Redox proteomics reveal a role for peroxiredoxinylation in stress protection.

The redox state of proteins is essential for their function and guarantees cell fitness. Peroxiredoxins protect cells against oxidative stress, maintain redox homeostasis, act as chaperones, and transmit hydrogen peroxide signals to redox regulators. Despite the profound structural and functional knowledge of peroxiredoxins action, information on how the different functions are concerted is still scarce.

Insights into the origin, hybridisation and adaptation of Candida metapsilosis hybrid pathogens.

Hybridisation is a source of genetic diversity, can drive adaptation to new niches and has been found to be a frequent event in lineages harbouring pathogenic fungi. However, little is known about the genomic implications of hybridisation nor its impact on pathogenicity-related traits. A common limitation for addressing these questions is the narrow representativity of sequenced genomes, mostly corresponding to strains isolated from infected patients.

The conserved lysine residue in transmembrane helix 5 is pivotal for the cytoplasmic gating of the L-amino acid transporters.

L-Amino acid transporters (LATs) play a key role in a wide range of physiological processes. Defects in LATs can lead to neurological disorders and aminoacidurias, while the overexpression of these transporters is related to cancer. BasC is a bacterial LAT transporter with an APC fold.

Clonal analysis of SepSecS-specific B and T cells in autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a rare chronic inflammatory liver disease characterized by the presence of autoantibodies, including those targeting O-phosphoseryl-tRNA:selenocysteine-tRNA synthase (SepSecS), also known as soluble liver antigen (SLA). Anti-SepSecS antibodies have been associated with a more severe phenotype, suggesting a key role for the SepSecS autoantigen in AIH. To analyze the immune response to SepSecS in patients with AIH at the clonal level, we combined sensitive high-throughput screening assays with the isolation of monoclonal antibodies (mAbs) and T cell clones.

New Potent Inhibitor of Transforming Growth Factor-Beta (TGFβ) Signaling that is Efficacious against Microsatellite Stable Colorectal Cancer Metastasis in Combination with Immune Checkpoint Therapy in Mice.

Blockade of the TGFβ signaling pathway has emerged from preclinical studies as a potential treatment to enhance the efficacy of immune checkpoint inhibition in advanced colorectal cancer (CRC) and several other types of cancer. However, clinical translation of first-generation inhibitors has shown little success. Here, we report the synthesis and characterization of HYL001, a potent inhibitor of TGFβ receptor 1 (ALK5), that is approximately 9 times more efficacious than the structurally related compound galunisertib, while maintaining a favorable safety profile.

A pilot and feasibility study investigating the abundance and activity of nitrate-reducing bacteria in women with pre-eclampsia.

Background: Oral health may influence blood pressure control by modulating the abundance and activity of nitrate-reducing bacteria, which are essential for enhancing nitrite and nitric oxide (NO) bioavailability. This study aimed to investigate the oral health and microbiome composition of women with pre-eclampsia (PET) compared to healthy controls (CN).

Methods: Ten PET and eleven CN women participated in this study, respectively.

Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease.

Dysregulation at the intestinal epithelial barrier is a driver of inflammatory bowel disease (IBD). However, the molecular mechanisms of barrier failure are not well understood. Here, we demonstrate dysregulated mitochondrial fusion in intestinal epithelial cells (IECs) of patients with IBD and show that impaired fusion is sufficient to drive chronic intestinal inflammation.

Flexibility in PAM Recognition Expands DNA Targeting in xCas9.

xCas9 is an evolved variant of the CRISPR-Cas9 genome editing system, engineered to improve specificity and reduce undesired off-target effects. How xCas9 expands the DNA targeting capability of Cas9 by recognizing a series of alternative Protospacer Adjacent Motif (PAM) sequences while ignoring others is unknown. Here, we elucidate the molecular mechanism underlying xCas9's expanded PAM recognition and provide critical insights for expanding DNA targeting.

BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia.

Background And Aims: Cancer cachexia is a complex syndrome affecting most cancer patients and is directly responsible for about 20% of cancer-related deaths. Previous studies showed muscle proteolysis hyper-activation and mitophagy induction in tumor-bearing animals. While basal mitophagy is required for maintaining muscle mass and quality, excessive mitophagy promotes uncontrolled protein degradation, muscle loss and impaired function.

Circadian clock communication during homeostasis and ageing.

Maintaining homeostasis is essential for continued health, and the progressive decay of homeostatic processes is a hallmark of ageing. Daily environmental rhythms threaten homeostasis, and circadian clocks have evolved to execute physiological processes in a manner that anticipates, and thus mitigates, their effects on the organism. Clocks are active in almost all cell types; their rhythmicity and functional output are determined by a combination of tissue-intrinsic and systemic inputs.

Long-range organization of intestinal 2D-crypts using exogenous Wnt3a micropatterning.

Intestinal epithelial cells are segregated into proliferative crypts and differentiated regions. This organization relies on specific signals, including Wnt3a, which regulates cell proliferation within crypts, and Eph/Ephrin, which dictates cell positioning along the crypt-villus axis. However, studying how the spatial distributions of these signals influences crypt-villus organization is challenging both in vitro and in vivo.

Measuring age-dependent viscoelasticity of organelles, cells and organisms with time-shared optical tweezer microrheology.

Quantifying the mechanical response of the biological milieu (such as the cell's interior) and complex fluids (such as biomolecular condensates) would enable a better understanding of cellular differentiation and aging and accelerate drug discovery. Here we present time-shared optical tweezer microrheology to determine the frequency- and age-dependent viscoelastic properties of biological materials. Our approach involves splitting a single laser beam into two near-instantaneous time-shared optical traps to carry out simultaneous force and displacement measurements and quantify the mechanical properties ranging from millipascals to kilopascals across five decades of frequency.

Single-Cell Lineage Tracing and Clonal State-Fate Analysis.

Lineage tracing has significantly advanced our comprehension in many areas of biology, such as development or immunity, by precisely measuring cellular processes like migration, division, or differentiation across labeled cells and their progeny. Traditional recombinase-based prospective lineage tracing is limited by the need for a priori cell type information and is constrained in the numbers of clones it can simultaneously track. In this sense, clonal lineage tracing with integrated random barcodes offers a robust alternative, enabling researchers to label and track a vast array of cells and their progeny over time.

Multi-omics profiling reveals altered mitochondrial metabolism in adipose tissue from patients with metabolic dysfunction-associated steatohepatitis.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe form steatohepatitis (MASH) contribute to rising morbidity and mortality rates. The storage of fat in humans is closely associated with these diseases' progression. Thus, adipose tissue metabolic homeostasis could be key in both the onset and progression of MASH.

potentiation of tetracyclines in by RW01, a new cyclic peptide.

The pipeline for new drugs against multidrug-resistant remains limited, highlighting the urgent need for innovative treatments. New strategies, such as membrane-targeting molecules acting as adjuvants, aim to enhance antibiotic effectiveness and combat resistance. RW01, a cyclic peptide with low antimicrobial activity, was selected as an adjuvant to enhance drug efficacy through membrane permeabilization.

The comparative effect of propolis and chlorhexidine mouthwash on oral nitrite-producing bacteria and blood pressure regulation.

Background: Propolis mouthwash (PROP-M) has demonstrated antibacterial properties like those of chlorhexidine mouthwash (CHX-M). However, its impact on the abundance of oral nitrite-producing species (NPS) and nitrite-producing activity (NPA) remains unexplored.

Methods: Forty-five healthy individuals were randomised into 2 groups to rinse their mouth twice a day for seven days with either CHX-M ( = 21) or PROP-M ( = 24).

Endogenous interactomes of MFN1 and MFN2 provide novel insights into interorganelle communication and autophagy.

MFN1 (mitofusin 1) and MFN2 are key players in mitochondrial fusion, endoplasmic reticulum (ER)-mitochondria juxtaposition, and macroautophagy/autophagy. However, the mechanisms by which these proteins participate in these processes are poorly understood. Here, we studied the interactomes of these two proteins by using CRISPR-Cas9 technology to insert an HA-tag at the C terminus of MFN1 and MFN2, and thus generating HeLa cell lines that endogenously expressed MFN1-HA or MFN2-HA.

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.

OpenVariant: a toolkit to parse and operate multiple input file formats.

Summary: Advances in high-throughput DNA sequencing technologies and decreasing costs have fueled the identification of small genetic variants (such as single nucleotide variants and indels) across tumors. Despite efforts to standardize variant formats and vocabularies, many sources of variability persist across databases and computational tools that annotate variants, hindering their integration within cancer genomic analyses. In this context, we present OpenVariant, an easily extendable Python package that facilitates seamless reading, parsing and refinement of diverse input file formats in a customizable structure, all within a single process.

HRK downregulation and augmented BCL-xL binding to BAK confer apoptotic protection to therapy-induced senescent melanoma cells.

Senescent cells are commonly detected in tumors after chemo and radiotherapy, leading to a characteristic cellular phenotype that resists apoptotic cell death. In this study, we used multiple melanoma cell lines, molecular markers, and therapies to investigate the key role of the BCL-2 family proteins in the survival of senescent cells. We first used BH3 profiling to assess changes in apoptotic priming upon senescence induction.

Reconstructing the last common ancestor of all eukaryotes.

Understanding the origin of eukaryotic cells is one of the most difficult problems in all of biology. A key challenge relevant to the question of eukaryogenesis is reconstructing the gene repertoire of the last eukaryotic common ancestor (LECA). As data sets grow, sketching an accurate genomics-informed picture of early eukaryotic cellular complexity requires provision of analytical resources and a commitment to data sharing.

Emerging insights in senescence: pathways from preclinical models to therapeutic innovations.

Senescence is a crucial hallmark of ageing and a significant contributor to the pathology of age-related disorders. As committee members of the young International Cell Senescence Association (yICSA), we aim to synthesise recent advancements in the identification, characterisation, and therapeutic targeting of senescence for clinical translation. We explore novel molecular techniques that have enhanced our understanding of senescent cell heterogeneity and their roles in tissue regeneration and pathology.

Acquired amphotericin B resistance leads to fitness trade-offs that can be mitigated by compensatory evolution in Candida auris.

Candida auris is a growing concern due to its resistance to antifungal drugs, particularly amphotericin B (AMB), detected in 30 to 60% of clinical isolates. However, the mechanisms of AMB resistance remain poorly understood. Here we investigated 441 in vitro- and in vivo-evolved C.