A fully human IgG1 antibody targeting connexin 32 extracellular domain blocks CMTX1 hemichannel dysfunction in an in vitro model.

Connexins (Cxs) are fundamental in cell-cell communication, functioning as gap junction channels (GJCs) that facilitate solute exchange between adjacent cells and as hemichannels (HCs) that mediate solute exchange between the cytoplasm and the extracellular environment. Mutations in the GJB1 gene, which encodes Cx32, lead to X-linked Charcot-Marie-Tooth type 1 (CMTX1), a rare hereditary demyelinating disorder of the peripheral nervous system (PNS) without an effective cure or treatment. In Schwann cells, Cx32 HCs are thought to play a role in myelination by enhancing intracellular and intercellular Ca signaling, which is crucial for proper PNS myelination.

Molecular Dynamics Simulation of Permeation Through Connexin Channels.

Molecular dynamics (MD) simulations are a collection of computational tools that can be used to trace intermolecular interactions at the sub-nanometer level. They offer possibilities that are often unavailable to experimental methods, making MD an ideal complementary technique for the understanding a plethora of biological processes. Thanks to significant efforts by many groups of developers around the world, setting up and running MD simulations has become progressively simpler.

Variability in excess deaths across countries with different vulnerability during 2020-2023.

Excess deaths provide total impact estimates of major crises, such as the COVID-19 pandemic. We evaluated excess death trajectories across countries with accurate death registration and population age structure data and assessed relationships with vulnerability indicators. Using the Human Mortality Database on 34 countries, excess deaths were calculated for 2020-2023 (to week 29, 2023) using 2017-2019 as reference, with adjustment for 5 age strata.

RAGE engagement by SARS-CoV-2 enables monocyte infection and underlies COVID-19 severity.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has fueled the COVID-19 pandemic with its enduring medical and socioeconomic challenges because of subsequent waves and long-term consequences of great concern. Here, we chart the molecular basis of COVID-19 pathogenesis by analyzing patients' immune responses at single-cell resolution across disease course and severity. This approach confirms cell subpopulation-specific dysregulation in COVID-19 across disease course and severity and identifies a severity-associated activation of the receptor for advanced glycation endproducts (RAGE) pathway in monocytes.

Development of a machine learning multiclass screening tool for periodontal health status based on non-clinical parameters and salivary biomarkers.

Aim: To develop a multiclass non-clinical screening tool for periodontal disease and assess its accuracy for differentiating periodontal health, gingivitis and different stages of periodontitis.

Materials And Methods: A cross-sectional diagnostic study on a convenience sample of 408 consecutive subjects was conducted by applying three non-clinical index tests estimating different features of the periodontal health-disease spectrum: a self-administered questionnaire, an oral rinse activated matrix metalloproteinase-8 (aMMP-8) point-of-care test (POCT) and determination of gingival bleeding on brushing (GBoB). Full-mouth periodontal examination was the reference standard.

A facile, semi-automatic protocol for the design and production of 3D printed, anatomical customized orthopedic casts for forearm fractures.

Closed fractures of distal radius and ulna are one of the most common skeletal injuries, occurring at all ages. Temporary arm immobilization through cast is part of the standard treatments. However, traditional casting procedures are time consuming, operator's skill dependent and do not always guarantee a satisfactory outcome.

Variability in excess deaths across countries with different vulnerability during 2020-2023.

Excess deaths provide total impact estimates of major crises, such as the COVID-19 pandemic. We evaluated excess death's trajectories during 2020-2023 across countries with accurate death registration and population age structure data; and assessed relationships with economic indicators of vulnerability. Using the Human Mortality Database on 34 countries, excess deaths were calculated for 2020-2023 (to week 29, 2023) using 2017-2019 as reference, with weekly expected death calculations and adjustment for 5 age strata.

Flaws and uncertainties in pandemic global excess death calculations.

Several teams have been publishing global estimates of excess deaths during the COVID-19 pandemic. Here, we examine potential flaws and underappreciated sources of uncertainty in global excess death calculations. Adjusting for changing population age structure is essential.

Excess death estimates from multiverse analysis in 2009-2021.

Excess death estimates have great value in public health, but they can be sensitive to analytical choices. Here we propose a multiverse analysis approach that considers all possible different time periods for defining the reference baseline and a range of 1 to 4 years for the projected time period for which excess deaths are calculated. We used data from the Human Mortality Database on 33 countries with detailed age-stratified death information on an annual basis during the period 2009-2021.

Antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice.

Background: Keratitis ichthyosis deafness (KID) syndrome is a rare disorder caused by hemichannel (HC) activating gain-of-function mutations in the GJB2 gene encoding connexin (Cx) 26, for which there is no cure, or current treatments based upon the mechanism of disease causation.

Methods: We applied Adeno Associated Virus (AAV) mediated mAb gene transfer (AAVmAb) to treat the epidermal features of KID syndrome with a well-characterized HC blocking antibody using male mice of a murine model that replicates the skin pathology of the human disease.

Findings: We demonstrate that in vivo AAVmAb treatment significantly reduced the size and thickness of KID lesions, in addition to blocking activity of mutant HCs in the epidermis in vivo.

Estimates of COVID-19 deaths in Mainland China after abandoning zero COVID policy.

Background: China witnessed a surge of Omicron infections after abandoning 'zero COVID' strategies on 7 December 2022. The authorities report very sparse deaths based on very restricted criteria, but massive deaths are speculated.

Methods: We aimed to estimate the COVID-19 fatalities in Mainland China until summer 2023 using the experiences of Hong Kong and of South Korea in 2022 as prototypes.

Estimates of COVID-19 deaths in Mainland China after abandoning zero COVID policy.

Background: China witnessed a surge of Omicron infections after abandoning zero COVID strategies on December 7, 2022. The authorities report very sparse deaths based on very restricted criteria, but massive deaths are speculated.

Methods: We aimed to estimate the COVID-19 fatalities in Mainland China until summer 2023 using the experiences of Hong Kong and of South Korea in 2022 as prototypes.

Left atrial appendage occlusion in ventricular assist device patients to decrease thromboembolic events: A computer simulation study.

Atrial fibrillation (AF) is a common comorbidity in left ventricular assist device (LVAD) patients and has been identified as a risk factor for thromboembolic stroke. Blood stagnation within the left atrial appendage (LAA) is considered a possible major source of thrombosis and clinical studies have shown reduced thromboembolic risk after LAA occlusion (LAAO). Therefore, this study aims to investigate the effect of LAAO on thrombosis-related parameters using patient-specific simulations.

Virus spread on a scale-free network reproduces the Gompertz growth observed in isolated COVID-19 outbreaks.

The counts of confirmed cases and deaths in isolated SARS-CoV-2 outbreaks follow the Gompertz growth function for locations of very different sizes. This lack of dependence on region size leads us to hypothesize that virus spread depends on the universal properties of the network of social interactions. We test this hypothesis by simulating the propagation of a virus on networks of different topologies or connectivities.

Excess death estimates from multiverse analysis in 2009-2021.

Excess death estimates have great value in public health, but they can be sensitive to analytical choices. Here we propose a multiverse analysis approach that considers all possible different time periods for defining the reference baseline and a range of 1 to 4 years for the projected time period for which excess deaths are calculated. We used data from the Human Mortality Database on 33 countries with detailed age-stratified death information on an annual basis during the period 2009-2021.

In Silico Maturation of a Nanomolar Antibody against the Human CXCR2.

The steady increase in computational power in the last 50 years is opening unprecedented opportunities in biology, as computer simulations of biological systems have become more accessible and can reproduce experimental results more accurately. Here, we wanted to test the ability of computer simulations to replace experiments in the limited but practically useful scope of improving the biochemical characteristics of the abN48 antibody, a nanomolar antagonist of the CXC chemokine receptor 2 (CXCR2) that was initially selected from a combinatorial antibody library. Our results showed a good correlation between the computed binding energies of the antibody to the peptide target and the experimental binding affinities.

Construction of a Deep Neural Network Energy Function for Protein Physics.

The traditional approach of computational biology consists of calculating molecule properties by using approximate classical potentials. Interactions between atoms are described by an energy function derived from physical principles or fitted to experimental data. Their functional form is usually limited to pairwise interactions between atoms and does not consider complex multibody effects.

A Quantitative Assay for Ca Uptake through Normal and Pathological Hemichannels.

Connexin (Cx) hemichannels (HCs) are large pore hexameric structures that allow the exchange of ions, metabolites and a variety of other molecules between the cell cytoplasm and extracellular milieu. HC inhibitors are attracting growing interest as drug candidates because deregulated fluxes through HCs have been implicated in a plethora of genetic conditions and other diseases. HC activity has been mainly investigated by electrophysiological methods and/or using HC-permeable dye uptake measurements.

Comparison of pandemic excess mortality in 2020-2021 across different empirical calculations.

Different modeling approaches can be used to calculate excess deaths for the COVID-19 pandemic period. We compared 6 calculations of excess deaths (4 previously published [3 without age-adjustment] and two new ones that we performed with and without age-adjustment) for 2020-2021. With each approach, we calculated excess deaths metrics and the ratio R of excess deaths over recorded COVID-19 deaths.

The Gompertz Growth of COVID-19 Outbreaks is Caused by Super-Spreaders.

In individual SARS-CoV-2 outbreaks, the count of confirmed cases and deaths follow a Gompertz growth function for locations of very different sizes. This lack of dependence on region size leads us to hypothesize that virus spread depends on universal properties of the network of social interactions. We test this hypothesis by simulating the propagation of a virus on networks of different topologies.

Rapid Assessment of Binding Affinity of SARS-COV-2 Spike Protein to the Human Angiotensin-Converting Enzyme 2 Receptor and to Neutralizing Biomolecules Based on Computer Simulations.

SARS-CoV-2 infects humans and causes Coronavirus disease 2019 (COVID-19). The S1 domain of the spike glycoprotein of SARS-CoV-2 binds to human angiotensin-converting enzyme 2 (hACE2) its receptor-binding domain, while the S2 domain facilitates fusion between the virus and the host cell membrane for entry. The spike glycoprotein of circulating SARS-CoV-2 genomes is a mutation hotspot.

Effects of the atrium on intraventricular flow patterns during mechanical circulatory support.

Simulations of the ventricular flow patterns during left ventricular assist device (LVAD) support are mainly performed with idealized cylindrical inflow, neglecting the influence of the atrial vortex. In this study, the influence of the left atrium (LA) on the intra-ventricular flow was investigated via Computational Fluid Dynamics (CFD) simulations. Ventricular flow was simulated by a combined Eulerian (carrier flow)/Lagrangian (particles) approach taking into account either the LA or a cylindrical inflow section to mimic a fully support condition.

GM-CSF Nitration Is a New Driver of Myeloid Suppressor Cell Activity in Tumors.

Reactive oxygen species, including RNS, contribute to the control of multiple immune cell functions within the tumor microenvironment (TME). Tumor-infiltrating myeloid cells (TIMs) represent the archetype of tolerogenic cells that actively contribute to dismantle effective immunity against cancer. TIMs inhibit T cell functions and promote tumor progression by several mechanisms including the amplification of the oxidative/nitrosative stress within the TME.