Miracle-dz/UniFAR-FTUs huggingface dataset:
Probabilistic Interpolation of Uncertain Local Activation Times on Human Atrial Manifolds

Objective: Local activation time (LAT) mapping of the atria is important for targeted treatment of atrial arrhythmias, but current methods do not interpolate on the atrial manifold and neglect uncertainties associated with LAT observations. In this paper, we describe novel methods to, first, quantify uncertainties in LAT arising from bipolar electrogram analysis and assignment of electrode recordings to the anatomical mesh, second, interpolate uncertain LAT measurements directly on left atrial manifolds to obtain complete probabilistic activation maps, and finally, interpolate LAT jointly across both the manifold and different S1–S2 pacing protocols. Methods: A modified center of mass approach was used to process bipolar electrograms, yielding a LAT estimate and error distribution from the electrogram morphology. An error distribution for assigning measurements to the anatomical mesh was estimated. Probabilistic LAT maps were produced by interpolating on a left atrial manifold using Gaussian Markov random fields, taking into account observation errors and characterizing LAT predictions by their mean and standard deviation. This approach was extended to interpolate across S1–S2 pacing protocols. Results: We evaluated our approach using recordings from three patients undergoing atrial ablation. Cross-validation showed consistent and accurate prediction of LAT observations both at different locations on the left atrium and for different S1–S2 intervals. Significance: Interpolation of scalar and vector fields across anatomical structures from point measurements is a challenging problem in biomedical engineering, compounded by uncertainties in measurements and meshes. New methods and approaches are required, and in this paper, we have demonstrated an effective method for probabilistic interpolation of uncertain LAT.
Light-Induced Pupillary Responses in Alzheimer's Disease

The impact of Alzheimer's disease (AD) on the pupillary light response (PLR) is controversial, being dependent on the stage of the disease and on the experimental pupillometric protocols. The main hypothesis driving pupillometry research in AD is based on the concept that the AD-related neurodegeneration affects both the parasympathetic and the sympathetic arms of the PLR (cholinergic and noradrenergic theory), combined with additional alterations of the afferent limb, involving the melanopsin expressing retinal ganglion cells (mRGCs), subserving the PLR. Only a few studies have evaluated the value of pupillometry as a potential biomarker in AD, providing various results compatible with parasympathetic dysfunction, displaying increased latency of pupillary constriction to light, decreased constriction amplitude, faster redilation after light offset, decreased maximum velocity of constriction (MCV) and maximum constriction acceleration (MCA) compared to controls. Decreased MCV and MCA appeared to be the most accurate of all PLR parameters allowing differentiation between AD and healthy controls while increased post-illumination pupillary response was the most consistent feature, however, these results could not be replicated by more recent studies, focusing on early and pre-clinical stages of the disease. Whether static or dynamic pupillometry yields useful biomarkers for AD screening or diagnosis remains unclear. In this review, we synopsize the current knowledge on pupillometric features in AD and other neurodegenerative diseases, and discuss potential roles of pupillometry in AD detection, diagnosis and monitoring, alone or in combination with additional biomarkers.
The Antidepressant Mirtazapine Inhibits Hepatic Innate Immune Networks to Attenuate Immune-Mediated Liver Injury in Mice

Activation of the innate immune system, including tissue macrophages and associated neutrophil infiltration, is an important driver of subsequent adaptive immune responses in many autoimmune diseases, including autoimmune hepatitis (AIH). The antidepressant mirtazapine has a unique complex pharmacology, altering signaling through a number of serotonin and histamine receptors that can impact macrophage function; an effect potentially influencing AIH outcome. In the mouse model of concanavalin A (Con A) induced liver injury (mimics many aspects of human AIH), in which early innate immune activation (i.e., stimulated hepatic macrophages/monocytes recruit neutrophils and additional monocytes to the liver) critically drives immune-mediated hepatitis induction, mirtazapine strikingly and dose-dependently inhibited Con A-induced liver injury. This inflammation-suppressing effect of mirtazapine was linked to an attenuation of Con A-stimulated early innate immune responses within the liver, including inhibition of hepatic macrophage/monocyte activation, decreased hepatic macrophage/monocyte-derived pro-inflammatory cytokine (e.g., TNFα) and chemokine (e.g., CXCL1 and CXCL2) production, suppression of Con A-induced increases in the hepatic expression of the neutrophil relevant endothelial cell adhesion molecule ICAM-1, with the resultant significant reduction in neutrophil recruitment into the liver. Consistent with our findings in the Con A model, mirtazapine also significantly reduced activation-induced release of cytokine/chemokine mediators from human CD14+ monocytes in vitro. Conclusion: Our data suggest that mirtazapine can attenuate hepatic innate immune responses that critically regulate the subsequent development of autoimmune liver injury. Therefore, given that it is a safe and widely used medication, mirtazapine may represent a novel therapeutic approach to autoimmune liver disease.
Blood Cell-Bound C4d as a Marker of Complement Activation in Patients With the Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a chronic and disabling condition characterized by recurrent thrombosis and miscarriages mediated by antibodies against phospholipid-binding proteins (aPL), such as beta2glycoprotein I (β2GPI). Complement is involved in APS animal models and complement deposits have been documented in placenta and thrombotic vessels despite normal serum levels. Analysis of circulating blood cells coated with C4d displays higher sensitivity than the conventional assays that measure soluble native complement components and their unstable activation products in systemic lupus erythematosus (SLE). As C4d-coated blood cell count has been reported to be more sensitive than serum levels of complement components and their activation products in systemic lupus erythematosus (SLE) patients, we decided to evaluate the percentage of C4d positive B lymphocytes (BC4d), erythrocytes (EC4d), and platelets (PC4d) in primary APS patients and asymptomatic aPL positive carriers as marker of complement activation in APS. We assessed by flow cytometry the percentages of BC4d, EC4d, and PC4d in primary APS (PAPS; n. 23), 8 asymptomatic aPL positive carriers, 11 APS-associated SLE (SAPS), 17 aPL positive SLE, 16 aPL negative SLE, 8 aPL negative patients with previous thrombosis, 11 immune thrombocytopenia (ITP) patients, and 26 healthy subjects. In addition, we used an in vitro model to evaluate the ability of a monoclonal anti-β2GPI antibody (MBB2) to bind to normal resting or activated platelets and fix complement. EC4d and PC4d percentages were significantly higher in PAPS and aPL carriers as well as aPL positive SLE and SAPS than in aPL negative controls. The highest values were found in PAPS and in SAPS. The EC4d and PC4d percentages were significantly correlated with serum C3/C4 and anti-β2GPI/anti-cardiolipin IgG. In vitro studies showed that MBB2 bound to activated platelets only and induced C4d deposition. The detection of the activation product C4d on circulating erythrocytes and platelets supports the role of complement activation in APS. Complement may represent a new therapeutic target for better treatment and prevention of disability of APS patients.
Testicular sperm extraction in men with sertoli cell-only testicular histology - 1680 cases

Objective: To study the outcomes of testicular sperm extraction (TESE) among men with pure Sertoli cell-only histology identified during diagnostic testicular biopsy. Methods: This retrospective cohort study involved 1680 cases of patients with nonobstructive azoospermia (NOA) diagnosed with pure Sertoli cell-only histology who underwent testicular biopsy with TESE in a reference center in Brazil by a single surgeon. Sperm retrieval rates (SSR) were the main outcome measure. Results: Overall, 14.83% of patients with Sertoli cell-only had sperm retrieved with TESE in quantity that allowed the performance of ICSI. No differences were observed in SSR based on testis volume (<15 mL vs. <15 mL) or serum FSH level. Conclusions: Patients with Sertoli cell-only histology can be counseled that they have some likelihood of sperm retrieval with TESE. Based on the findings, patients to be submitted to testicular biopsy for histologic analysis may be concomitantly prepared for ICSI with TESE in case sperm is available.
Local Epidemics Gone Viral: Evolution and Diffusion of the Italian HIV-1 Recombinant Form CRF60_BC

The molecular epidemiology of HIV-1 in Italy is becoming increasingly complex, mainly due to the spread of non-B subtypes and the emergence of new recombinant forms. We previously characterized the outbreak of the first Italian circulating recombinant form (CRF60_BC), occurring among young MSM living in Apulia between the years 2009 and 2011. Here we show a 5-year follow-up surveillance to trace the evolution of CRF60_BC and to investigate its further spread in Italy. We collected additional sequences and clinical data from patients harboring CRF60_BC, enrolled at the Infectious Diseases Clinic of the University of Bari. In addition to the 24 previously identified sequences, we retrieved 27 CRF60_BC sequences from patients residing in Apulia, whose epidemiological and clinical features did not differ from those of the initial outbreak, i.e., the Italian origin, young age at HIV diagnosis (median: 24 years; range: 18–37), MSM risk factor (23/25, 92%) and recent infection (from 2008 to 2017). Sequence analysis revealed a growing overall nucleotide diversity, with few nucleotide changes that were fixed over time. Twenty-seven additional sequences were detected across Italy, spanning multiple distant regions. Using a BLAST search, we also identified a CRF60_BC sequence isolated in United Kingdom in 2013. Three patients harbored a unique second generation recombinant form in which CRF60_BC was one of the parental strains. Our data show that CRF60_BC gained epidemic importance, spreading among young MSM in multiple Italian regions and increasing its population size in few years, as the number of sequences identified so far has triplicated since our first report. The observed further divergence of CRF60_BC is likely due to evolutionary bottlenecks and host adaptation during transmission chains. Of note, we detected three second-generation recombinants, further supporting a widespread circulation of CRF60_BC and the increasing complexity of the HIV-1 epidemic in Italy.
Analysis of the roles of phosphatidylinositol-4,5-bisphosphate and individual subunits in assembly, localization, and function of Saccharomyces cerevisiae target of rapamycin complex 2

Eukaryotic cell survival requires maintenance of plasma membrane (PM) homeostasis in response to environmental insults and changes in lipid metabolism. In yeast, a key regulator of PM homeostasis is target of rapamycin (TOR) complex 2 (TORC2), a multiprotein complex containing the evolutionarily conserved TOR protein kinase isoform Tor2. PM localization is essential for TORC2 function. One core TORC2 subunit (Avo1) and two TORC2-associated regulators (Slm1 and Slm2) contain pleckstrin homology (PH) domains that exhibit specificity for binding phosphatidylinositol-4,5-bisphosphate (PtdIns4,5P2). To investigate the roles of PtdIns4,5P2 and constituent subunits of TORC2, we used auxin-inducible degradation to systematically eliminate these factors and then examined localization, association, and function of the remaining TORC2 components. We found that PtdIns4,5P2 depletion significantly reduced TORC2 activity, yet did not prevent PM localization or disassembly of TORC2. Moreover, truncated Avo1 (lacking its C-terminal PH domain) was still recruited to the PM and supported growth. Even when all three PH-containing proteins were absent, the remaining TORC2 subunits were PM-bound. Revealingly, Avo3 localized to the PM independent of both Avo1 and Tor2, whereas both Tor2 and Avo1 required Avo3 for their PM anchoring. Our findings provide new mechanistic information about TORC2 and pinpoint Avo3 as pivotal for TORC2 PM localization and assembly in vivo.
CD4+ T Cell-Dependent Macrophage Activation Modulates Sustained PS Exposure on Intracellular Amastigotes of Leishmania amazonensis

Leishmania amazonensis amastigotes can make use of surface-exposed phosphatidylserine (PS) molecules to promote infection and non-classical activation of macrophages (MΦ), leading to uncontrolled intracellular proliferation of the parasites. This mechanism was quoted as apoptotic mimicry. Moreover, the amount of PS molecules exposed on the surface of amastigotes correlates with the susceptibility of the host. In this study, we tested whether host cellular responses influence PS expression on intracellular amastigotes. We found that the level of PS exposure on intracellular amastigotes was modulated by CD4+ T cell and MΦ activation status in vitro and in vivo. L. amazonensis infection generated a Th1/Th2-mixed cytokine profile, providing the optimal MΦ stimulation that favored PS exposure on intracellular amastigotes. Maintenance of PS exposed on the parasite was dependent on low, but sustained, levels of nitric oxide and polyamine production. Amastigotes obtained from lymphopenic nude mice did not expose PS on their surface, and adoptive transfer of CD4+ T cells reversed this phenotype. In addition, histopathological analysis of mice treated with anti-PS antibodies showed increased inflammation and similarities to nude mouse lesions. Collectively, our data confirm the role of pathogenic CD4+ T cells for disease progression and point to PS as a critical parasite strategy to subvert host immune responses.
Dominant-negative inhibition of canonical Notch signaling in trophoblast cells does not disrupt placenta formation

ABSTRACT Proper development and function of the mammalian placenta requires interactions between embryo-derived trophoblasts and uterine endothelial cells to form mosaic vessels that facilitate blood flow to a developing conceptus. Notch signaling utilizes a cell–cell contact dependent mechanism to drive cell behaviors, such as differentiation and invasion. In mice, Notch2 is needed for proper placentation and embryo survival. We used transgenic mice with a dominant-negative form of Mastermind-like1 and Cyp19-Cre and Tpbpa-Cre drivers to inhibit canonical Notch signaling in trophoblasts. Both Cre drivers resulted in robust placental expression of dominant-negative Mastermind-like1. All pregnancies progressed beyond mid-gestation and morphological analyses of placentas revealed no differences between mutants and controls. Our data suggest that mouse placentation occurs normally despite dominant negative inhibition of trophoblast canonical Notch signaling and that Notch2 signaling via the canonical pathway is not necessary for placentation. Summary: Using transgenic mice with a dominant-negative form of Mastermind-like1 and Cyp19-Cre and Tpbpa-Cre drivers, we found that dominant negative inhibition of canonical Notch signaling in trophoblast cells does not disrupt placenta formation.
Diversity of clinical, radiographic and genealogical findings in 41 families with amelogenesis imperfecta

Abstract Amelogenesis imperfecta (AI) is a group of enamel development disorders that alter the structure and chemical composition of the tissue. There is great variability in the clinical presentation; according to Witkop, AI can be categorized into 14 subtypes, which makes its diagnosis extremely complex. Objective: This study aimed to describe and determine the frequency of clinical and radiographic features and inheritance patterns found in 41 Chilean families diagnosed with diverse types of AI. Material and Methods: We analyzed the clinical records, photographs, pedigrees and radiographs of 121 individuals recruited between 2003 and 2016. All of the information was included in a database that was analyzed using the application Stata 14. Results: The 72 affected individuals had average age of 16 years, and no sex association with the presence of AI was found. The most frequent clinical subtypes were as follows: 43% hypomature, 25% hypoplastic, 21% hypomature/hypoplastic, 7% hypocalcified and 4% hypocalcified/hypoplastic. The number of severely affected teeth was 22, which occurred in the patients with hypocalcified and hypocalcified/hypoplasic AI who presented the highest number of damaged teeth. Caries and periodontal disease were found in 47 and 32% of the patients, respectively. Malocclusions were observed in 43% of the individuals with AI, with open bite being the most frequent. Radiographically, the thickness of the enamel decreased in 51% of the patients, and 80% showed decreased radiopacity of the enamel compared to that of dentin. Autosomal dominant inheritance pattern was found in 37% of the families with hypoplastic AI, and autosomal recessive pattern was present in 56% of the other clinical subtypes, but more frequently in those affected with hypomature and hypocalcified AI. Conclusion: Of the five clinical subtypes, autosomal recessive hypomature, autosomal dominant hypoplastic and autosomal recessive hypomature/hypoplastic AI were the most prevalent subtypes in this group.
Premedication practices for delivery room intubations in premature infants in France: Results from the EPIPAGE 2 cohort study

Objectives To assess premedication practices before tracheal intubation of premature newborns in the delivery room (DR). Study design From the national population-based prospective EPIPAGE 2 cohort in 2011, we extracted all live born preterms intubated in the DR in level-3 centers, without subsequent circulatory resuscitation. Studied outcomes included the rate and type of premedication, infants’ and maternities’ characteristics and survival and major neonatal morbidities at discharge from hospital. Univariate and multivariate analysis were performed and a generalized estimating equation was used to identify factors associated with premedication use. Results Out of 1494 included neonates born in 65 maternities, 76 (5.1%) received a premedication. Midazolam was the most used drug accounting for 49% of the nine drugs regimens observed. Premedicated, as compared to non premedicated neonates, had a higher median [IQR] gestational age (30 [28–31] vs 28 [27–30] weeks, p<10−3), median birth weight (1391 [1037–1767] vs 1074 [840–1440] g, p<10−3) and median 1-minute Apgar score (8 [6–9] vs 6 [3–8], p<10−3). Using univariate analyses, premedication was significantly less frequent after maternal general anesthesia and during nighttime and survival without major morbidity was significantly higher among premedicated neonates (56/73 (81.4%) vs 870/1341 (69.3%), p = 0.028). Only 10 centers used premedication at least once and had characteristics comparable to the 55 other centers. In these 10 centers, premedication rates varied from 2% to 75%, and multivariate analysis identified gestational age and 1-minute Apgar score as independent factors associated with premedication use. Conclusion Premedication rate before tracheal intubation was only 5.1% in the DR of level-3 maternities for premature neonates below 34 weeks of gestation in France in 2011 and seemed to be mainly associated with centers’ local policies.
Why Do Birds Flock? A Role for Opioids in the Reinforcement of Gregarious Social Interactions

The formation of social groups provides safety and opportunities for individuals to develop and practice important social skills. However, joining a social group does not result in any form of obvious, immediate reinforcement (e.g., it does not result in immediate copulation or a food reward), and individuals often remain in social groups despite agonistic responses from conspecifics. Much is known about neural and endocrine mechanisms underlying the motivation to perform mate- or offspring-directed behaviors. In contrast, relatively little is known about mechanisms underlying affiliative behaviors outside of these primary reproductive contexts. Studies on flocking behavior in songbirds are beginning to fill this knowledge gap. Here we review behavioral evidence that supports the hypothesis that non-sexual affiliative, flocking behaviors are both (1) rewarded by positive social interactions with conspecifics, and (2) reinforced because affiliative contact reduces a negative affective state caused by social isolation. We provide evidence from studies in European starlings, Sturnus vulgaris, that mu opioid receptors in the medial preoptic nucleus (mPOA) play a central role in both reward and the reduction of a negative affective state induced by social interactions in flocks, and discuss potential roles for nonapeptide/opioid interactions and steroid hormones. Finally, we develop the case that non-sexual affiliative social behaviors may be modified by two complementary output pathways from mPOA, with a projection from mPOA to the periaqueductal gray integrating information during social interactions that reduces negative affect and a projection from mPOA to the ventral tegmental area integrating information leading to social approach and reward.
Attention in Bilingual Children With Developmental Language Disorder

Purpose Attention and language are hypothesized to interact in bilingual children and in children with developmental language disorder (DLD). In children who are bilingual, attentional control may be enhanced by repeated experience regulating 2 languages. In children with DLD, subtle weaknesses in sustained attention may relate to impaired language processing. This study measured attentional control and sustained attention in monolingual and bilingual children with and without DLD in order to examine the potential influences of bilingualism and DLD, as well as their intersection, on attention. Method Monolingual English-only and bilingual Spanish–English children aged 6–8 years were categorized into participant groups based on eligibility testing and parent interviews. Parent interviews included standardized assessment of language environment and parent concern regarding language. Participants completed 2 nonlinguistic computerized assessments: a flanker task to measure attentional control and a continuous performance task to measure sustained attention. Results One hundred nine children met all eligibility criteria for inclusion in a participant group. Regression models predicting performance on the attention tasks were similar for both sustained attention and attentional control. For both tasks, DLD was a significant predictor, and bilingualism was not. Measuring bilingualism continuously using parent-reported exposure did not alter results. Conclusions This study found no evidence of a “bilingual cognitive advantage” on 2 types of attention among sequential Spanish–English bilingual children but also found a negative effect of DLD that was consistent across both types of attention and both bilingual and monolingual children. Results are consistent with the broader literature on subtle nonlinguistic deficits in children with DLD and suggest these deficits are minimally affected by diverse linguistic experience.