Extreme Phenotypic Variability of -Related Disorders in Hearing Loss.

Hearing loss is the most common sensory defect in humans, affecting normal communication. In most cases, hearing loss is a multifactorial disorder caused by both genetic and environmental factors, but single-gene mutations can lead to syndromic or non-syndromic hearing loss. Monoallelic variants in , coding for gamma (γ)-actin, are associated with classical Baraitser-Winter Syndrome type 2 (BRWS2, nonsyndromic deafness, and a variety of clinical presentations not fitting the original BRWS2 description or nonsyndromic deafness.

The Benzoxazole Heterocycle: A Comprehensive Review of the Most Recent Medicinal Chemistry Developments of Antiproliferative, Brain-Penetrant, and Anti-inflammatory Agents.

The benzoxazole is one of the most widely exploited heterocycles in drug discovery. Natural occurring and synthetic benzoxazoles show a broad range of biological activities. Many benzoxazoles are available for treating several diseases, and, to date, a few are in clinical trials.

Selection of DNA aptamers that prevent the fibrillization of α-synuclein protein in cellular and mouse models.

A neuropathological hallmark of Parkinson's disease (PD) is the aggregation and spreading of misfolded α-synuclein (αSyn) protein. In this study, a selection method was developed to identify aptamers that showed affinity for monomeric αSyn and inhibition of αSyn aggregation. Aptamer exhibited strong inhibition of αSyn aggregation by transmission electron microscopy and Thioflavin T fluorescence.

Integrated transcriptomics- and structure-based drug repositioning identifies drugs with proteasome inhibitor properties.

Computational pharmacogenomics can potentially identify new indications for already approved drugs and pinpoint compounds with similar mechanism-of-action. Here, we used an integrated drug repositioning approach based on transcriptomics data and structure-based virtual screening to identify compounds with gene signatures similar to three known proteasome inhibitors (PIs; bortezomib, MG-132, and MLN-2238). In vitro validation of candidate compounds was then performed to assess proteasomal proteolytic activity, accumulation of ubiquitinated proteins, cell viability, and drug-induced expression in A375 melanoma and MCF7 breast cancer cells.

Quantitative flow ratio for the functional assessment of extracranial internal carotid artery stenosis.

Background: In asymptomatic patients presenting with significant internal carotid artery (ICA) stenoses undergoing endovascular revascularization, a selective angiography before stenting (CAS) is required. Sometimes, angiographic findings could be discordant from non-invasive assessment and a tool able to evaluate functional relevance of the stenosis could be of value. We sought to evaluate the usefulness of quantitative flow ratio (QFR) as angiography-based tool for functional assessment of ICA stenoses.

Noncompetitive Determination of Small Analytes by Sandwich-Type Lateral Flow Assay Based on an Aptamer Kissing Complex.

Here, we present the proof-of-concept of a lateral flow assay (LFA) that is capable of detecting small-molecule targets in a noncompetitive manner by deploying a sandwich-type format based on the aptamer kissing complex (AKC) strategy. A fluorescently labeled hairpin aptamer served as the signaling agent, while a specific RNA hairpin grafted onto the strip served as the capture element. The hairpin aptamer switched from an unfolded to a folded form in the presence of the target, resulting in kissing interactions between the loops of the reporter and the capture agents.

Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons.

Frontotemporal dementia (FTD) is an incurable group of early-onset dementias that can be caused by the deposition of hyperphosphorylated tau in patient brains. However, the mechanisms leading to neurodegeneration remain largely unknown. Here, we combined single-cell analyses of FTD patient brains with a stem cell culture and transplantation model of FTD.

: a prominent platform for modeling and drug screening in neurological disorders.

Introduction: Human neurodevelopmental and neurodegenerative diseases (NDevDs and NDegDs, respectively) encompass a broad spectrum of disorders affecting the nervous system with an increasing incidence. In this context, the nematode , has emerged as a benchmark model for biological research, especially in the field of neuroscience.

Areas Covered: The authors highlight the numerous advantages of this tiny worm as a model for exploring nervous system pathologies and as a platform for drug discovery.

Hearing Loss: Genetic Testing, Current Advances and the Situation in Latin America.

Congenital hearing loss is the most common birth defect, estimated to affect 2-3 in every 1000 births, with ~50-60% of those related to genetic causes. Technological advances enabled the identification of hundreds of genes related to hearing loss (HL), with important implications for patients, their families, and the community. Despite these advances, in Latin America, the population with hearing loss remains underdiagnosed, with most studies focusing on a single locus encompassing the / genes.

The neurohormone tyramine stimulates the secretion of an Insulin-Like Peptide from the intestine to modulate the systemic stress response in C. elegans.

The DAF-2/insulin/insulin-like growth factor signaling (IIS) pathway plays an evolutionarily conserved role in regulating reproductive development, lifespan, and stress resistance. In , DAF-2/IIS signaling is modulated by an extensive array of insulin-like peptides (ILPs) with diverse spatial and temporal expression patterns. However, the release dynamics and specific functions of these ILPs in adapting to different environmental conditions remain poorly understood.

Invasive Assessment of Coronary Microcirculation: A State-of-the-Art Review.

A significant proportion of patients presenting with signs and symptoms of myocardial ischemia have no "significant" epicardial disease; thereby, the assessment of coronary microcirculation gained an important role in improving diagnosis and guiding therapy. In fact, coronary microvascular dysfunction (CMD) could be found in a large proportion of these patients, supporting both symptoms and signs of myocardial ischemia. However, CMD represents a diagnostic challenge for two main reasons: (1) the small dimension of the coronary microvasculature prevents direct angiographic visualization, and (2) despite the availability of specific diagnostic tools, they remain invasive and underused in the current clinical practice.

Hepatitis C: The Story of a Long Journey through First, Second, and Third Generation NS3/4A Peptidomimetic Inhibitors. What Did We Learn?

Hepatitis C viral (HCV) infection is the leading cause of liver failure and still represents a global health burden. Over the past decade, great advancements made HCV curable, and sustained viral remission significantly improved to more than 98%. Historical treatment with pegylated interferon alpha and ribavirin has been displaced by combinations of direct-acting antivirals.

A Modified Basophil Activation Test for the Clinical Management of Immediate Hypersensitivity Reactions to Paclitaxel: A Proof-of-Concept Study.

Immediate hypersensitivity reactions (iHSRs) to taxanes are observed in 6% and 4% of gynecologic and breast cancer patients, respectively. Drug desensitization is the only option, as no comparable alternative therapy is available. Surfactants in the taxane formulation have been implicated in the immunopathogenesis of iHSRs, although sporadic skin test (ST) positivity and iHSRs to nab-paclitaxel have suggested the involvement of the taxane moiety and/or IgE-mediated pathomechanisms.

In-silico guided chemical exploration of KDM4A fragments hits.

Background: Lysine demethylase enzymes (KDMs) are an emerging class of therapeutic targets, that catalyse the removal of methyl marks from histone lysine residues regulating chromatin structure and gene expression. KDM4A isoform plays an important role in the epigenetic dysregulation in various cancers and is linked to aggressive disease and poor clinical outcomes. Despite several efforts, the KDM4 family lacks successful specific molecular inhibitors.

Drug repurposing: a nexus of innovation, science, and potential.

The urgency of finding therapeutic solutions for emerging and existing health challenges has never been more pronounced. In the pursuit of this goal, the value of a strategy that makes use of existing resources is being recognized: drug repurposing or repositioning of compounds for new indications. Such approaches are employed against cancer, rheumatoid arthritis, multiple sclerosis, HIV/AIDS, and many other diseases.

A community effort in SARS-CoV-2 drug discovery.

The COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the "Billion molecules against COVID-19 challenge", to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors.

Iodinated organic molecule as tag for inductively coupled Plasma-mass spectrometry aptamer assays.

Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) aptamer-based assays using metallic nanostructures or chelates as exogenous tags have gained growing attention in the last decade. We describe here a proof-of-concept study based on the exploitation of a simple organic molecule as a tag, i.e.

Prediction of CD44 Structure by Deep Learning-Based Protein Modeling.

CD44 is a cell surface glycoprotein transmembrane receptor that is involved in cell-cell and cell-matrix interactions. It crucially associates with several molecules composing the extracellular matrix, the main one of which is hyaluronic acid. It is ubiquitously expressed in various types of cells and is involved in the regulation of important signaling pathways, thus playing a key role in several physiological and pathological processes.

Non-invasive Monitoring of α-Synuclein in Saliva for Parkinson's Disease Using Organic Electrolyte-Gated FET Aptasensor.

Parkinson's disease (PD) currently affects more than 1 million people in the US alone, with nearly 8.5 million suffering from the disease worldwide, as per the World Health Organization. However, there remains no fast, pain-free, and effective method of screening for the disease in the ageing population, which also happens to be the most susceptible to this neurodegenerative disease.

Aptamer-based colorimetric and lateral flow assay approaches for the detection of toxic metal ions, thallium(i) and lead(ii).

Thallium(i) and lead(ii) ions are heavy metals and extremely toxic. These metals are environmental pollutants, posing a severe risk to the environment and human health. In this study, two approaches were examined using aptamer and nanomaterial-based conjugates for thallium and lead detection.

Structural properties and binding mechanism of DNA aptamers sensing saliva melatonin for diagnosis and monitoring of circadian clock and sleep disorders.

Circadian desynchrony with the external light-dark cycle influences the rhythmic secretion of melatonin which is among the first signs of circadian rhythm sleep disorders. An accurate dim light melatonin onset (established indicator of circadian rhythm sleep disorders) measurement requires lengthy assays, and antibody affinities alterations, especially in patients with circadian rhythm disorders whose melatonin salivary levels vary significantly, making antibodies detection mostly inadequate. In contrast, aptamers with their numerous advantages (e.