Altered chromatin landscape and 3D interactions associated with primary constitutional MLH1 epimutations.

Background: Lynch syndrome (LS), characterised by an increased risk for cancer, is mainly caused by germline pathogenic variants affecting a mismatch repair gene (MLH1, MSH2, MSH6, PMS2). Occasionally, LS may be caused by constitutional MLH1 epimutation (CME) characterised by soma-wide methylation of one allele of the MLH1 promoter. Most of these are "primary" epimutations, arising de novo without any apparent underlying cis-genetic cause, and are reversible between generations.

Open problems in synthetic multicellularity.

Multicellularity is one of the major evolutionary transitions, and its rise provided the ingredients for the emergence of a biosphere inhabited by complex organisms. Over the last decades, the potential for bioengineering multicellular systems has been instrumental in interrogating nature and exploring novel paths to regeneration, disease, cognition, and behaviour. Here, we provide a list of open problems that encapsulate many of the ongoing and future challenges in the field and suggest conceptual approaches that may facilitate progress.

Cyclin O controls entry into the cell-cycle variant required for multiciliated cell differentiation.

Multiciliated cells (MCCs) ensure fluid circulation in various organs. Their differentiation is marked by the amplification of cilia-nucleating centrioles, driven by a genuine cell-cycle variant, which is characterized by wave-like expression of canonical and non-canonical cyclins such as Cyclin O (CCNO). Patients with CCNO mutations exhibit a subtype of primary ciliary dyskinesia called reduced generation of motile cilia (RGMC).

Leveraging Cryptic Ligand Envelopes through Enhanced Molecular Simulations.

Protein-bound ligands can adopt a range of different conformations, collectively defining a ligand envelope that has proven to be crucial for the design of potent and selective drugs. Yet, the cryptic nature of this ligand envelope makes it difficult to visualize, characterize, and ultimately exploit for drug design. Using enhanced molecular dynamics simulations, here, we provide a general framework to reconstruct the cryptic ligand envelope that is dynamically accessible by protein-bound small molecules in solution.

A novel way to use cross-validation to measure connectivity by machine learning allows epilepsy surgery outcome prediction.

The rate of success of epilepsy surgery, ensuring seizure-freedom, is limited by the lack of epileptogenicity biomarkers. Previous evidence supports the critical role of functional connectivity during seizure generation to characterize the epileptogenic network (EN). However, EN dynamics is highly variable across patients, hindering the development of diagnostic biomarkers.

Energy poverty and health inequalities in Barcelona: A cross-sectional trends study in the context of COVID-19, energy crisis and climate change, 2016-2021.

The aim of this study was to analyse the time trends in Barcelona before and during the adverse context of COVID-19, energy crisis, and climate change in 1) the energy poverty (EP) prevalence; 2) the association between EP and health and 3) the impact of EP on health, according to the axes of inequality (sex, age, social class, and country of birth). We conducted a cross-sectional trends study using data from the 2016 and 2021 Barcelona Health Survey. This study clearly recognizes that EP continues to be an important public health problem in the context of Barcelona.

Design of Small Non-Peptidic Ligands That Alter Heteromerization between Cannabinoid CB and Serotonin 5HT Receptors.

Activation of cannabinoid CB receptors (CBR) by agonists induces analgesia but also induces cognitive impairment through the heteromer formed between CBR and the serotonin 5HT receptor (5HTR). This side effect poses a serious drawback in the therapeutic use of cannabis for pain alleviation. Peptides designed from the transmembrane helices of CBR, which are predicted to bind 5HTR and alter the stability of the CBR-5HTR heteromer, have been shown to avert CBR agonist-induced cognitive impairment while preserving analgesia.

Fast and accurate prediction of drug induced proarrhythmic risk with sex specific cardiac emulators.

In silico trials for drug safety assessment require many high-fidelity 3D cardiac simulations to predict drug-induced QT interval prolongation, which is often computationally prohibitive. To streamline this process, we developed sex-specific emulators for a fast prediction of QT interval, trained on a dataset of 900 simulations. Our results show significant differences between 3D and 0D single-cell models as risk levels increase, underscoring the ability of 3D modeling to capture more complex cardiac responses.

Air pollution exposure is associated with gene expression in children.

Environmental exposures, including air pollutants and lack of natural spaces, are associated with suboptimal health outcomes in children. We aimed to study the associations between environmental exposures and gene expression in children. Associations of exposure to particulate matter (PM) with diameter <2.

vCPP2319 interacts with metastatic breast cancer extracellular vesicles (EVs) and transposes a human blood-brain barrier model.

Brain metastases (BM) are frequently found in cancer patients and, though their precise incidence is difficult to estimate, there is evidence for a correlation between BM and specific primary cancers, such as lung, breast, and skin (melanoma). Among all these, breast cancer is the most frequently diagnosed among women and, in this case, BM cause a critical reduction of the overall survival (OS), especially in triple negative breast cancer (TNBC) patients. The main challenge of BM treatment is the impermeable nature of the blood-brain barrier (BBB), which shields the central nervous systems (CNS) from chemotherapeutic drugs.

Clinical Implications of Functional Imaging in the Assessment of Bronchiectasis-Associated Sarcopenia.

Introduction: Bronchiectasis is a complex lung disease with poorly studied systemic manifestations. Patients with bronchiectasis-associated sarcopenia exhibit a specific differential profile of functional muscle phenotype (vastus lateralis, VL), which may be analyzed using imaging (ultrasound and magnetic resonance imaging, MRI).

Methods: Ultrasound and MRI were used to explore functional imaging parameters in quadriceps of 20 patients with stable bronchiectasis and 10 healthy controls.

Developing and testing a new Ecological Quality Status index based on marine nematode metabarcoding: A proof of concept.

Nematodes are the most diverse and dominant group of marine meiofauna with high potential as bioindicators of the ecological quality status (EcoQS). The present study explores, for the first time, the applicability of the nematode metabarcoding to infer EcoQS index based on the calibration of ecological behaviors of nematodes Amplicon Sequence Variants (ASVs). To achieve this, we analyzed the nematode community in sediment eDNA samples collected in 2018 and 2021 in areas around three offshore oil platforms in the Danish west coast of the North Sea.

Methylmercury contamination in Mediterranean seafood: Exposure assessment and cost of illness implications.

Methylmercury (MeHg) is a widespread contaminant that bioaccumulates in marine food webs, including those in the Mediterranean sea. It poses serious health risks, especially to developing infants and children, where exposure can cause neurological damage and developmental delays. In addition to health concerns, high MeHg levels in seafood can lead to economic losses through cognitive impairments that reduce productivity.

The projected impacts of climate change and fishing pressure on a tropical marine food web.

Small-scale fisheries, especially those from developing countries, are vital for millions. Understanding the impact of environmental and human factors on fish stocks and yields and how they might change is crucial to ensure the sustainable use of aquatic resources. We developed an ecosystem model using Ecopath and Ecosim (EwE) to investigate changes in target species biomass and ecosystem attributes over 83 years (2017-2100) caused by different scenarios of fishing pressure and ocean warming in the Brazilian Northeastern continental shelf.

Microbial functional diversity and redundancy: moving forward.

Microbial functional ecology is expanding as we can now measure the traits of wild microbes that affect ecosystem functioning. Here, we review techniques and advances that could be the bedrock for a unified framework to study microbial functions. These include our newfound access to environmental microbial genomes, collections of microbial traits, but also our ability to study microbes' distribution and expression.

Evaluation of the Efficacy of the Addition of a Combination of Pyrimidine Nucleotides and Vitamin B1 and B12 to Standard Treatment in the Management of Painful Radiculopathy and in the Quality of Life of Patients.

: Radiculopathy leads to pain, consequently reducing patient's quality of life (QoL). Research indicates that certain nucleotides, such as cytidine and uridine, along with vitamins B1 and B12, may help alleviate pain and enhance QoL. This study assessed the impact of adding a supplement containing cytidine and uridine nucleotides and vitamins B1 and B12, alongside standard treatment, on radiculopathy-associated pain.

Intradialytic Parenteral Nutrition in Patients on Hemodialysis: A Multicenter Retrospective Study.

Background And Objective: To evaluate the effectiveness and safety of intradialytic parenteral nutrition (IDPN) on different nutritional outcomes.

Methods: This was a retrospective analysis for a "routinely collected data bank" in a multicenter cohort, conducted on consecutive malnourished or at-risk of malnutrition patients with chronic kidney disease on hemodialysis who underwent IDPN with a three-in-one parenteral nutrition formula for a period ≥ 2 weeks. The primary endpoint was the mean change in the malnutrition inflammation score (MIS) score between baseline and the last follow-up visit on IDPN.

Salvage Therapy with Second-Generation Inhibitors for FLT3 Mutated Acute Myeloid Leukemia: A Real-World Study by the CETLAM and PETHEMA Groups.

Background/objectives: Patients with relapsed/refractory (R/R) AML with mutation () have a dismal prognosis. offers a target for therapy in these patients. Gilteritinib (gilter) and quizartinib (quizar) have demonstrated efficacy as single agents in two phase 3 clinical trials.

Accelerated cell-type-specific regulatory evolution of the human brain.

The molecular basis of human brain evolution is a key piece in understanding the evolution of human-specific cognitive and behavioral traits. Comparative studies have suggested that human brain evolution was accompanied by accelerated changes of gene expression (referred to as "regulatory evolution"), especially those leading to an increase of gene products involved in energy production and metabolism. However, the signals of accelerated regulatory evolution were not always consistent across studies.

Host-specific viral predation network on coral reefs.

Viral infections are major modulators of marine microbial community assembly and biogeochemical cycling. In coral reefs, viral lysis controls bacterial overgrowth that is detrimental to coral health. However, methodological limitations have prevented the identification of viral hosts and quantification of their interaction frequencies.

Characterization of thrombosis risk in ambulatory patients with cancer: results of the observational, prospective, multicenter CARTAGO study.

Background: Venous thromboembolism (VTE) is one of the leading causes of death in patients with cancer. Currently, there is a need to develop an easily applicable risk model that can identify patients who will benefit from receiving primary thromboprophylaxis to reduce the incidence of VTE.

Patients And Methods: This was a non-interventional, multicenter, observational, prospective study carried out in 62 Oncology and Hematology services in Spain and Portugal between January 2018 and December 2019.

E93 controls adult differentiation by repressing in .

In , successful development relies on the precise coordination of both spatial and temporal regulatory axes. The temporal axis governs stage-specific identity and developmental transitions through a number of genes, collectively forming the . Among these, Ecdysone inducible protein 93F (E93) serves as the critical determinant for adult specification, but its mechanism of action remains unclear.

New developments for the Quest for Orthologs benchmark service.

The Quest for Orthologs (QfO) orthology benchmark service (https://orthology.benchmarkservice.org) hosts a wide range of standardized benchmarks for orthology inference evaluation.