Exploring the relationship between admixture and genetic susceptibility to attention deficit hyperactivity disorder in two Latin American cohorts.

Contemporary research on the genomics of Attention Deficit Hyperactivity Disorder (ADHD) often underrepresents admixed populations of diverse genomic ancestries, such as Latin Americans. This study explores the relationship between admixture and genetic associations for ADHD in Colombian and Mexican cohorts. Some 546 participants in two groups, ADHD and Control, were genotyped with Infinium PsychArray®. Global ancestry levels were estimated using overall admixture proportions and principal component analysis, while local ancestry was determined using a method to estimate ancestral components along the genome. Genome-wide association analysis (GWAS) was conducted to identify significant associations. Differences between Colombia and Mexico were evaluated using appropriate statistical tests. 354 Single-nucleotide polymorphisms (SNPs) and Single-nucleotide variants (SNVs) related to some genes and intergenic regions exhibited suggestive significance (p-value < 5*10e-5) in the GWAS. None of the variants revealed genome-wide significance (p-value < 5*10e-8). The study identified a significant relationship between risk SNPs and the European component of admixture, notably observed in the LOC105379109 gene. Despite differences in risk association loci, such as FOXP2, our findings suggest a possible homogeneity in genetic variation's impact on ADHD between Colombian and Mexican populations. Current reference datasets for ADHD predominantly consist of samples with high European ancestry, underscoring the need for further research to enhance the representation of reference populations and improve the identification of ADHD risk traits in Latin Americans.

Esthetic integration area concept in digitally guided veneer rehabilitation: A dental technique.

Computer-aided design and computer-aided manufacturing (CAD-CAM) technologies have been integrated into the dental digital workflow. However, pretreatment virtual veneer preparations and the digital design and manufacturing of guided preparation and cementation templates has not yet been incorporated into the clinical routine. This article presents a novel protocol for digitally guided veneer rehabilitation by following the esthetic integration area concept, facilitating precise control over tooth structure removal and obviating the need for interim restorations.

Prospective study of thyroid function in the first year of life in infants with Down syndrome.

Current American Academy of Pediatrics (AAP) Guidelines recommend monitoring thyroid function in infants with Down syndrome (DS) at birth, 6 and 12 months, and annually thereafter. This study aimed to determine whether these guidelines are optimal for early diagnosis and treatment of (subclinical) hypothyroidism. Enrolled infants with DS less than age 7 months, born at ≥ 30 weeks gestation to monitor thyroid function test (TFT). A filter paper (FP) blood sample was analyzed for TSH and total T4 at ages 2 and 4 weeks and monthly thereafter until 12 months. Subjects with abnormal FP sample and confirmatory serum TFT for hypothyroidism promptly started treatment. Subjects with thyroid dysfunction identified had thyroid antibodies measured at diagnosis and 12 months. Descriptive statistics determined average time to diagnosis of abnormal TFT. Sixteen (30%) of 54 subjects were diagnosed with a thyroid disorder, the majority with subclinical hypothyroidism (SH) and 1 with hyperthyroidism. Diagnosis occurred in 6 (11%), 9 (17%), and 12 (22.2%) infants in the first 30, 60, and 90 days of life (DOL), respectively. Eight infants had an abnormal NBS and half were diagnosed with a thyroid disorder by DOL 8 and the remainder prior to 4 months. Among subjects with a normal NBS, four were diagnosed at a mean of 104 days and three at a mean of 101 days prior to the 6-month and 12-month routine screens, respectively.  Conclusion: Based on current AAP guidelines, thyroid disorder diagnosis would have been delayed in nearly 20% of the subjects. An additional TFT screen at 1 and 3 months can lead to earlier diagnosis and treatment. What is Known: • Current American Academy of Pediatrics (AAP) Guidelines recommend thyroid function tests (TFT) in infants with Down syndrome (DS) at birth and 6 and 12 months. • Peer- reviewed retrospective studies report an increased incidence of hypothyroidism in infants with DS undetected by the newborn screen (NBS) and prior to 6 months. What is New: • This prospective study monitored TFT in infants with DS at age 2 weeks and monthly throughout the first year of life. • The findings in this study support additional TFT screens at 1 and 3 months in infants with DS.

BioModels-15 years of sharing computational models in life science.

Computational modelling has become increasingly common in life science research. To provide a platform to support universal sharing, easy accessibility and model reproducibility, BioModels (https://www.ebi.ac.uk/biomodels/), a repository for mathematical models, was established in 2005. The current BioModels platform allows submission of models encoded in diverse modelling formats, including SBML, CellML, PharmML, COMBINE archive, MATLAB, Mathematica, R, Python or C++. The models submitted to BioModels are curated to verify the computational representation of the biological process and the reproducibility of the simulation results in the reference publication. The curation also involves encoding models in standard formats and annotation with controlled vocabularies following MIRIAM (minimal information required in the annotation of biochemical models) guidelines. BioModels now accepts large-scale submission of auto-generated computational models. With gradual growth in content over 15 years, BioModels currently hosts about 2000 models from the published literature. With about 800 curated models, BioModels has become the world's largest repository of curated models and emerged as the third most used data resource after PubMed and Google Scholar among the scientists who use modelling in their research. Thus, BioModels benefits modellers by providing access to reliable and semantically enriched curated models in standard formats that are easy to share, reproduce and reuse.

Major Histocompatibility Complex Class I Chain-Related α (MICA) STR Polymorphisms in COVID-19 Patients.

The SARS-CoV-2 disease presents different phenotypes of severity. Comorbidities, age, and being overweight are well established risk factors for severe disease. However, innate immunity plays a key role in the early control of viral infections and may condition the gravity of COVID-19. Natural Killer (NK) cells are part of innate immunity and are important in the control of virus infection by killing infected cells and participating in the development of adaptive immunity. Therefore, we studied the short tandem repeat (STR) transmembrane polymorphisms of the major histocompatibility complex class I chain-related A (MICA), an NKG2D ligand that induces activation of NK cells, among other cells. We compared the alleles and genotypes of MICA in COVID-19 patients versus healthy controls and analyzed their relation to disease severity. Our results indicate that the MICA*A9 allele is related to infection as well as to symptomatic disease but not to severe disease. The MICA*A9 allele may be a risk factor for SARS-CoV-2 infection and symptomatic disease.

COVID-19-Associated Mold Infection in Critically Ill Patients, Chile.

Patients with severe coronavirus disease (COVID-19) may have COVID-19-associated invasive mold infection (CAIMI) develop. We report 16 cases of CAIMI among 146 nonimmunocompromised patients with severe COVID-19 at an academic hospital in Santiago, Chile. These rates correspond to a CAIMI incidence of 11%; the mortality rate for these patients was 31.2%.

SBML Level 3: an extensible format for the exchange and reuse of biological models.

Systems biology has experienced dramatic growth in the number, size, and complexity of computational models. To reproduce simulation results and reuse models, researchers must exchange unambiguous model descriptions. We review the latest edition of the Systems Biology Markup Language (SBML), a format designed for this purpose. A community of modelers and software authors developed SBML Level 3 over the past decade. Its modular form consists of a core suited to representing reaction-based models and packages that extend the core with features suited to other model types including constraint-based models, reaction-diffusion models, logical network models, and rule-based models. The format leverages two decades of SBML and a rich software ecosystem that transformed how systems biologists build and interact with models. More recently, the rise of multiscale models of whole cells and organs, and new data sources such as single-cell measurements and live imaging, has precipitated new ways of integrating data with models. We provide our perspectives on the challenges presented by these developments and how SBML Level 3 provides the foundation needed to support this evolution.

Development of neutralizing antibody responses against SARS-CoV-2 in COVID-19 patients.

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) are new global problems. The understanding of the host immune response in COVID-19 and its implications in the development of therapeutic agents are new challenges. Here, we evaluated the development of immunoglobulin G (IgG) and neutralizing (Nt) antibodies in symptomatic hospitalized COVID-19 patients. We followed up 117 COVID-19 confirmed patients from a reference health center for COVID-19 during the epidemic in Santiago de Chile. One and two sequential blood samples from 117 to 68 cases were, respectively, obtained to evaluate the immune response. Immunofluorescence and neutralization assays in Vero E6 cells with a Chilean SARS-CoV-2 strain were performed. Out of the 68 patients, 44% were women and 56% men, and the most frequent comorbidities were hypertension (47.7%) and diabetes (27.4%). The most frequent symptoms or signs related to COVID-19 were dyspnea, cough, fever, myalgia, and headache. In all the study population, 76.1% and 60.7% of patients were positive for IgG and Nt antibodies in the first blood sample. All patients except one were positive for IgG and Nt antibodies in the second sample. IgG and Nt antibodies positivity increased significantly according to the disease evolution periods. Higher Nt antibody titers were observed in the first sample in patients under 60 years of age. Obese and diabetic patients had no increase in Nt antibodies, unlike normal weight and diabetes-free patients. Both hypertensive and normotensive patients showed a significant increase in Nt antibodies. These results show an early and robust immune response against SARS-CoV-2 infection during severe COVID-19.

Binding and crossing: Methods for the characterization of membrane-active peptides interactions with membranes at the molecular level.

Antimicrobial and cell-penetrating peptides have been the object of extensive studies for more than 60 years. Initially these two families were studied separately, and more recently parallels have been drawn. These studies have given rise to numerous methodological developments both in terms of observation techniques and membrane models. This review presents some of the most recent original and innovative developments in this field, namely droplet interface bilayers (DIBs), new fluorescence approaches, force measurements, and photolabelling.

Tumor Escape Phenotype in Bladder Cancer Is Associated with Loss of HLA Class I Expression, T-Cell Exclusion and Stromal Changes.

Cancer eradication and clinical outcome of immunotherapy depend on tumor cell immunogenicity, including HLA class I (HLA-I) and PD-L1 expression on malignant cells, and on the characteristics of the tumor microenvironment, such as tumor immune infiltration and stromal reaction. Loss of tumor HLA-I is a common mechanism of immune escape from cytotoxic T lymphocytes and is linked to cancer progression and resistance to immunotherapy with the inhibitors of PD-L1/PD-1 signaling. Here we observed that HLA-I loss in bladder tumors is associated with T cell exclusion and tumor encapsulation with stromal elements rich in FAP-positive cells. In addition, PD-L1 upregulation in HLA-I negative tumors demonstrated a correlation with high tumor grade and worse overall- and cancer-specific survival of the patients. These changes define common immuno-morphological signatures compatible with cancer immune escape and acquired resistance to therapeutic interventions across different types of malignancy. They also may contribute to the search of new targets for cancer treatment, such as FAP-expressing cancer-associated fibroblasts, in refractory bladder tumors.

Safety and Performance of Titanium Suture Anchors Used in Knee Ligament Repair Procedures.

Injuries to the knee ligaments can be particularly disabling in young patients, given the risk of long-term disability if adequate fixation is not achieved during initial repair. The TWINFIX™ titanium (Ti) suture anchor with ULTRABRAID™ Suture (Smith and Nephew, London, UK) was designed to secure tendon and ligament reconstructions with increased boney ingrowth at the anchor site with minimal invasive technique. This retrospective analysis looked at 33 patients (41 implants) operated with this device between 2015 and 2019 at a single institution. The average age of patients was 33.18 years (standard deviation [SD], 15.26), with an average body mass index of 24.88 (SD, 3.49). The indications were lateral extra-articular tenodesis during anterior cruciate ligament reconstruction, medial patellofemoral ligament reconstruction, quadriceps or patellar tendon repair and medial collateral ligament repair. After an average follow up of 24.3 + 6.53 months, there was no reports of clinical failure or radiographic evidence of implant failure or loosening. One patient experienced a complication unrelated to the study device, requiring manipulation under anesthesia with resolution of symptoms. This case series supports the safety and performance of this implants for the knee procedures in which its use is indicated. Additional follow-up will be required to determine whether these effects are sustained at medium- and long-term durations.

Salivary cortisol levels as a biomarker for severity of withdrawal in opioid-exposed newborns.

BACKGROUND: Scoring tools used to quantify withdrawal in infants with neonatal abstinence syndrome (NAS) are often confounded by subjective measurements. This study assessed salivary cortisol as an objective biomarker of withdrawal severity in opioid-exposed newborns. METHODS: A prospective study was conducted in 25 full-term opioid-exposed newborns monitored for NAS. Morning and evening salivary cortisol levels were collected starting within 48 h post birth until initiation of pharmacologic treatment for withdrawal (Pre-Treatment) or when the infant was discharged without pharmacotherapy (No Treatment). RESULTS: Cortisol levels in the Pre-Treatment group (n = 11) were significantly higher within the first week of life (median 1.74 µg/dl) than in the No Treatment group (n = 11; median 0.72 µg/dl; P = 0.003); three infants had inadequate saliva volume for cortisol assay. Cortisol significantly decreased after 72 h post birth among infants discharged without pharmacotherapy (≤72 h median 1.25 µg/dl; ≥72 h median 0.58 µg/dl; P = 0.022), whereas cortisol remained elevated for infants subsequently treated for severity of withdrawal. No cortisol circadian rhythm was observed for either group. CONCLUSIONS: Salivary cortisol in opioid-exposed newborns may provide an index of stress and help identify infants who will have more severe clinical presentation of NAS. Such a biomarker would allow risk stratification for early treatment and discharge decisions.

BioModels: expanding horizons to include more modelling approaches and formats.

BioModels serves as a central repository of mathematical models representing biological processes. It offers a platform to make mathematical models easily shareable across the systems modelling community, thereby supporting model reuse. To facilitate hosting a broader range of model formats derived from diverse modelling approaches and tools, a new infrastructure for BioModels has been developed that is available at http://www.ebi.ac.uk/biomodels. This new system allows submitting and sharing of a wide range of models with improved support for formats other than SBML. It also offers a version-control backed environment in which authors and curators can work collaboratively to curate models. This article summarises the features available in the current system and discusses the potential benefit they offer to the users over the previous system. In summary, the new portal broadens the scope of models accepted in BioModels and supports collaborative model curation which is crucial for model reproducibility and sharing.

Association between Genetic Polymorphisms of Inflammatory Response Genes and Acute Pancreatitis.

Inflammation plays a central role in the pathophysiology of acute pancreatitis (AP). We hypothesized that changes in the function of key components of the inflammatory cascade, caused by genetic polymorphisms, could determine the development and/or severity of AP. We studied the following polymorphisms in 269 patients: IL23R rs11209026, TNF rs1800629, RIPK2 rs42490, NOD2 rs9302752, MCP1 rs1024611 and NFKB1 rs28362491. The rs11209026 A allele was related to the presence of AP (p = 0.007261; OR = 1 .523). Epistasis analysis revealed that AP susceptibility was increased by interaction between IL23R rs11209026 and TNF rs1800629 (p = 1.205 × 10-5; ORinteraction = 4.031). The rs42490-G allele was associated with an increased risk of severe pancreatitis (p = 0.01583; OR = 2.736), severe or moderately severe pancreatitis (p = 0.04206; OR = 1.609), and death (p = 0.03226; OR = 3.010). In conclusion, these results point to a plausible role for genetic polymorphisms in IL23R and RIPK2 in the development and severity of AP.

Snapshot of sequential SNARE assembling states between membranes shows that N-terminal transient assembly initializes fusion.

Many prominent biological processes are driven by protein assembling between membranes. Understanding the mechanisms then entails determining the assembling pathway of the involved proteins. Because the intermediates are by nature transient and located in the intermembrane space, this determination is generally a very difficult, not to say intractable, problem. Here, by designing a setup with sphere/plane geometry, we have been able to freeze one transient state in which the N-terminal domains of SNARE proteins are assembled. A single camera frame is sufficient to obtain the complete probability of this state with the transmembrane distance. We show that it forms when membranes are 20 nm apart and stabilizes by further assembling of the SNAREs at 8 nm. This setup that fixes the intermembrane distance, and thereby the transient states, while optically probing the level of molecular assembly by Förster resonance energy transfer (FRET) can be used to characterize any other transient transmembrane complexes.

Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial.

Importance: Abnormal peripheral perfusion after septic shock resuscitation has been associated with organ dysfunction and mortality. The potential role of the clinical assessment of peripheral perfusion as a target during resuscitation in early septic shock has not been established. Objective: To determine if a peripheral perfusion-targeted resuscitation during early septic shock in adults is more effective than a lactate level-targeted resuscitation for reducing mortality. Design, Setting, and Participants: Multicenter, randomized trial conducted at 28 intensive care units in 5 countries. Four-hundred twenty-four patients with septic shock were included between March 2017 and March 2018. The last date of follow-up was June 12, 2018. Interventions: Patients were randomized to a step-by-step resuscitation protocol aimed at either normalizing capillary refill time (n = 212) or normalizing or decreasing lactate levels at rates greater than 20% per 2 hours (n = 212), during an 8-hour intervention period. Main Outcomes and Measures: The primary outcome was all-cause mortality at 28 days. Secondary outcomes were organ dysfunction at 72 hours after randomization, as assessed by Sequential Organ Failure Assessment (SOFA) score (range, 0 [best] to 24 [worst]); death within 90 days; mechanical ventilation-, renal replacement therapy-, and vasopressor-free days within 28 days; intensive care unit and hospital length of stay. Results: Among 424 patients randomized (mean age, 63 years; 226 [53%] women), 416 (98%) completed the trial. By day 28, 74 patients (34.9%) in the peripheral perfusion group and 92 patients (43.4%) in the lactate group had died (hazard ratio, 0.75 [95% CI, 0.55 to 1.02]; P = .06; risk difference, -8.5% [95% CI, -18.2% to 1.2%]). Peripheral perfusion-targeted resuscitation was associated with less organ dysfunction at 72 hours (mean SOFA score, 5.6 [SD, 4.3] vs 6.6 [SD, 4.7]; mean difference, -1.00 [95% CI, -1.97 to -0.02]; P = .045). There were no significant differences in the other 6 secondary outcomes. No protocol-related serious adverse reactions were confirmed. Conclusions and Relevance: Among patients with septic shock, a resuscitation strategy targeting normalization of capillary refill time, compared with a strategy targeting serum lactate levels, did not reduce all-cause 28-day mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT03078712.

Binding of sperm protein Izumo1 and its egg receptor Juno drives Cd9 accumulation in the intercellular contact area prior to fusion during mammalian fertilization.

Little is known about the molecular mechanisms that induce gamete fusion during mammalian fertilization. After initial contact, adhesion between gametes only leads to fusion in the presence of three membrane proteins that are necessary, but insufficient, for fusion: Izumo1 on sperm, its receptor Juno on egg and Cd9 on egg. What happens during this adhesion phase is a crucial issue. Here, we demonstrate that the intercellular adhesion that Izumo1 creates with Juno is conserved in mouse and human eggs. We show that, along with Izumo1, egg Cd9 concomitantly accumulates in the adhesion area. Without egg Cd9, the recruitment kinetics of Izumo1 are accelerated. Our results suggest that this process is conserved across species, as the adhesion partners, Izumo1 and its receptor, are interchangeable between mouse and human. Our findings suggest that Cd9 is a partner of Juno, and these discoveries allow us to propose a new model of the molecular mechanisms leading to gamete fusion, in which the adhesion-induced membrane organization assembles all key players of the fusion machinery.

BioModels: ten-year anniversary.

BioModels (http://www.ebi.ac.uk/biomodels/) is a repository of mathematical models of biological processes. A large set of models is curated to verify both correspondence to the biological process that the model seeks to represent, and reproducibility of the simulation results as described in the corresponding peer-reviewed publication. Many models submitted to the database are annotated, cross-referencing its components to external resources such as database records, and terms from controlled vocabularies and ontologies. BioModels comprises two main branches: one is composed of models derived from literature, while the second is generated through automated processes. BioModels currently hosts over 1200 models derived directly from the literature, as well as in excess of 140,000 models automatically generated from pathway resources. This represents an approximate 60-fold growth for literature-based model numbers alone, since BioModels' first release a decade ago. This article describes updates to the resource over this period, which include changes to the user interface, the annotation profiles of models in the curation pipeline, major infrastructure changes, ability to perform online simulations and the availability of model content in Linked Data form. We also outline planned improvements to cope with a diverse array of new challenges.

The systems biology format converter.

BACKGROUND: Interoperability between formats is a recurring problem in systems biology research. Many tools have been developed to convert computational models from one format to another. However, they have been developed independently, resulting in redundancy of efforts and lack of synergy. RESULTS: Here we present the System Biology Format Converter (SBFC), which provide a generic framework to potentially convert any format into another. The framework currently includes several converters translating between the following formats: SBML, BioPAX, SBGN-ML, Matlab, Octave, XPP, GPML, Dot, MDL and APM. This software is written in Java and can be used as a standalone executable or web service. CONCLUSIONS: The SBFC framework is an evolving software project. Existing converters can be used and improved, and new converters can be easily added, making SBFC useful to both modellers and developers. The source code and documentation of the framework are freely available from the project web site.

JSBML 1.0: providing a smorgasbord of options to encode systems biology models.

UNLABELLED: JSBML, the official pure Java programming library for the Systems Biology Markup Language (SBML) format, has evolved with the advent of different modeling formalisms in systems biology and their ability to be exchanged and represented via extensions of SBML. JSBML has matured into a major, active open-source project with contributions from a growing, international team of developers who not only maintain compatibility with SBML, but also drive steady improvements to the Java interface and promote ease-of-use with end users. AVAILABILITY AND IMPLEMENTATION: Source code, binaries and documentation for JSBML can be freely obtained under the terms of the LGPL 2.1 from the website http://sbml.org/Software/JSBML. More information about JSBML can be found in the user guide at http://sbml.org/Software/JSBML/docs/. CONTACT: jsbml-development@googlegroups.com or andraeger@eng.ucsd.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.