High-efficiency base editing in the retina in primates and human tissues.

Stargardt disease is a currently untreatable, inherited neurodegenerative disease that leads to macular degeneration and blindness due to loss-of-function mutations in the ABCA4 gene. We have designed a dual adeno-associated viral vector encoding a split-intein adenine base editor to correct the most common mutation in ABCA4 (c.5882G>A, p.

Cytosine base editing inhibits hepatitis B virus replication and reduces HBsAg expression and .

Chronic hepatitis B virus (HBV) infection remains a global health problem due to the lack of treatments that prevent viral rebound from HBV covalently closed circular (ccc)DNA. In addition, HBV DNA integrates in the human genome, serving as a source of hepatitis B surface antigen (HBsAg) expression, which impairs anti-HBV immune responses. Cytosine base editors (CBEs) enable precise conversion of a cytosine into a thymine within DNA.

Tuberculosis Severity Predictive Model Using Mtb Variants and Serum Biomarkers in a Colombian Cohort of APTB Patients.

Currently, tuberculosis (TB) is a bacterial infection caused by (Mtb) that primarily affects the lungs. The severity of active pulmonary TB (APTB) is an important determinant of transmission, morbidity, mortality, disease experience, and treatment outcomes. Several publications have shown a high prevalence of disabling complications in individuals who have had severe APTB.

Large genomic deletions delineate Mycobacterium tuberculosis L4 sublineages in South American countries.

Mycobacterium tuberculosis (Mtb) is still one of the primary pathogens of humans causing tuberculosis (TB) disease. Mtb embraces nine well-defined phylogenetic lineages with biological and geographical disparities. The lineage L4 is the most globally widespread of all lineages and was introduced to America with European colonization.

Brønsted Acid versus Phase-Transfer Catalysis in the Enantioselective Transannular Aminohalogenation of Enesultams.

We have studied the enantioselective transannular aminohalogenation reaction of unsaturated medium-sized cyclic benzosulfonamides by using both chiral Brønsted acid and phase-transfer catalysis. Under optimized conditions, a variety of bicyclic adducts can be obtained with good yields and high enantioselectivities. The mechanism of the reaction was also studied by using computational tools; we observed that the reaction involves the participation of a conformer of the nine-membered cyclic substrate with planar chirality in which the stereochemical outcome is controlled by the relative reactivity of the two pseudorotational enantiomers when interacting with the chiral catalyst.

Transannular Approach to 2,3-Dihydropyrrolo[1,2-]isoquinolin-5(1)-ones through Brønsted Acid-Catalyzed Amidohalogenation.

A transannular approach has been developed for the construction of pyrrolo[1,2-]isoquinolinones starting from benzo-fused nine-membered enelactams. This process takes place in the presence of a halogenating agent and under Brønsted acid catalysis and proceeds via a transannular amidohalogenation, followed by elimination. The reaction has been found to be wide in scope, enabling the formation of a variety of tricyclic products in good overall yield, regardless of the substitution pattern in the initial lactam substrate.

Cytosine base editing enables quadruple-edited allogeneic CART cells for T-ALL.

Allogeneic chimeric antigen receptor T-cell (CART) therapies require multiple gene edits to be clinically tractable. Most allogeneic CARTs have been created using gene editing techniques that induce DNA double-stranded breaks (DSBs), resulting in unintended on-target editing outcomes with potentially unforeseen consequences. Cytosine base editors (CBEs) install C•G to T•A point mutations in T cells, with between 90% and 99% efficiency to silence gene expression without creating DSBs, greatly reducing or eliminating undesired editing outcomes following multiplexed editing as compared with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9).

Dual RNA Sequencing of -Infected Human Splenic Macrophages Reveals a Strain-Dependent Host-Pathogen Response to Infection.

Tuberculosis (TB) is caused by (Mtb), leading to pulmonary and extrapulmonary TB, whereby Mtb is disseminated to many other organs and tissues. Dissemination occurs early during the disease, and bacteria can be found first in the lymph nodes adjacent to the lungs and then later in the extrapulmonary organs, including the spleen. The early global gene expression response of human tissue macrophages and intracellular clinical isolates of Mtb has been poorly studied.

Modulatory Impact of the sRNA Mcr11 in Two Clinical Isolates of Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) is a successful pathogen causing tuberculosis (TB) disease in humans. It has been shown, that some circulating strains of Mtb in TB endemic populations, are more virulent and more transmissible than others, which may be related to their evolved adaptations to modulate the host immune responses. Underlying these adaptations to the stressful conditions, different genetic regulatory networks involved sRNAs that are mostly unknown for Mtb.

Use of a neuron-glia genome-scale metabolic reconstruction to model the metabolic consequences of the Arylsulphatase a deficiency through a systems biology approach.

Metachromatic leukodystrophy (MLD) is a human neurodegenerative disorder characterized by progressive damage on the myelin band in the nervous system. MLD is caused by the impaired function of the lysosomal enzyme Arylsulphatase A (ARSA). The physiopathology mechanisms and the biochemical consequences in the brain of ARSA deficiency are not entirely understood.

Rationally Designed Base Editors for Precise Editing of the Sickle Cell Disease Mutation.

Base editors are fusions of a deaminase and CRISPR-Cas ribonucleoprotein that allow programmable installment of transition mutations without double-strand DNA break intermediates. The breadth of potential base editing targets is frequently limited by the requirement of a suitably positioned Cas9 protospacer adjacent motif. To address this, we used structures of Cas9 and TadA to design a set of inlaid base editors (IBEs), in which deaminase domains are internal to Cas9.

Human recombinant lysosomal β-Hexosaminidases produced in Pichia pastoris efficiently reduced lipid accumulation in Tay-Sachs fibroblasts.

GM2 gangliosidosis, Tay-Sachs and Sandhoff diseases, are lysosomal storage disorders characterized by the lysosomal accumulation of GM2 gangliosides. This accumulation is due to deficiency in the activity of the β-hexosaminidases Hex-A or Hex-B, which are dimeric hydrolases formed by αβ or ββ subunits, respectively. These disorders show similar clinical manifestations that range from mild systemic symptoms to neurological damage and premature death.

Nanoparticle-templated conversion of glucose to a high surface area biocarbon for the removal of organic pollutants in water.

While extensive work has been done on the generation of adsorbents by carbonization of large polymeric structures, few works are currently available for the use of monomeric carbon molecules as precursors during carbonization. In this work we report the formation of a carbon adsorbent material from the carbonization of glucose in the presence of zinc oxide (ZnO) nanoparticle templates. Carbonization at 1,000 °C under inert atmosphere yields a product with Brunauer-Emmett-Teller (BET) surface area of 1,228.

New Conjugated Compound T5 Epidioxy-Sterol-ANB Inhibits the Growth of Affecting the Cholesterol and Folate Pathways.

The upsurge and persistence of drug resistant strains of (Mtb) is an important limitant to the battery of drugs available for the elimination of tuberculosis (TB). To avoid future scarcity of antibiotics against Mtb, it is important to discover new effective anti-mycobacterial agents. In this study, we present data from a series of experiments to determine and anti-mycobacterial activity of a library of epidioxy-sterol analogs.

Tissue paper-derived porous carbon encapsulated transition metal nanoparticles as advanced non-precious catalysts: Carbon-shell influence on the electrocatalytic behaviour.

Porous carbon encapsulated non-precious metal nanocatalysts have recently opened the ways towards the development of high-performance water remediation and energy conversion technologies. Herein, we report a facile, scalable and green synthetic methodology to fabricate porous carbon encapsulated transition metal nanocatalysts (M@TP: M = Cu, Ni, Fe and Co) using commercial tissue paper. The morphology, crystalline structure, chemical composition and textural properties of the M@TP nanocatalysts were thoroughly characterized.

Acquired factor XIII deficiency in patients under therapeutic plasma exchange: A poorly explored etiology.

Introduction: Factor XIII (FXIII) deficiency may cause bleeding under certain clinical circumstances. Therapeutic plasma exchange (TPE) may lead to a transient deficiency.

Objectives: To describe the clinical evolution of patients with acquired FXIII deficiency secondary to TPE.

Functionalized lipid-like nanoparticles for in vivo mRNA delivery and base editing.

Messenger RNA (mRNA) therapeutics have been explored to treat various genetic disorders. Lipid-derived nanomaterials are currently one of the most promising biomaterials that mediate effective mRNA delivery. However, efficiency and safety of this nanomaterial-based mRNA delivery remains a challenge for clinical applications.

[Argentine Consensus in effective management of anticoagulation clinics for the use of vitamin k antagonists].

Treating an anticoagulated patient with vitamin K antagonists (VKA) remains a challenge, especially in areas where dicoumarins are still the first drug of choice due to the cost of other oral anticoagulants. Anticoagulation clinics have proven to be the most efficient and safe way to avoid thrombotic and hemorrhagic complications and to keep patients in optimal treatment range. However, they require adequate infrastructure and trained personnel to work properly.

Nonimmune-acquired factor XIII deficiency: a cause of high volume and delayed postoperative hemorrhage.

: Factor XIII (FXIII) levels may decrease because of surgical consumption. Acquired FXIII deficiency could be a cause of postoperative hemorrhage usually underdiagnosed in clinical practice. To determine the diagnosis confirmation rate of acquired FXIII deficiency in postsurgical patients with clinical suspicion and to compare the characteristics and evolution of patients with or without FXIII deficiency.

PEARL-seq: A Photoaffinity Platform for the Analysis of Small Molecule-RNA Interactions.

RNA is emerging as a valuable target for the development of novel therapeutic agents. The rational design of RNA-targeting small molecules, however, has been hampered by the relative lack of methods for the analysis of small molecule-RNA interactions. Here, we present our efforts to develop such a platform using photoaffinity labeling.

A systematic evaluation of Mycobacterium tuberculosis Genome-Scale Metabolic Networks.

Metabolism underpins the pathogenic strategy of the causative agent of TB, Mycobacterium tuberculosis (Mtb), and therefore metabolic pathways have recently re-emerged as attractive drug targets. A powerful approach to study Mtb metabolism as a whole, rather than just individual enzymatic components, is to use a systems biology framework, such as a Genome-Scale Metabolic Network (GSMN) that allows the dynamic interactions of all the components of metabolism to be interrogated together. Several GSMNs networks have been constructed for Mtb and used to study the complex relationship between the Mtb genotype and its phenotype.

Growth Plate Pathology in the Mucopolysaccharidosis Type VI Rat Model-An Experimental and Computational Approach.

Background: Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases caused by impaired function or absence of lysosomal enzymes involved in degradation of glycosaminoglycans. Clinically, MPS are skeletal dysplasias, characterized by cartilage abnormalities and disturbances in the process of endochondral ossification. Histologic abnormalities of growth cartilage have been reported at advanced stages of the disease, but information regarding growth plate pathology progression either in humans or in animal models, as well as its pathophysiology, is limited.