Miracle-dz/UniFAR-FTUs huggingface dataset:
Association of low‐frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts

Genome‐wide scans have shown that common risk alleles for orofacial clefts (OFC) tend to be located in noncoding regulatory elements and cumulatively explain only part of the heritability of OFCs. Low‐frequency variants may account for some of the “missing” heritability. Therefore, we scanned low‐frequency variants located within putative craniofacial enhancers to identify novel OFC risk variants and implicate new regulatory elements in OFC pathogenesis. Analyses were performed in a multiethnic sample of 1,995 cases of cleft lip with or without cleft palate (CL/P), 221 cases with cleft palate (CP) only, and 1,576 unaffected controls. One hundred and nineteen putative craniofacial enhancers identified from ChIP‐Seq studies in craniofacial tissues or cell lines contained multiple low‐frequency (0.01–1%) variants, which we genotyped in participants using a custom Illumina panel. Two complementary statistical approaches, sequence kernel association test and combined multivariate and collapsing, were used to test association of the aggregated low‐frequency variants across each enhancer region with CL/P and CP. We discovered a significant association between CP and a branchial arch enhancer near FOXP1 (mm60; p‐value = .0002). Additionally, we observed a suggestive association between CL/P and a forebrain enhancer near FOXE1 (hs1717; p‐value = .001). These findings suggest that low‐frequency variants in craniofacial enhancer regions contribute to the complex etiology of nonsyndromic OFCs.
Neuronal drebrin A directly interacts with mDia2 formin to inhibit actin assembly

Dendritic spines (DS) are actin-rich postsynaptic terminals of neurons that are critical for higher-order brain functions. Maturation of DS is accompanied by a change in actin architecture from linear to branched filamentous structures. Presumably, the underlying cause of this is a switch in a mode of actin assembly from formin-driven to Arp2/3-mediated via an undefined mechanism. Here we present data suggesting that neuron-specific actin-binding drebrin A may be a part of such a switch. It is well documented that DS are highly enriched in drebrin A, which is critical for their plasticity and function. At the same time, mDia2 is known to mediate the formation of filopodia-type (immature) spines. We found that neuronal drebrin A directly interacts with mDia2 formin. Drebrin inhibits formin-mediated nucleation of actin and abolishes mDia2-induced actin bundling. Using truncated protein constructs we identified the domain requirements for drebrin–mDia2 interaction. We hypothesize that accumulation of drebrin A in DS (that coincides with spine maturation) leads to inhibition of mDia2-driven actin polymerization and, therefore, may contribute to a change in actin architecture from linear to branched filaments.
The distance function and defect energy

Several energies measuring jump discontinuities of a unit length gradient field are considered and are called defect energies. The main example is a total variation I(φ) of the hessian of a function φ in a domain. It is shown that the distance function is the unique minimiser of I(φ) among all non-negative Lipschitz solutions of the eikonal equation |grad φ| = 1 with zero boundary data, provided that the domain is a two-dimensional convex domain. An example shows that the distance function is not a minimiser of I if the domain is noncovex. This suggests that the selection mechanism by I is different from that in the theory of viscosity solutions in general. It is often conjectured that the minimiser of a defect energy is a distance function if the energy is formally obtained as a singular limit of some variational problem. Our result suggests that this conjecture is very subtle even if it is true.
Human cytomegalovirus G protein-coupled receptor US28 promotes latency by attenuating c-fos

Significance Human cytomegalovirus (HCMV) is a widespread pathogen that remains with an individual for life in a quiescent/latent state, posing little threat to an otherwise healthy person. However, when an individual’s immune system is severely compromised, HCMV can reactivate to its active/lytic state, resulting in viral spread and disease that is often fatal. The biological mechanisms underlying HCMV latency and reactivation remain poorly understood. Herein we show that the viral-encoded G protein-coupled receptor (GPCR) US28 aids in the establishment and the maintenance of viral latency. Furthermore, we find that US28 modulates host-cell proteins to suppress viral processes associated with active/lytic replication, thereby promoting latent infection. This work provides the mechanism by which HCMV modulates the host-cell environment to its advantage. Human cytomegalovirus (HCMV) is a ubiquitous pathogen that undergoes latency in cells of the hematopoietic compartment, although the mechanisms underlying establishment and maintenance of latency remain elusive. We previously reported that the HCMV-encoded G protein-coupled receptor (GPCR) homolog US28 is required for successful latent infection. We now show that US28 protein (pUS28) provided in trans complements the US28Δ lytic phenotype in myeloid cells, suggesting that sustained US28 expression is necessary for long-term latency. Furthermore, expression of pUS28 at the time of infection represses transcription from the major immediate early promoter (MIEP) within 24 h. However, this repression is only maintained in the presence of continual pUS28 expression provided in trans. Our data also reveal that pUS28-mediated signaling attenuates both expression and phosphorylation of cellular fos (c-fos), an AP-1 transcription factor subunit, to repress MIEP-driven transcription. AP-1 binds to the MIEP and promotes lytic replication, and in line with this we find that US28Δ infection results in an increase in AP-1 binding to the MIEP, compared with WT latent infection. Pharmacological inhibition of c-fos represses the MIEP during US28Δ infection to levels similar to those we observe during WT latent infection. Together, our data reveal that US28 is required for both establishment and long-term maintenance of HCMV latency, which is modulated, at least in part, by repressing functional AP-1 binding to the MIEP.
Leap Motion Device Used to Control a Real Anthropomorphic Gripper

This paper presents for the first time the use of the Leap Motion device to control an anthropomorphic gripper with five fingers. First, a description of the Leap Motion device is presented, highlighting its main functional characteristics, followed by testing of its use for capturing the movements of a human hand's fingers in different configurations. Next, the HandCommander soft module and the Interface Controller application are described. The HandCommander is a software module created to facilitate interaction between a human hand and the GraspIT virtual environment, and the Interface Controller application is required to send motion data to the virtual environment and to test the communication protocol. For the test, a prototype of an anthropomorphic gripper with five fingers was made, including a proper hardware system of command and control, which is briefly presented in this paper. Following the creation of the prototype, the command system performance test was conducted under real conditions, evaluating the recognition efficiency of the objects to be gripped and the efficiency of the command and control strategies for the gripping process. The gripping test is exemplified by the gripping of an object, such as a screw spanner. It was found that the command system, both in terms of capturing human hand gestures with the Leap Motion device and effective object gripping, is operational. Suggestive figures are presented as examples.
Proteomic Studies Reveal Disrupted in Schizophrenia 1 as a Player in Both Neurodevelopment and Synaptic Function

A balanced chromosomal translocation disrupting DISC1 (Disrupted in Schizophrenia 1) gene has been linked to psychiatric diseases, such as major depression, bipolar disorder and schizophrenia. Since the discovery of this translocation, many studies have focused on understating the role of the truncated isoform of DISC1, hypothesizing that the gain of function of this protein could be behind the neurobiology of mental conditions, but not so many studies have focused in the mechanisms impaired due to its loss of function. For that reason, we performed an analysis on the cellular proteome of primary neurons in which DISC1 was knocked down with the goal of identifying relevant pathways directly affected by DISC1 loss of function. Using an unbiased proteomic approach, we found that the expression of 31 proteins related to neurodevelopment (e.g., CRMP-2, stathmin) and synaptic function (e.g., MUNC-18, NCS-1) is altered by DISC1 in primary mouse neurons. Hence, this study reinforces the idea that DISC1 is a unifying regulator of both neurodevelopment and synaptic function, thereby providing a link between these two key anatomical and cellular circuitries.
Rates and pathways of CH4 oxidation in ferruginous Lake Matano, Indonesia

This study evaluates rates and pathways of methane (CH4) oxidation and uptake using 14C‐based tracer experiments throughout the oxic and anoxic waters of ferruginous Lake Matano. Methane oxidation rates in Lake Matano are moderate (0.36 nmol L−1 day−1 to 117 μmol L−1 day−1) compared to other lakes, but are sufficiently high to preclude strong CH4 fluxes to the atmosphere. In addition to aerobic CH4 oxidation, which takes place in Lake Matano's oxic mixolimnion, we also detected CH4 oxidation in Lake Matano's anoxic ferruginous waters. Here, CH4 oxidation proceeds in the apparent absence of oxygen (O2) and instead appears to be coupled to some as yet uncertain combination of nitrate ( NO3− ), nitrite ( NO2− ), iron (Fe) or manganese (Mn), or sulfate ( SO42− ) reduction. Throughout the lake, the fraction of CH4 carbon that is assimilated vs. oxidized to carbon dioxide (CO2) is high (up to 93%), indicating extensive CH4 conversion to biomass and underscoring the importance of CH4 as a carbon and energy source in Lake Matano and potentially other ferruginous or low productivity environments.
Complex‐centric proteome profiling by SEC‐SWATH‐MS

Proteins are major effectors and regulators of biological processes that can elicit multiple functions depending on their interaction with other proteins. The organization of proteins into macromolecular complexes and their quantitative distribution across these complexes is, therefore, of great biological and clinical significance. In this paper we describe an integrated experimental and computational technique to quantify hundreds of protein complexes in a single operation. The method consists of size exclusion chromatography (SEC) to fractionate native protein complexes, SWATH/DIA mass spectrometry to precisely quantify the proteins in each SEC fraction and the computational framework CCprofiler to detect and quantify protein complexes by error-controlled, complex-centric analysis using prior information from generic protein interaction maps. Our analysis of the HEK293 cell line proteome delineates 462 complexes composed of 2127 protein subunits. The technique identifies novel subcomplexes and assembly intermediates of central regulatory complexes while assessing the quantitative subunit distribution across them. We make the toolset CCprofiler freely accessible, and provide a web platform, SECexplorer, for custom exploration of the HEK293 proteome modularity. Highlights Introduction of the concept of complex-centric proteome profiling Development of CCprofiler, a software framework for complex-centric data analysis Detection and quantification of subunit distribution of 462 distinct protein complexes containing 2127 proteins from a SEC-SWATH-MS dataset of HEK293 cells, and identification of novel complex variants such as assembly intermediates Statistical target-decoy model to estimate accurate false discovery rates for complexes quantified by complex-centric analysis SECexplorer, an online platform to support custom complex-centric exploration of SEC-SWATH-MS datasets.
Plasma CLEC-2 (C-Type Lectin Receptor 2) in Patients With Acute Ischemic Stroke.

See related article, p 45 Stroke is the leading cause of death globally, despite recent declines in cerebrovascular mortality, and its contemporary burden remains to be adequately addressed. Recent studies have reported that effective control of smoking, proper nutrition, development of a healthy city, polypill strategies, the use of mobile technology, salt intake reduction, and other dietary interventions are effective in primary stroke prevention. Unraveling the pathophysiology of atherothrombosis remains crucial to better predict, diagnose, and manage stroke, and the focus on platelets constitutes a key aspect of stroke research given their unique role in this condition. CLEC-2 (C-type lectin receptor 2) belongs to the large family of Ca2+dependent proteins with carbohydrate-binding ability, which are extensively represented in the human body. Specifically, CLEC-2 is highly expressed on the plasma membranes of platelets and has functional roles in platelet activation. The central question is whether CLEC-2 can predict progression of stroke and mortality in the short and long term. The role of CLEC-2 in stroke pathophysiology was recently addressed by Zhang et al in a dedicated study in the Journal. Specifically, the authors conducted a prospective observational study, including 352 patients with acute ischemic stroke and compared them to 112 healthy controls, during a 3-month period. Patients with recurrent strokes, autoimmune diseases, severe infection, severe hepatic, renal, cardiac, or respiratory diseases, pregnancy, and known malignancy were excluded. The primary end point was the modified Rankin Scale. In addition, stroke progression was defined as the presence of new neurological symptoms or signs, any neurological worsening within 7 days after stroke onset. Poor outcome was defined as modified Rankin Scale scores >2 at 90 days. Notably, their findings supporting the important prognostic role of CLEC-2 in stroke complement previous work that CLEC-2 can predict stroke progression in patients with a single small subcortical infarction. In addition, CLEC-2 was found to be increased in patients experiencing coronary artery disease. Accordingly, this biomarker may provide the mechanistic link between cerebral thromboembolism, myocardial infarction, and neurological deterioration, as part of a wider thromboinflammatory state. There are some limitations of this study. First, the follow-up period was relatively short, and studies during a longer timescale are needed to confirm its prognostic value. Second, simpler hematologic and inflammatory indices were also not reported, and these could provide incremental value for risk stratification, complementing other investigations, such as electrocardiography. With these points in mind, the study by Zhang et al has provided us the foundation that plasma CLEC-2 is a useful risk marker, and further studies on this novel biomarker are warranted.
Upregulation of long noncoding RNA TUG1 by EGR1 promotes adenomyotic epithelial cell migration and invasion through recruiting EZH2 and suppressing TIMP2

Emerging studies showed that lncRNA taurine upregulated 1 (TUG1) plays important roles in diverse biological processes. However, there is no previously published research reporting the regulatory role of lncRNAs in the progression of adenomyosis. In the present study, we found that TUG1 is upregulated in human adenomyosis, and the overexpression of TUG1 is associated with the transcription factor early growth response 1 (EGR1). Functionally, the knockdown of TUG1 inhibited adenomyotic epithelial cell migration and invasion but not growth. The mechanistic experiments demonstrated that the function of TUG1 in adenomyotic epithelial cell invasion is, at least in part, through recruiting the enhancer of zeste homolog 2 (EZH2) to the promoter of tissue inhibitor of metalloproteinases 2 (TIMP2) and negatively regulating its expression. Our study demonstrated that TUG1 promotes the migration and invasion of human adenomyotic epithelial cells, and EGR1/TUG1/EZH2/TIMP2 may be a potential therapeutic target for adenomyosis.
Discovery of Distinct Immune Phenotypes Using Machine Learning in Pulmonary Arterial Hypertension

Rationale: Accumulating evidence implicates inflammation in pulmonary arterial hypertension (PAH) and therapies targeting immunity are under investigation, although it remains unknown if distinct immune phenotypes exist. Objective: Identify PAH immune phenotypes based on unsupervised analysis of blood proteomic profiles. Methods and Results: In a prospective observational study of group 1 PAH patients evaluated at Stanford University (discovery cohort; n=281) and University of Sheffield (validation cohort; n=104) between 2008 and 2014, we measured a circulating proteomic panel of 48 cytokines, chemokines, and factors using multiplex immunoassay. Unsupervised machine learning (consensus clustering) was applied in both cohorts independently to classify patients into proteomic immune clusters, without guidance from clinical features. To identify central proteins in each cluster, we performed partial correlation network analysis. Clinical characteristics and outcomes were subsequently compared across clusters. Four PAH clusters with distinct proteomic immune profiles were identified in the discovery cohort. Cluster 2 (n=109) had low cytokine levels similar to controls. Other clusters had unique sets of upregulated proteins central to immune networks—cluster 1 (n=58; TRAIL [tumor necrosis factor-related apoptosis-inducing ligand], CCL5 [C-C motif chemokine ligand 5], CCL7, CCL4, MIF [macrophage migration inhibitory factor]), cluster 3 (n=77; IL [interleukin]-12, IL-17, IL-10, IL-7, VEGF [vascular endothelial growth factor]), and cluster 4 (n=37; IL-8, IL-4, PDGF-&bgr; [platelet-derived growth factor beta], IL-6, CCL11). Demographics, PAH clinical subtypes, comorbidities, and medications were similar across clusters. Noninvasive and hemodynamic surrogates of clinical risk identified cluster 1 as high-risk and cluster 3 as low-risk groups. Five-year transplant-free survival rates were unfavorable for cluster 1 (47.6%; 95% CI, 35.4%–64.1%) and favorable for cluster 3 (82.4%; 95% CI, 72.0%–94.3%; across-cluster P<0.001). Findings were replicated in the validation cohort, where machine learning classified 4 immune clusters with comparable proteomic, clinical, and prognostic features. Conclusions: Blood cytokine profiles distinguish PAH immune phenotypes with differing clinical risk that are independent of World Health Organization group 1 subtypes. These phenotypes could inform mechanistic studies of disease pathobiology and provide a framework to examine patient responses to emerging therapies targeting immunity.
The slow force response to stretch: Controversy and contradictions

When exposed to an abrupt stretch, cardiac muscle exhibits biphasic active force enhancement. The initial, instantaneous, force enhancement is well explained by the Frank‐Starling mechanism. However, the cellular mechanisms associated with the second, slower phase remain contentious. This review explores hypotheses regarding this “slow force response” with the intention of clarifying some apparent contradictions in the literature. The review is partitioned into three sections. The first section considers pathways that modify the intracellular calcium handling to address the role of the sarcoplasmic reticulum in the mechanism underlying the slow force response. The second section focuses on extracellular calcium fluxes and explores the identity and contribution of the stretch‐activated, non‐specific, cation channels as well as signalling cascades associated with G‐protein coupled receptors. The final section introduces promising candidates for the mechanosensor(s) responsible for detecting the stretch perturbation.
Sur l'algorithme de Fortune

L'algorithme de balayage de Fortune est connu comme l'algorithme le plus efficace pour construire le diagramme de Voronoi d'un ensemble fini S de points du plan. Nous proposons ici differentes ameliorations : nous construisons le diagramme de Delaunay et non une triangulation, nous traitons tous les cas particuliers des points cocycliques ou alignes, nous utilisons les cartes comme structures de donnees et nous reduisons le nombre d'evenements. Le temps d'execution de l'algorithme est ainsi divise par 2.
Environmental, Individual and Personal Goal Influences on Older Adults’ Walking in the Helsinki Metropolitan Area

Physical activity is a fundamental factor in healthy ageing, and the built environment has been linked to individual health outcomes. Understanding the linkages between older adult's walking and the built environment are key to designing supportive environments for active ageing. However, the variety of different spatial scales of human mobility has been largely overlooked in the environmental health research. This study used an online participatory mapping method and a novel modelling of individual activity spaces to study the associations between both the environmental and the individual features and older adults' walking in the environments where older adult's actually move around. Study participants (n = 844) aged 55+ who live in Helsinki Metropolitan Area, Finland reported their everyday errand points on a map and indicated which transport mode they used and how frequently they accessed the places. Respondents walking trips were drawn from the data and the direct and indirect effects of the personal, psychological as well as environmental features on older adults walking were examined. Respondents marked on average, six everyday errand points and walked for transport an average of 20 km per month. Residential density and the density of walkways, public transit stops, intersections and recreational sports places were significantly and positively associated with older adult's walking for transport. Transit stop density was found having the largest direct effect to older adults walking. Built environment had an independent effect on older adults walking regardless of individual demographic or psychological features. Education and personal goals related to physical activities had a direct positive, and income a direct negative, effect on walking. Gender and perceived health had an indirect effect on walking, which was realized through individuals' physical activity goals.
Fast parallel selection on the linear array with reconfigurable pipelined bus system

The Linear Array with a Reconfigurable Pipelined Bus System (LARPBS) is a newly introduced parallel computational model based on current optical bus technology. We show that the selection problem can be solved on the LARPBS model in O((log log N)/sup 2//log log log N) bus cycles deterministically. To our best knowledge, this is the best deterministic selection algorithm on the LARPBS model.