Human alveolar lining fluid from the elderly promotes Mycobacterium tuberculosis intracellular growth and translocation into the cytosol of alveolar epithelial cells.

The elderly population is highly susceptible to developing respiratory diseases, including tuberculosis, a devastating disease caused by the airborne pathogen Mycobacterium tuberculosis (M.tb) that kills one person every 18 seconds. Once M.

Selective Removal of 7KC by a Novel Atherosclerosis Therapeutic Candidate Reverts Foam Cells to a Macrophage-like Phenotype.

The removal of the toxic oxidized cholesterol, 7-ketocholesterol (7KC), from cells through the administration of therapeutics has the potential to treat atherosclerosis and various other pathologies. While cholesterol is a necessary building block for homeostasis, oxidation of cholesterol can lead to the formation of toxic oxysterols involved in various pathologies, the most prominent of which is 7KC, which is formed through the non-enzymatic oxidation of cholesterol. Oxidized LDL (oxLDL) particles, highly implicated in heart disease, contain high levels of 7KC, and molecular 7KC is implicated in the pathogenesis of numerous diseases, including multiple sclerosis, hypercholesterolemia, sickle cell anemia, and multiple age related diseases.

Addressing the complexities in measuring cyclodextrin-sterol binding constants: A multidimensional study.

A class of cyclodextrin (CD) dimers has emerged as a potential new treatment for atherosclerosis; they work by forming strong, soluble inclusion complexes with oxysterols, allowing the body to reduce and heal arterial plaques. However, characterizing the interactions between CD dimers and oxysterols presents formidable challenges due to low sterol solubility, the synthesis of modified CDs resulting in varying number and position of molecular substitutions, and the diversity of interaction mechanisms. To address these challenges and illuminate the nuances of CD-sterol interactions, we have used multiple orthogonal approaches for a comprehensive characterization.

Cellular and electrophysiological characterization of triadin knockout syndrome using induced pluripotent stem cell-derived cardiomyocytes.

Triadin knockout syndrome (TKOS) is a malignant arrhythmia disorder caused by recessive null variants in TRDN-encoded cardiac triadin. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated from two unrelated TKOS patients and an unrelated control. CRISPR-Cas9 gene editing was used to insert homozygous TRDN-p.

Efficacy and safety of an innovative short-course regimen containing clofazimine for treatment of drug-susceptible tuberculosis: a clinical trial.

In preclinical studies, a new antituberculosis drug regimen markedly reduced the time required to achieve relapse-free cure. This study aimed to preliminarily evaluate the efficacy and safety of this four-month regimen, consisting of clofazimine, prothionamide, pyrazinamide and ethambutol, with a standard six-month regimen in patients with drug-susceptible tuberculosis. An open-label pilot randomized clinical trial was conducted among the patients with newly diagnosed bacteriologically-confirmed pulmonary tuberculosis.

Atomic Structure of IglD Demonstrates Its Role as a Component of the Baseplate Complex of the Type VI Secretion System.

Francisella tularensis, a Tier 1 select agent of bioterrorism, contains a type VI secretion system (T6SS) encoded within the pathogenicity island (FPI), which is critical for its pathogenesis. Among the 18 proteins encoded by FPI is IglD, which is essential to 's intracellular growth and virulence, but neither its location within T6SS nor its functional role has been established. Here, we present the cryoEM structure of IglD from Francisella novicida and show that the IglD forms a homotrimer that is structurally homologous to the T6SS baseplate protein TssK in Escherichia coli.

Ibuprofen molecular aggregation by direct back-face transmission steady-state fluorescence.

Direct back-face transmission steady-state fluorescence was successfully applied to the study of aggregation of ibuprofen and ibuprofenate anion in solution taking advantage of its own fluorescence. The analysis of the experimental data involves the use of the differential reabsorption model to account for re-absorption phenomenon and the closed association model to describe aggregation. The fluorescence quantum yield of ibuprofenate increases when it aggregates in the presence of sodium, but it markedly decreases when 1-butyl-3-methylimidazolium is used as counterion.

Stimuli-responsive polyelectrolyte surfactant complexes for the reversible control of solution viscosity.

Interactions of polyelectrolytes with oppositely charged surfactants can give rise to a large variety of self-assembled structures. Some of these systems cause a drastic increase in solution viscosity, which is related to the surfactant forming aggregates interconnecting several polyelectrolyte chains. For these aggregates to form, the surfactant needs to be sufficiently hydrophobic.

Cyclodextrin dimers: A versatile approach to optimizing encapsulation and their application to therapeutic extraction of toxic oxysterols.

We have developed a novel class of specifically engineered, dimerized cyclodextrin (CD) nanostructures for the encapsulation of toxic biomolecules such as 7-ketocholesterol (7KC). 7KC accumulates over time and causes dysfunction in many cell types, linking it to several age-related diseases including atherosclerosis and age-related macular degeneration (AMD). Presently, treatments for these diseases are invasive, expensive, and show limited benefits.

Phenotype-guided whole genome analysis in a patient with genetically elusive long QT syndrome yields a novel TRDN-encoded triadin pathogenetic substrate for triadin knockout syndrome and reveals a novel primate-specific cardiac TRDN transcript.

Background: Triadin knockout syndrome (TKOS) is a rare arrhythmia syndrome caused by recessive null variants in TRDN-encoded cardiac triadin 1. TKOS has presented frequently with cardiac arrest in childhood.

Objective: The purpose of this study was to elucidate the underlying genetic mechanism of disease in a genetically elusive patient displaying a characteristic TKOS phenotype.

Correction: An advanced structural characterization of templated meso-macroporous carbon monoliths by small- and wide-angle scattering techniques.

[This corrects the article DOI: 10.3762/bjnano.11.

VE-1902-A direct thrombin inhibitor with reversible covalent mechanism of action shows efficacy with reduced bleeding in rodent models of thrombosis.

Introduction: High incidence of bleeding events remains a key risk for patients taking anticoagulants, especially those in need of long-term combination therapy with antiplatelet agents. As a consequence, patients may not receive clinically indicated combination antithrombotic therapy. Here, we report on VE-1902, a member of a novel class of precision oral anticoagulants (PROACs) that combines effective anticoagulation with reduced bleeding in preclinical testing.

Triadin Knockout Syndrome Is Absent in a Multi-Center Molecular Autopsy Cohort of Sudden Infant Death Syndrome and Sudden Unexplained Death in the Young and Is Extremely Rare in the General Population.

Background: Triadin knockout syndrome (TKOS) is a potentially lethal arrhythmia disorder caused by recessively inherited null variants in -encoded cardiac triadin. Despite its malignant phenotype, the prevalence of TKOS in sudden infant death syndrome and sudden unexplained death in the young is unknown.

Methods: Exome sequencing was performed on 599 sudden infant death syndrome and 258 sudden unexplained death in the young cases.

An advanced structural characterization of templated meso-macroporous carbon monoliths by small- and wide-angle scattering techniques.

This study is dedicated to link the nanoscale pore space of carbon materials, prepared by hard-templating of meso-macroporous SiO monoliths, to the corresponding nanoscale polyaromatic microstructure using two different carbon precursors wthat generally exhibit markedly different carbonization properties, i.e., a graphitizable pitch and a non-graphitizable resin.

Human Induced Pluripotent Stem Cell-Derived Non-Cardiomyocytes Modulate Cardiac Electrophysiological Maturation Through Connexin 43-Mediated Cell-Cell Interactions.

The functional maturation status of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has a notable impact upon their use in pharmacological studies, disease modeling, and therapeutic applications. Non-cardiomyocytes (non-CMs) produced in the differentiation process have previously been identified as having an extrinsic influence upon hiPSC-CM development, yet the underlying mechanisms are not fully understood. Herein, we aimed to modulate electrophysiological properties of hiPSC-CMs within co-cultures containing varied proportions of non-CMs and investigate the nature of interactions between these different cell types.

Atomic Structure of the Francisella T6SS Central Spike Reveals a Unique α-Helical Lid and a Putative Cargo.

Francisella bacteria rely on a phylogenetically distinct type VI secretion system (T6SS) to escape host phagosomes and cause the fatal disease tularemia, but the structural and molecular mechanisms involved are unknown. Here we report the atomic structure of the Francisella T6SS central spike complex, obtained by cryo-electron microscopy. Our structural and functional studies demonstrate that, unlike the single-protein spike composition of other T6SS subtypes, Francisella T6SS's central spike is formed by two proteins, PdpA and VgrG, akin to T4-bacteriophage gp27 and gp5, respectively, and that PdpA has unique characteristics, including a putative cargo within its cavity and an N-terminal helical lid.

Utilization of the genome aggregation database, in silico tools, and heterologous expression patch-clamp studies to identify and demote previously published type 2 long QT syndrome: Causative variants from pathogenic to likely benign.

Background: Loss-of-function variants in the KCNH2-encoded Kv11.1 potassium channel cause long QT syndrome (LQTS) type 2 (LQT2). Presently, hundreds of KCNH2 missense variants (MVs) have been published as "disease-causative.

Intracellular Photothermal Delivery for Suspension Cells Using Sharp Nanoscale Tips in Microwells.

Efficient intracellular delivery of biomolecules into cells that grow in suspension is of great interest for biomedical research, such as for applications in cancer immunotherapy. Although tremendous effort has been expended, it remains challenging for existing transfer platforms to deliver materials efficiently into suspension cells. Here, we demonstrate a high-efficiency photothermal delivery approach for suspension cells using sharp nanoscale metal-coated tips positioned at the edge of microwells, which provide controllable membrane disruption for each cell in an array.

The domain swapping of human cystatin C induced by synchrotron radiation.

Domain swapping is observed for many proteins with flexible conformations. This phenomenon is often associated with the development of conformational diseases. Importantly, domain swapping has been observed for human cystatin C (HCC), a protein capable of forming amyloid deposits in brain arteries.

Artificial intelligence enabled parabolic response surface platform identifies ultra-rapid near-universal TB drug treatment regimens comprising approved drugs.

Background: Shorter, more effective treatments for tuberculosis (TB) are urgently needed. While many TB drugs are available, identification of the best regimens is challenging because of the large number of possible drug-dose combinations. We have found consistently that responses of cells or whole animals to drug-dose stimulations fit a parabolic response surface (PRS), allowing us to identify and optimize the best drug combinations by testing only a small fraction of the total search space.

BFSP1 C-terminal domains released by post-translational processing events can alter significantly the calcium regulation of AQP0 water permeability.

BFSP1 (beaded filament structural protein 1, filensin) is a cytoskeletal protein expressed in the eye lens. It binds AQP0 in vitro and its C-terminal sequences have been suggested to regulate the water channel activity of AQP0. A myristoylated fragment from the C-terminus of BFSP1 was found in AQP0 enriched fractions.

International Triadin Knockout Syndrome Registry.

Background: Triadin knockout syndrome (TKOS) is a rare, inherited arrhythmia syndrome caused by recessive null mutations in TRDN-encoded cardiac triadin. Based previously on 5 triadin null patients, TKOS has been characterized by extensive T-wave inversions, transient QT prolongation, and severe disease expression of exercise-induced cardiac arrest in early childhood refractory to conventional therapy.

Methods: We have established the International Triadin Knockout Syndrome Registry to include patients who have genetically proven homozygous/compound heterozygous TRDN null mutations.