Physiological shedding and C-terminal proteolytic processing of TMEM106B.

Genetic variants in TMEM106B, coding for a transmembrane protein of unknown function, have been identified as critical genetic modulators in various neurodegenerative diseases with a strong effect in patients with frontotemporal degeneration. The luminal domain of TMEM106B can form amyloid-like fibrils upon proteolysis. Whether this luminal domain is generated under physiological conditions and which protease(s) are involved in shedding remain unclear.

Drug Interaction Studies of Cabamiquine:Ganaplacide Combination against Hepatic .

New antimalarial combination therapies with novel modes of action are required to counter the emergence and spread of drug resistance against existing therapeutics. Here, we present a study to evaluate the preventive activity of a combination of clinical antimalarial drug candidates, cabamiquine and ganaplacide, that have multistage activity against the liver and blood stages of infection. Cabamiquine (DDD107498, M5717) inhibits parasite protein synthesis, and ganaplacide (KAF156) inhibits protein trafficking, blocks the establishment of new permeation pathways, and causes endoplasmic reticulum expansion.

Antiplasmodial and Insecticidal Activities of Third-Generation Ivermectin Hybrids.

Preclinical and/or clinical studies have demonstrated the potential of Ivermectin (IVM) for malaria control. In order to improve its antiplasmodial activity and build on previous knowledge, we have designed a third generation of hybrid molecules in which selected pharmacophores were appended to the IVM macrolide, while retaining one or both sugar moieties at the C-13 position. Moreover, we synthesized IVM hybrids that contain structural features of potent IVM metabolites.

A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants.

Artemisinin-based combination therapy (ACT) is the mainstay of effective treatment of Plasmodium falciparum malaria. However, the long-term utility of ACTs is imperiled by widespread partial artemisinin resistance in Southeast Asia and its recent emergence in parts of East Africa. This underscores the need to identify chemotypes with new modes of action (MoAs) to circumvent resistance to ACTs.

Ion Beam-Induced Luminescence (IBIL) for Studying Manufacturing Conditions in Ceramics: An Application to Ceramic Body Tiles.

The first experimental results obtained by the ion beam-induced luminescence technique from the ceramic bodies of ancient tiles are reported in this work. The photon emission from the ceramic bodies is related to the starting minerals and the manufacturing conditions, particularly the firing temperature and cooling processes. Moreover, the results indicate that this non-destructive technique, performed under a helium-rich atmosphere instead of an in-vacuum setup and with acquisition times of only a few seconds, presents a promising alternative to traditional, often destructive, compositional characterisation methods.

Recent advances in proteomic analysis to study carotid artery plaques.

Objective: We sought to identify differentially expressed proteins in serum, plasma, and plaque samples of patients with carotid atherosclerotic lesions.

Methods: We performed a systematic review of the proteomic profile of serum, plasma, and plaque samples of patients with carotid artery disease. We included full-length peer-reviewed studies of adult humans and reported them using PRISMA guidelines.

Whole-sporozoite malaria vaccines: where we are, where we are going.

The malaria vaccination landscape has seen significant advancements with the recent endorsement of RTS,S/AS01 and R21/Matrix-M vaccines, which target the pre-erythrocytic stages of Plasmodium falciparum (Pf) infection. However, several challenges remain to be addressed, including the incomplete protection afforded by these vaccines, their dependence on a single Pf antigen, and the fact that they were not designed to protect against P. vivax (Pv) malaria.

Cross-cultural adaptation of the Parent Hearing Aid Management Inventory into Brazilian Portuguese.

Purpose: to translate and cross-culturally adapt the Parent Hearing Aid Management Inventory into Brazilian Portuguese.

Methods: study of the methodological type of cross-cultural adaptation, which followed the recommendations of the literature for its execution. Two steps and eight steps were performed to achieve the adaptation: obtaining permission from the authors; formation of a committee of specialists who acted in some of the steps for the validation of the translation, translation by 2 proficient translators, synthesis of the translations and evaluation of equivalences, reverse translation and synthesis of the same, pilot study with 10 families to verify the applicability of the instrument and synthesis of the final version of the instrument.

"Seasoning" antimalarial drugs' action: chloroquine bile salts as novel triple-stage antiplasmodial hits.

Malaria is one of the "big three" global infectious diseases, having caused above two hundred million cases and over half a million deaths in 2020. The continuous demand for new treatment options prioritizes the cost-effective development of new chemical entities with multi-stage antiplasmodial activity, for higher efficacy and lower propensity to elicit drug-resistant parasite strains. Following up on our long-term research towards the rescue of classical antimalarial aminoquinolines like chloroquine and primaquine, we have developed new organic salts by acid-base pairing of those drugs with natural bile acids.

Innovative Multistage ML-QSAR Models for Malaria: From Data to Discovery.

Malaria presents a significant challenge to global public health, with around 247 million cases estimated to occur annually worldwide. The growing resistance of parasites to existing therapies underscores the urgent need for new and innovative antimalarial drugs. This study leveraged artificial intelligence (AI) to tackle this complex challenge.

Repurposing antiplasmodial leads for cancer: Exploring the antiproliferative effects of N-cinnamoyl-aminoacridines.

Drug repurposing and rescuing have been widely explored as cost-effective approaches to expand the portfolio of chemotherapeutic agents. Based on the reported antitumor properties of both trans-cinnamic acids and quinacrine, an antimalarial aminoacridine, we explored the antiproliferative properties of two series of N-cinnamoyl-aminoacridines recently identified as multi-stage antiplasmodial leads. The compounds were evaluated in vitro against three cancer cell lines (MKN-28, Huh-7, and HepG2), and human primary dermal fibroblasts.

Structure-activity relationship of anticancer and antiplasmodial gold bis(dithiolene) complexes.

Monoanionic gold bis(dithiolene) complexes were recently shown to display activity against ovarian cancer cells, Gram-positive bacteria, strains and the rodent malaria parasite, . To date, only monoanionic gold(III) bis(dithiolene) complexes with a thiazoline backbone substituted with small alkyl chains have been evaluated for biomedical applications. We now analyzed the influence of the length and the hydrophobicity hydrophilicity of these complexes' alkyl chain on their anticancer and antiplasmodial properties.

Discovery of harmiprims, harmine-primaquine hybrids, as potent and selective anticancer and antimalarial compounds.

Although cancer and malaria are not etiologically nor pathophysiologically connected, due to their similarities successful repurposing of antimalarial drugs for cancer and vice-versa is known and used in clinical settings and drug research and discovery. With the growing resistance of cancer cells and Plasmodium to the known drugs, there is an urgent need to discover new chemotypes and enrich anticancer and antimalarial drug portfolios. In this paper, we present the design and synthesis of harmiprims, hybrids composed of harmine, an alkaloid of the β-carboline type bearing anticancer and antiplasmodial activities, and primaquine, 8-aminoquinoline antimalarial drug with low antiproliferative activity, covalently bound via triazole or urea.

Generation and characterization of monoclonal antibodies against pathologically phosphorylated TDP-43.

Inclusions containing TAR DNA binding protein 43 (TDP-43) are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). One of the disease-specific features of TDP-43 inclusions is the aberrant phosphorylation of TDP-43 at serines 409/410 (pS409/410). Here, we developed rabbit monoclonal antibodies (mAbs) that specifically detect pS409/410-TDP-43 in multiple model systems and FTD/ALS patient samples.

Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial.

Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger-containing (PIKfyve) inhibitor with a favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis (ALS) models. In this ALS clinical trial, the safety, tolerability, CNS penetrance and modulation of pharmacodynamic target engagement biomarkers were evaluated. This phase 2a, randomized, double-blind, placebo-controlled, biomarker-end-point clinical trial was conducted in four US centres (ClinicalTrials.

Disclosure of cinnamic acid/4,9-diaminoacridine conjugates as multi-stage antiplasmodial hits.

4,9-diaminoacridines with reported antiplasmodial activity were coupled to different trans-cinnamic acids, delivering a new series of conjugates inspired by the covalent bitherapy concept. The new compounds were more potent than primaquine against hepatic stages of Plasmodium berghei, although this was accompanied by cytotoxic effects on Huh-7 hepatocytes. Relevantly, the conjugates displayed nanomolar activities against blood stage P.

Erratum: Neurofilament light chain and vaccination status associate with clinical outcomes in severe COVID-19.

[This corrects the article DOI: 10.1016/j.isci.

A new malaria vaccination tool based on replication-competent Plasmodium falciparum parasites.

Recently licensed subunit vaccines represent the first and, thus far, the only approved agents for vaccination against malaria. However, these vaccines still fail to confer highly effective long-lasting protective immunity. Whole-organism vaccines, employing attenuated sporozoites as immunization agents, constitute a promising alternative for highly effective malaria vaccination.

TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes.

In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus. TDP-43 loss leads to cryptic exon inclusion but a role in other RNA processing events remains unresolved. Here, we show that loss of TDP-43 causes widespread changes in alternative polyadenylation, impacting expression of disease-relevant genes (e.

Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD.

ProtPipe: A Multifunctional Data Analysis Pipeline for Proteomics and Peptidomics.

Mass spectrometry (MS) is a technique widely employed for the identification and characterization of proteins, personalized medicine, systems biology and biomedical applications. By combining MS with different proteomics approaches such as immunopurification MS, immunopeptidomics, and total protein proteomics, researchers can gain insights into protein-protein interactions, immune responses, cellular processes, and disease mechanisms. The application of MS-based proteomics in these areas continues to advance our understanding of protein function, cellular signaling, and complex biological systems.