added the morphological information in terms of morpho-syntactic description (MSD) tags that were attached to words. A MSD tag includes all morpho-syntactic information in position-dependent attributes. Tags were attached to words by TreeTagger. Several experiments were performed using MSD tags to improve the translation results. First, factored translation was studied, and different configurations were tested. They show that factored translation improves modeling of short distance collocations. To capture long-distance dependencies in languages, operation sequence models (OSM) were added in the second set of experiments. An additional improvement was obtained. The overall results show that the morpho-syntactic information of inflectional language is an important factor in translation. Factored translation with OSM models brought 9% relative improvement. The most successful configuration was tSaMaL-SaMaL (OSM: 0-0, 1-1, 2-2). The conclusions of our work can be applied to other Slavic languages, as they to some extent share the same morphological characteristics.
Sustained Persistence of IL2 Signaling Enhances the Antitumor Effect of Peptide Vaccines through T-cell Expansion and Preventing PD-1 Inhibition

IL2 signaling improves potency of peptide vaccines but at the cost of toxicity. Improving persistence of IL2 avoids toxicity and promotes antitumor T cells by enhancing their expansion and preventing PD-1 inhibition. Peptide vaccines can be a successful and cost-effective way of generating T-cell responses against defined tumor antigens, especially when combined with immune adjuvants such as poly-IC. However, strong immune adjuvants can induce a collateral increase in numbers of irrelevant, nonspecific T cells, which limits the effectiveness of the peptide vaccines. Here, we report that providing prolonged IL2 signaling in the form of either IL2/anti-IL2 complexes or pegylated IL2 overcomes the competitive suppressive effect of irrelevant T cells, allowing the preferential expansion of antigen-specific T cells. In addition to increasing the number of tumor-reactive T cells, sustained IL2 enhanced the ability of T cells to resist PD-1–induced negative signals, increasing the therapeutic effectiveness of the vaccines against established tumors. This vaccination strategy using peptides and sustained IL2 could be taken into the clinic for the treatment of cancer. Cancer Immunol Res; 6(5); 617–27. ©2018 AACR.
Quantitative 3-Dimensional Imaging of Murine Neointimal and Atherosclerotic Lesions by Optical Projection Tomography

Objective Traditional methods for the analysis of vascular lesion formation are labour intensive to perform - restricting study to ‘snapshots’ within each vessel. This study was undertaken to determine the suitability of optical projection tomographic (OPT) imaging for the 3-dimensional representation and quantification of intimal lesions in mouse arteries. Methods and Results Vascular injury was induced by wire-insertion or ligation of the mouse femoral artery or administration of an atherogenic diet to apoE-deficient mice. Lesion formation was examined by OPT imaging of autofluorescent emission. Lesions could be clearly identified and distinguished from the underlying vascular wall. Planimetric measurements of lesion area correlated well with those made from histological sections subsequently produced from the same vessels (wire-injury: R2 = 0.92; ligation-injury: R2 = 0.89; atherosclerosis: R2 = 0.85), confirming both the accuracy of this methodology and its non-destructive nature. It was also possible to record volumetric measurements of lesion and lumen and these were highly reproducible between scans (coefficient of variation = 5.36%, 11.39% and 4.79% for wire- and ligation-injury and atherosclerosis, respectively). Conclusions These data demonstrate the eminent suitability of OPT for imaging of atherosclerotic and neointimal lesion formation, providing a much needed means for the routine 3-dimensional analysis of vascular morphology in studies of this type.
Bcr‐Abl regulation of sphingomyelin synthase 1 reveals a novel oncogenic‐driven mechanism of protein up‐regulation

Bcr‐Abl (break‐point cluster region‐abelson), the oncogenic trigger of chronic myelogenous leukemia (CML), has previously been shown to up‐regulate the expression and activity of sphingomyelin synthase 1 (SMS1), which contributes to the proliferation of CML cells; however, the mechanism by which this increased expression of SMS1 is mediated remains unknown. In the current study, we show that Bcr‐Abl enhances the expression of SMS1 via a 30‐fold up‐regulation of its transcription. Of most interest, the Bcr‐Abl‐regulated transcription of SMS1 is initiated from a novel transcription start site (TSS) that is just upstream of the open reading frame. This shift in TSS utilization generates an SMS1 mRNA with a substantially shorter 5′ UTR compared with its canonical mRNA. This shorter 5′ UTR imparts a 20‐fold greater translational efficiency to SMS1 mRNA, which further contributes to the increase of its expression in CML cells. Therefore, our study demonstrates that Bcr‐Abl increases SMS1 protein levels via 2 concerted mechanisms: up‐regulation of transcription and enhanced translation as a result of the shift in TSS utilization. Remarkably, this is the first time that an oncogene—Bcr‐Abl—has been demonstrated to drive such a mechanism that up‐regulates the expression of a functionally important target gene, SMS1. —Moorthi, S. , Burns, T. A. , Yu, G. ‐Q. , Luberto, C. Bcr‐Abl regulation of sphingomyelin synthase 1 reveals a novel oncogenic‐driven mechanism of protein up‐regulation. FASEB J. 32, 4270–4283 (2018). www.fasebj. org
Cohort Profile Cohort profile : The NSPN 2400 Cohort : a developmental sample supporting the Wellcome Trust NeuroScience in Psychiatry Network

Cohort profile: The NSPN 2400 Cohort: a developmental sample supporting the Wellcome Trust NeuroScience in Psychiatry Network Beatrix Kiddle, Becky Inkster, Gita Prabhu, Michael Moutoussis, Kirstie J. Whitaker, the NSPN Consortium, Edward T. Bullmore, Raymond J. Dolan, Peter Fonagy, Ian M. Goodyer, and Peter B. Jones* Department of Psychiatry, University of Cambridge, United Kingdom, Wellcome Trust Centre for Neuroimaging, University College London, United Kingdom, Cambridgeshire and Peterborough National Health Service Foundation Trust, Cambridge, United Kingdom, Research Department of Clinical, Educational and Health Psychology, University College London, United Kingdom, Max Planck University College London Centre for Computational Psychiatry and Ageing Research, University College London, United Kingdom, Medical Research Council/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, United Kingdom, ImmunoPsychiatry, GlaxoSmithKline Research and Development, Stevenage, United Kingdom
Smart Phones Support Smart Labor

Besides enabling communication, mobile phones and smartphones support information flows and financial transactions, especially in developing countries, where the coverage of landline networks is limited. Drawing upon new data from rural households in Southeast Asia, this paper shows that mobile phone or smartphone ownership supports local employment and commuting while it reduces incentives for migration of workers.
An Analysis of Memory-based Processing Costs using Incremental Deep Syntactic Dependency Parsing

Reading experiments using naturalistic stimuli have shown unanticipated facilitations for completing center embeddings when frequency e ects are factored out. To eliminate possible confounds due to surface structure, this paper introduces a processing model based on deep syntactic dependencies. Results on eye-tracking data indicate that completing deep syntactic embeddings yields significantly more facilitation than completing surface embeddings.
TAF10 and TAF10b partially redundant roles during Drosophila melanogaster morphogenesis

ABSTRACT Transcription of eukaryotic genes requires the cooperative action of the RNA polymerase complex, the general transcription factors (TFIIB, TFIID, TFIIE, TFIIF and TFIIH) and chromatin modifiers. The TFIID complex contributes to transcriptional activation by several mechanisms and has a subunit with associated histone acetyltransferase (HAT) activity. The histone modifier SAGA complex has both HAT and deubiquitylase (DUB) activities. TFIID and SAGA share several TBP-associated factors (TAFs), but not their HAT subunit. Recently, several duplicated TAF proteins have been identified in higher eukaryotes, but their functional diversity has been so far poorly characterized. Here, we report the functional similarities and differences of TAF10 and TAF10b, the two TAF10 orthologs of Drosophila melanogaster. Results from in silico modeling suggest that dTAF10 and dTAF10b have similar secondary structures characterized by the presence of a histone-fold domain. Additionally, dTAF10 and dTAF10b share interaction partners and show similar expression patterns in neuronal tissues. Nonetheless, dTAF10 and dTAF10b seem to have partly distinct functions. To investigate their roles, we generated dTaf10-dTaf10b double-mutants and rescued the mutant flies with transgenes, which allowed the translation of either dTAF10 or dTAF10b protein. We found that the loss of dTAF10b resulted in pupal lethality, while animals lacking dTAF10 were able to form puparium. dTaf10 mutant adults showed distorted eye morphology. During DNA repair, dTAF10 and dTAF10b act redundantly, suggesting that these proteins have distinct but partially overlapping functions.
A Switched Multibeam Antenna Array using Butler Matrix Feed Network

In this paper, Smart Antenna system of 4- element microstrip linear array antenna with Butler matrix beam forming network is designed, analyzed and implemented using microstrip technology in completely planar structure. The performance of this smart antenna system is analyzed and the beam forming features are monitored as function of geometrical antenna and Butler matrix parameters at frequency 2.4 GHz.
Hypoxia–ischemia is not an antecedent of most preterm brain damage: the illusion of validity

Brain injury in preterm newborn infants is often attributed to hypoxia–ischemia even when neither hypoxia nor ischemia is documented, and many causative speculations are based on the same assumption. We review human and animal study contributions with their strengths and limitations, and conclude that – despite all the work done in human fetal neuropathology and developmental models in animals – the evidence remains unconvincing that hypoxemia, in the fetus or newborn infant, contributes appreciably to any encephalopathy of prematurity. Giving an inappropriate causal name to a disorder potentially limits the options for change, should our understanding of the etiologies advance. The only observationally‐based title we think appropriate is ‘encephalopathy of prematurity’. Future pathophysiological research should probably include appropriately designed epidemiology studies, highly active developmental processes, infection and other inflammatory stimuli, the immature immune system, long chain fatty acids and their transporters, and growth (neurotrophic) factors.
Structural and Functional Basis for an EBNA1 Hexameric Ring in Epstein-Barr Virus Episome Maintenance

ABSTRACT Epstein-Barr virus (EBV) establishes a stable latent infection that can persist for the life of the host. EBNA1 is required for the replication, maintenance, and segregation of the latent episome, but the structural features of EBNA1 that confer each of these functions are not completely understood. Here, we have solved the X-ray crystal structure of an EBNA1 DNA-binding domain (DBD) and discovered a novel hexameric ring oligomeric form. The oligomeric interface pivoted around residue T585 as a joint that links and stabilizes higher-order EBNA1 complexes. Substitution mutations around the interface destabilized higher-order complex formation and altered the cooperative DNA-binding properties of EBNA1. Mutations had both positive and negative effects on EBNA1-dependent DNA replication and episome maintenance with OriP. We found that one naturally occurring polymorphism in the oligomer interface (T585P) had greater cooperative DNA binding in vitro, minor defects in DNA replication, and pronounced defects in episome maintenance. The T585P mutant was compromised for binding to OriP in vivo as well as for assembling the origin recognition complex subunit 2 (ORC2) and trimethylated histone 3 lysine 4 (H3K4me3) at OriP. The T585P mutant was also compromised for forming stable subnuclear foci in living cells. These findings reveal a novel oligomeric structure of EBNA1 with an interface subject to naturally occurring polymorphisms that modulate EBNA1 functional properties. We propose that EBNA1 dimers can assemble into higher-order oligomeric structures important for diverse functions of EBNA1. IMPORTANCE Epstein-Barr virus is a human gammaherpesvirus that is causally associated with various cancers. Carcinogenic properties are linked to the ability of the virus to persist in the latent form for the lifetime of the host. EBNA1 is a sequence-specific DNA-binding protein that is consistently expressed in EBV tumors and is the only viral protein required to maintain the viral episome during latency. The structural and biochemical mechanisms by which EBNA1 allows the long-term persistence of the EBV genome are currently unclear. Here, we have solved the crystal structure of an EBNA1 hexameric ring and characterized key residues in the interface required for higher-order complex formation and long-term plasmid maintenance.
Human activity recognition and gymnastics analysis through depth imagery

Depth imagery is transforming many areas of computer vision, such as object recognition, human detection, human activity recognition, and sports analysis. The goal of my work is twofold: (1) use depth imagery to effectively analyze the pommel horse event in men’s gymnastics, and (2) explore and build upon the use of depth imagery to recognize human activities through skeleton representation. I show that my gymnastics analysis system can accurately segment a scene based on depth to identify a ‘depth of interest’, ably recognize activities on the pommel horse using only the gymnast’s silhouette, and provide an informative analysis of the gymnast’s performance. This system runs in real-time on an inexpensive laptop, and has been built into an application in use by elite gymnastics coaches. Furthermore, I present my work expanding on a bio-inspired skeleton representation obtained through depth data. This representation outperforms existing methods in classification accuracy on benchmark datasets. I then show that it can be used to interact in real-time with a Baxter humanoid robot, and is more accurate at recognizing both complete and ongoing interactions than current state-of-the-art methods.