Characterization of p38α Signaling Networks in Cancer Cells Using Quantitative Proteomics and Phosphoproteomics.

p38α (encoded by MAPK14) is a protein kinase that regulates cellular responses to almost all types of environmental and intracellular stresses. Upon activation, p38α phosphorylates many substrates both in the cytoplasm and nucleus, allowing this pathway to regulate a wide variety of cellular processes. While the role of p38α in the stress response has been widely investigated, its implication in cell homeostasis is less understood.

Esmethadone-HCl (REL-1017): a promising rapid antidepressant.

This review article presents select recent studies that form the basis for the development of esmethadone into a potential new drug. Esmethadone is a promising member of the pharmacological class of uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists that have shown efficacy for major depressive disorder (MDD) and other diseases and disorders, such as Alzheimer's dementia and pseudobulbar affect. The other drugs in the novel class of NMDAR antagonists with therapeutic uses that are discussed for comparative purposes in this review are esketamine, ketamine, dextromethorphan, and memantine.

The atypical CDK activator RingoA/Spy1 regulates exit from quiescence in neural stem cells.

In the adult mammalian brain, most neural stem cells (NSCs) are held in a reversible state of quiescence, which is essential to avoid NSC exhaustion and determine the appropriate neurogenesis rate. NSCs of the mouse adult subependymal niche provide neurons for olfactory circuits and can be found at different depths of quiescence, but very little is known on how their quiescence-to-activation transition is controlled. Here, we identify the atypical cyclin-dependent kinase (CDK) activator RingoA as a regulator of this process.

Apolipoprotein E induces pathogenic senescent-like myeloid cells in prostate cancer.

Tumor cells promote the recruitment of immunosuppressive neutrophils, a subset of myeloid cells driving immune suppression, tumor proliferation, and treatment resistance. Physiologically, neutrophils are known to have a short half-life. Here, we report the identification of a subset of neutrophils that have upregulated expression of cellular senescence markers and persist in the tumor microenvironment.

Slice2Volume: Fusion of multimodal medical imaging and light microscopy data of irradiation-injured brain tissue in 3D.

Comprehending cellular changes of radiation-induced brain injury is crucial to prevent and treat the pathology. We provide a unique open dataset of proton-irradiated mouse brains consisting of medical imaging, radiation dose simulations, and large-scale microscopy images, all registered into a common coordinate system. This allows dose-dependent analyses on single-cell level.

Enantioselective Ir-Catalyzed Hydrogenation of Terminal Homoallyl Sulfones: Total Synthesis of (-)-Curcumene.

A novel methodology for the preparation of chiral methyl benzylic compounds is reported. Terminal homoallyl sulfones were prepared from homoallyl alcohols, which are easily accessible through the recently reported Lewis acid isomerization of oxetanes. The iridium-catalyzed asymmetric hydrogenation of homoallylic sulfones afforded γ-chiral sulfones with excellent enantioselectivities (up to 98% ee).

Targeting Mitochondria to Control Ageing and Senescence.

Ageing is accompanied by a progressive impairment of cellular function and a systemic deterioration of tissues and organs, resulting in increased vulnerability to multiple diseases. Here, we review the interplay between two hallmarks of ageing, namely, mitochondrial dysfunction and cellular senescence. The targeting of specific mitochondrial features in senescent cells has the potential of delaying or even reverting the ageing process.

Client Applications and Server-Side Docker for Management of RNASeq and/or VariantSeq Workflows and Pipelines of the GPRO Suite.

The GPRO suite is an in-progress bioinformatic project for -omics data analysis. As part of the continued growth of this project, we introduce a client- and server-side solution for comparative transcriptomics and analysis of variants. The client-side consists of two Java applications called "" and "" to manage pipelines and workflows based on the most common command line interface tools for RNA-seq and Variant-seq analysis, respectively.

Peptide-Platinum(IV) Conjugation Minimizes the Negative Impact of Current Anticancer Chemotherapy on Nonmalignant Cells.

The relative success of platinum (Pt)-based chemotherapy comes at the cost of severe adverse side effects and is associated with a high risk of pro-oncogenic activation in the tumor microenvironment. Here, we report the synthesis of C-POC, a novel Pt(IV) cell-penetrating peptide conjugate showing a reduced impact against nonmalignant cells. In vitro and in vivo evaluation using patient-derived tumor organoids and laser ablation inductively coupled plasma mass spectrometry indicates that C-POC maintains robust anticancer efficacy while displaying diminished accumulation in healthy organs and reduced adverse toxicity compared to the standard Pt-based therapy.

EvolClustDB: Exploring Eukaryotic Gene Clusters with Evolutionarily Conserved Genomic Neighbourhoods.

Conservation of gene neighbourhood over evolutionary distances is generally indicative of shared regulation or functional association among genes. This concept has been broadly exploited in prokaryotes but its use on eukaryotic genomes has been limited to specific functional classes, such as biosynthetic gene clusters. We here used an evolutionary-based gene cluster discovery algorithm (EvolClust) to pre-compute evolutionarily conserved gene neighbourhoods, which can be searched, browsed and downloaded in EvolClustDB.

How genomics can help biodiversity conservation.

The availability of public genomic resources can greatly assist biodiversity assessment, conservation, and restoration efforts by providing evidence for scientifically informed management decisions. Here we survey the main approaches and applications in biodiversity and conservation genomics, considering practical factors, such as cost, time, prerequisite skills, and current shortcomings of applications. Most approaches perform best in combination with reference genomes from the target species or closely related species.

i-Motif folding intermediates with zero-nucleotide loops are trapped by 2'-fluoroarabinocytidine via F···H and O···H hydrogen bonds.

G-quadruplex and i-motif nucleic acid structures are believed to fold through kinetic partitioning mechanisms. Such mechanisms explain the structural heterogeneity of G-quadruplex metastable intermediates which have been extensively reported. On the other hand, i-motif folding is regarded as predictable, and research on alternative i-motif folds is limited.

Decreased expression of mitochondrial aminoacyl-tRNA synthetases causes downregulation of OXPHOS subunits in type 2 diabetic muscle.

Type 2 diabetes mellitus (T2D) affects millions of people worldwide and is one of the leading causes of morbidity and mortality. The skeletal muscle (SKM) is one of the most important tissues involved in maintaining glucose homeostasis and substrate oxidation, and it undergoes insulin resistance in T2D. In this study, we identify the existence of alterations in the expression of mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) in skeletal muscle from two different forms of T2D: early-onset type 2 diabetes (YT2) (onset of the disease before 30 years of age) and the classical form of the disease (OT2).

Copy number footprints of platinum-based anticancer therapies.

Recently, distinct mutational footprints observed in metastatic tumors, secondary malignancies and normal human tissues have been demonstrated to be caused by the exposure to several chemotherapeutic drugs. These characteristic mutations originate from specific lesions caused by these chemicals to the DNA of exposed cells. However, it is unknown whether the exposure to these chemotherapies leads to a specific footprint of larger chromosomal aberrations.

Active Glycogen Synthase in the Liver Prevents High-Fat Diet-Induced Glucose Intolerance, Decreases Food Intake, and Lowers Body Weight.

Many lines of evidence demonstrate a correlation between liver glycogen content and food intake. We previously demonstrated that mice overexpressing protein targeting to glycogen (PTG) specifically in the liver-which have increased glycogen content in this organ-are protected from high-fat diet (HFD)-induced obesity by reduced food intake. However, the use of PTG to increase liver glycogen implies certain limitations.

Synthesis and Biological Activity of a VHL-Based PROTAC Specific for p38α.

We report a series of small molecule proteolysis-targeting chimeras (PROTACs) that target the protein kinase p38α for degradation. These PROTACs are based on a ligand of the VHL E3 ubiquitin ligase, which is linked to an ATP competitive inhibitor of p38α. We provide evidence that these compounds can induce the specific degradation of p38α, but not p38β and other related kinases, at nanomolar concentrations in several mammalian cell lines.

Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy.

A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased.

Multiplexed target enrichment of coding and non-coding transcriptomes enables studying spp. infections from human derived samples.

The study of transcriptomic interactions between host and pathogens in conditions is challenged by the low relative amounts of the pathogen RNA. Yeast opportunistic pathogens of the genus can cause life-threatening systemic infections in immunocompromised patients, and are of growing medical concern. Four phylogenetically diverse species account for over 90% of infections, and their specific interactions with various human tissues are still poorly understood.

Aberrant phase separation and nucleolar dysfunction in rare genetic diseases.

Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus.

A NIR fluorescent probe for the detection of renal damage based on overrepresentation of alanine aminopeptidase enzyme.

Kidney damage generates changes at the phenotypic and genotypic levels that allow its monitoring using different biomarkers in blood, urine or serum. Among these biomarkers, kidney failure causes the urine overrepresentation of the alanine aminopeptidase (APN) enzyme. Here, we describe the design of a molecular probe (NB-ALA) based on the Nile Blue fluorophore (NB), which can detect the APN enzyme in urine by simple fluorometric measurements.

pH-Dependent Capping Interactions Induce Large-Scale Structural Transitions in i-Motifs.

We study here a DNA oligonucleotide having the ability to form two different i-motif structures whose relative stability depends on pH and temperature. The major species at neutral pH is stabilized by two C:C base pairs capped by two minor groove G:C:G:C tetrads. The high pH and thermal stability of this structure are mainly due to the favorable effect of the minor groove tetrads on their adjacent positively charged C:C base pairs.

MmCMS: mouse models' consensus molecular subtypes of colorectal cancer.

Background: Colorectal cancer (CRC) primary tumours are molecularly classified into four consensus molecular subtypes (CMS1-4). Genetically engineered mouse models aim to faithfully mimic the complexity of human cancers and, when appropriately aligned, represent ideal pre-clinical systems to test new drug treatments. Despite its importance, dual-species classification has been limited by the lack of a reliable approach.

The power of geohistorical boundaries for modeling the genetic background of human populations: The case of the rural catalan Pyrenees.

The genetic variation of the European population at a macro-geographic scale follows genetic gradients which reflect main migration events. However, less is known about factors affecting mating patterns at a micro-geographic scale. In this study we have analyzed 726,718 autosomal single nucleotide variants in 435 individuals from the catalan Pyrenees covering around 200 km of a vast and abrupt region in the north of the Iberian Peninsula, for which we have information about the geographic origin of all grand-parents and parents.

Microtubule nucleation and γTuRC centrosome localization in interphase cells require ch-TOG.

Organization of microtubule arrays requires spatio-temporal regulation of the microtubule nucleator γ-tubulin ring complex (γTuRC) at microtubule organizing centers (MTOCs). MTOC-localized adapter proteins are thought to recruit and activate γTuRC, but the molecular underpinnings remain obscure. Here we show that at interphase centrosomes, rather than adapters, the microtubule polymerase ch-TOG (also named chTOG or CKAP5) ultimately controls γTuRC recruitment and activation.