Blood transcriptomic analysis reveals a distinct molecular subtype of treatment resistant depression compared to non-treatment resistant depression.

Treatment-resistant depression (TRD) is a severe condition characterized by chronic and recurrent depressive symptoms, leading to significant morbidity and a considerable socio-economic impact. Genetic and biological studies suggest that TRD is associated with distinct biological characteristics. In this study, we analysed whole-transcriptome differences in 293 patients with major depressive disorder (MDD) to compare TRD (N = 150) vs non-TRD (N = 143) cases.

Stromagenesis and cancer-associated fibroblast heterogeneity in primary tumors and metastasis: focus in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the most common lung cancer type and one of the deadliest neoplasias worldwide. NSCLC is histologically classified into adenocarcinoma, squamous cell carcinoma, and other less frequent subtypes. Both subtypes and other solid tumors are increasingly regarded as abnormal organs, highlighting the critical role of the desmoplastic tumor stroma rich in cancer-associated fibroblasts (CAFs) in driving tumor progression and therapeutic resistance.

Longitudinal association of shorter leukocyte telomere length with CSF biomarker dynamics across early Alzheimer's disease stages in at-risk individuals.

Background: Short telomere length (TL), a hallmark of biological ageing, has been associated with an increased risk of Alzheimer's disease (AD), but its pathophysiological role remains unclear. This study explored the relationship between blood leukocyte TL (LTL), cerebrospinal fluid (CSF) AD biomarkers changes, and brain structure across early stages of the AD continuum.

Methods: We included 346 cognitively unimpaired participants (aged 49-71) from the ALFA cohort, enriched for AD risk (53.

Neuropilin-2 upregulation by stromal TGFβ1 induces lung disseminated tumor cells dormancy escape and promotes metastasis outgrowth.

Metastasis is the main cause of death from solid tumors. Therefore, identifying the mechanisms that govern metastatic growth poses a major biomedical challenge. Tumor microenvironment signals regulate the fate and survival of disseminated tumor cells (DTCs) in secondary organs.

The PRC2-associated factor EPOP is required for Hox gene regulation during axial development in mice.

The Polycomb repressive complex 2 (PRC2) is an essential modulator of gene repression. We previously reported that, in mouse embryonic stem cells, PRC2 associates with elonginB/C through EPOP, which allows for low-level expression of target genes. Here we investigate the role of EPOP in vivo by generating a mouse knockout (KO) model.

Novel 3D-Printed Biophotonic Scaffold Displaying Luminescence under Near-Infrared Light for Photopharmacological Activation and Biological Signaling Compound Release.

Despite significant efforts in developing novel biomaterials to regenerate tissue, only a few of them have successfully reached clinical use. It has become clear that the next generation of biomaterials must be multifunctional. Smart biomaterials can respond to environmental or external stimuli, interact in a spatial-temporal manner, and trigger specific tissue/organism responses.

A roadmap for next-generation nanomotors.

Since their discovery in 2004, there has been remarkable progress in research on nanomotors, from the elucidation of different propulsion mechanisms to the study of their collective behaviour, culminating in investigations into their applications in biomedicine and environmental remediation. This Perspective reviews this evolution in nanomotor research and discusses the key challenges ahead, including the need for developing advanced characterization techniques, precise motion control, materials innovation, theory and modelling, and translationally feasible in vivo biomedical applications. These challenges highlight the current limitations of synthetic nanomotors and point to exciting future opportunities to revolutionize theranostics and create 'living' hybrid systems.

Tenascin-c functionalised self-assembling peptide hydrogels for critical-sized bone defect reconstruction.

Critical-sized bone defects cannot heal spontaneously and receive poor clinical prognosis due to limitations in modern treatment strategies. Next-generation therapies are applying biomaterials incorporating BMP-2 to effectively promote and support bone regeneration, but adverse effects are linked to uncontrolled BMP-2 egress from the biomaterial. Implementing extracellular matrix proteins to biomaterials is a favourable approach to alleviate these drawbacks, and self-assembling peptide hydrogels are rapidly emerging as modulable and versatile biomaterials.

Temperature-dependent funnel-like DNA folding landscapes.

Nucleic acid hybridization in bimolecular and folding reactions is a fundamental kinetic process susceptible to water solvation, counterions, and chemical modifications with intricate enthalpy-entropy compensation effects. Such effects hinder the typically weak temperature dependencies of enthalpies and entropies quantified by the heat capacity change upon duplex formation. Using a temperature-jump optical trap, we investigate the folding thermodynamics and kinetics of DNA hairpins of varying stem sequences and loop sizes in the temperature range of 5-40○C.

Predicting interacting hotspots for nanobodies' binding using triplets of residues.

Protein-protein interactions (PPI) are fundamental to cellular signaling, forming robust networks that govern critical biological processes such as immune response, cell growth, and signal transduction. Nanobody-based therapies have emerged as a key strategy for modulating PPIs, offering exceptional potential due to their high specificity, stability, and ability to access challenging epitopes on PPI interfaces inside cells. The rational design of nanobodies relies mainly on understanding and predicting their binding regions, particularly the residues that contribute the most to the binding energy (binding hotspots).

Artificial intelligence and first-principle methods in protein redesign: A marriage of convenience?

Since AlphaFold2's rise, many deep learning methods for protein design have emerged. Here, we validate widely used and recognized tools, compare them with first-principle methods, and explore their combinations, focusing on their effectiveness in protein redesign and potential for therapeutic repurposing. We address two challenges: evaluating tools and combinations ability to detect the effects of multiple concurrent mutations in protein variants, and leveraging large-scale datasets to compare modeling-free methods, namely force fields, which handle point mutations well with limited backbone rearrangement, and inverse folding tools, which excel at native sequence recovery but may struggle with non-natural proteins.

Gelatin vs GelMA in alginate-based bioinks as a platform for versatile 3D bioprintable in vitro systems.

3D in vitro model systems, such as hydrogels, have garnered popularity due to their ability to more accurately recapitulate in vivo environments compared to 2D cell culture systems. However, methods which involve casting hydrogels by hand may be time consuming, have poor reproducibility, and reduced capacity to generate complex structures. Hence, 3D bioprinting has emerged as a useful tool for the high throughput production of in vitro tissue models such as hydrogels and complex constructs.

Joint inference of mutational signatures from indels and single-nucleotide substitutions reveals prognostic impact of DNA repair deficiencies.

Background: Mutational signatures are increasingly used to understand the mechanisms causing cancer. However, their important applications in predicting prognosis and stratifying patients for therapy are hampered by inaccurate inference of the various featureless, dense trinucleotide mutational spectra, which are often confounded with one another. One of them is the homologous recombination deficiency (HRd)-associated signature SBS3, relevant because of its association with prognosis in ovarian and breast cancer and because of its potential as a biomarker for synthetic lethality therapies.

Technology Roadmap of Micro/Nanorobots.

Inspired by Richard Feynman's 1959 lecture and the 1966 film , the field of micro/nanorobots has evolved from science fiction to reality, with significant advancements in biomedical and environmental applications. Despite the rapid progress, the deployment of functional micro/nanorobots remains limited. This review of the technology roadmap identifies key challenges hindering their widespread use, focusing on propulsion mechanisms, fundamental theoretical aspects, collective behavior, material design, and embodied intelligence.

Dietary Selenium Deficiency Accelerates the Onset of Aging-Related Gut Microbial Changes in Aged Telomere-Humanized Mice, With Akkermansia muciniphila Being the Most Prominent and Alleviating Selenium Deficiency-Induced Type 2 Diabetes.

Previous studies have shown that dietary selenium (Se) deficiency in mice reshapes gut microbiota, exacerbates healthspan deterioration (e.g., type 2 diabetes), and paradoxically activates beneficial longevity pathways.

Chromosome-Scale Genome Assembly Provides Insights Into Condor Evolution and Conservation.

Rare species are highly vulnerable to anthropogenic threats due to their unique life-history traits and specialised adaptations. The Andean condor (Vultur gryphus), the world's largest soaring bird, exemplifies these challenges with exceptional flight efficiency, delayed maturity, long lifespan, extreme sexual dimorphism and a critical scavenging role. The species faces significant threats, including habitat loss, persecution and poisoning.

Proteostasis in cellular dormancy: lessons from yeast to oocytes.

Cellular dormancy is characterized by a prolonged, reversible cell cycle arrest and absence of growth. Dormancy allows organisms to endure unfavorable environmental conditions and to maintain long-lived quiescent progenitor cells essential for tissue homeostasis and reproduction. Protein homeostasis (proteostasis) is central to the maintenance of intracellular integrity in all cell types, particularly in long-lived, non-dividing cells.

Disease-specific neuropathological alterations of the locus coeruleus in Alzheimer's disease, Down syndrome, and Parkinson's disease.

Introduction: The locus coeruleus (LC), the brain's primary source of noradrenaline (NA), undergoes early neurodegeneration in Parkinson's disease (PD), Alzheimer's diseases (AD), and Down syndrome (DS); however, differences have not been examined in parallel.

Methods: Post mortem brains (n = 67) from individuals with AD, DS-AD, and PD without and with dementia (PD-D) and controls were analyzed for amyloid beta (Aβ), phosphorylated tau (pTau), α-synuclein, endo-lysosomal alterations, biogenic amines, and selective biomarkers.

Results: LC degeneration correlated with age, peaking in AD and PD-D, while NA and dopaminergic metabolites were significantly reduced only in PD-D.

Massively parallel genetic perturbation suggests the energetic structure of an amyloid-β transition state.

Amyloid aggregates are pathological hallmarks of many human diseases, but how soluble proteins nucleate to form amyloids is poorly understood. Here, we use combinatorial mutagenesis, a kinetic selection assay, and machine learning to massively perturb the energetics of the nucleation reaction of amyloid-β (Aβ42), the protein that aggregates in Alzheimer's disease. In total, we measure the nucleation rates of >140,000 variants of Aβ42 to accurately quantify the changes in free energy of activation of the reaction for all possible amino acid substitutions in a protein and, in addition, to quantify >600 energetic interactions between mutations.

Sequential activation of transcription factors promotes liver regeneration through specific and developmental enhancers.

The mammalian liver exhibits remarkable regenerative capabilities after injury or resection. Central to this process is the precise modulation of gene expression, driven by changes in chromatin structure and the temporal activation of distal regulatory elements. In this study, we integrated chromatin accessibility and transcriptomic data after partial hepatectomy in mice.

ER tubular body: an ER-derived compartment for redirecting autophagy to secretory functions.

The secretion of proteins that do not follow the well-characterized endoplasmic reticulum (ER)-Golgi apparatus pathway, known as unconventional protein secretion (UCPS), is gradually revealing its complexities. Our study has identified an ER-based tubulovesicular network, termed ER tubular body (ER-TB), as a central compartment in this process. We demonstrate that ER-TBs are formed by two reticulophagy receptors, ATL3 and RTN3L, under conditions of cellular stress.

RAS-p110α signalling in macrophages is required for effective inflammatory response and resolution of inflammation.

Macrophages are crucial in the body's inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS-p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models.

NaBC1 Boron Transporter Enables Myoblast Response to Substrate Rigidity via Fibronectin-Binding Integrins.

Cells are sensitive to the physical properties of their microenvironment and transduce them into biochemical cues that trigger gene expression and alter cell behavior. Numerous proteins, including integrins, are involved in these mechanotransductive events. Here, a novel role for the boron transporter NaBC1 is identified as a mechanotransducer.

Molecular Tools to Study and Control Dopaminergic Neurotransmission With Light.

Dopaminergic neurotransmission is involved in several important brain functions, such as motor control, learning, reward-motivated behavior, and emotions. Dysfunctions of dopaminergic system may lead to the development of various neurological and psychiatric disorders, like Parkinson's disease, schizophrenia, depression, and addictions. Despite years of sustained research, it is not fully established how dopaminergic neurotransmission governs these important functions through a relatively small number of neurons that release dopamine.