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Alternative microexon splicing code for a four-amino acid peptide of PTPRD governs behavioral development
Microexons of 3 to 27 nucleotides selectively regulated in the vertebrate nervous system have attracted attention as new elements for modifying the function of neuronal proteins. Protein tyrosine phosphatase δ (PTPRD) is one of presynaptic hubs for neuronal synaptic organization. Alternative splicing (AS) of three microexons, meA3, meA6, and meB, encoding 3, 6, and 4 amino acid-peptides, respectively, imparts structural diversity to PTPRD, due to which the resulting eight splice variants exhibit distinct synaptogenic properties. However, the regulatory mechanisms of AS and physiological significance of the AS code for Ptprd gene remain largely unknown. Here, we report the AS of the three microexons is genetically regulated to generate spatiotemporally distinct expression pattern of eight Ptprd splice variants across brain regions and is modulated by neuronal activity. We identified both the intronic splicing enhancer region (ISE) for meB contributing to the spatiotemporal patterning of the AS and the neuronal activity–dependent intronic splicing silencer region for meB (ISS). Heterozygous deletion of the ISE in mice led to a decreased meB selection rate by ~25% with unaltered total amount of PTPRD protein and caused severe sensory, motor, social, and emotional behavioral abnormalities but no obvious changes in learning and memory, while heterozygous Ptprd knockout mice with unaltered meB selection rate and ~50% decrease in total PTPRD protein showed much fewer behavioral abnormalities. Interestingly, deletion of the ISS for meB caused selective impairments in motor learning and fear memory. Our findings demonstrate the spatiotemporal and activity-dependent AS code for Ptprd meB plays a crucial role in proper behavioral development.
An interpretable piecewise model for human mortality: the Christopher–Samba model
STAG2 loss amplifies EWS-FLI1-driven microsatellite enhancer activity promoting Ewing sarcoma aggressiveness
Ewing sarcoma is driven by chromosomal translocations that fuse a FET RNA-binding protein to an ETS transcription factor, most commonly generating the EWS-FLI1 fusion oncoprotein. EWS-FLI1 engages GGAA microsatellite repeats to form de novo enhancers that activate oncogenic transcriptional programs essential for tumorigenesis. In addition to this truncal driver, recurrent loss-of-function alterations in the cohesin subunit STAG2 occur in approximately 10 to 15% of Ewing sarcomas and are associated with adverse clinical outcomes. However, how STAG2 loss reshapes EWS-FLI1 chromatin engagement and transcriptional output remains poorly understood. Here, using genetic STAG2 loss-of-function models combined with integrative multiomic profiling, we demonstrate that STAG2–cohesin deficiency reprograms the EWS-FLI1 chromatin landscape by altering its binding at GGAA-microsatellite enhancers. Despite increased EWS-FLI1 protein abundance, STAG2 loss eliminates over 40% of EWS-FLI1 binding sites, predominantly at enhancers containing short (1–4) GGAA repeats, while concurrently increasing binding at multimeric enhancers with ≥5 GGAA-repeat motifs. These reprogrammed sites show changes in both chromatin accessibility and H3K27ac, leading to selective amplification of EWS-FLI1 activity at multimeric microsatellite enhancers. By integrating Hi-C chromatin interaction maps with altered EWS-FLI1 occupancy, we define distinct monomeric and multimeric GGAA enhancer–driven transcriptional gene signatures and demonstrate that STAG2 loss selectively augments the multimeric transcriptional program. Consistently, the long GGAA microsatellite-activated gene signature is enriched in patient tumors with aggressive clinical features and deleterious STAG2 alterations. Together, these findings reveal that STAG2 loss reprograms, rather than globally attenuates, EWS-FLI1 function, amplifying a high-risk oncogenic transcriptional state in Ewing sarcoma.
Retraction Note: Effects of Novel Calpain Inhibitors in Transgenic Animal Model of Parkinson’s disease/dementia with Lewy bodies
Nocturnal hydration prepares desert cyanobacteria for dawn-light harvesting by inducing phycoerythrin synthesis
As crucial ecosystem engineers in global drylands, desert cyanobacteria regulate biogeochemical cycling and contribute to the stabilization of arid soils. These extremophiles frequently exploit nocturnal dew deposition to resume metabolism, activate photosynthesis during brief dawn illumination, and then return to diurnal quiescence. Although phycobilisome remodeling is a key evolutionary adaptation for light capture under dim conditions, the molecular mechanisms that optimize light harvesting during the narrow window of hydration/light overlap remain unclear. Here, we show that genes involved in phycoerythrin (PE) synthesis are induced primarily by nighttime rehydration, prior to light exposure. We identify SigB1 as an essential regulator of PE synthesis, where it functions in concert with the activator CpeR1. Deletion of sigB1 disrupts PE production, thereby establishing its central role in this pathway. We further identify Hrr1 (hydration-responsive regulator 1) as an upstream transcription factor that is induced following nighttime water uptake and, in turn, activates sigB1 and cpeR1 , thereby initiating transcription of PE biosynthetic genes. Notably, we also find that SigB1 is regulated by the chromatic acclimation factor RcaF, which suppresses PE synthesis as weak dawn light emerges. Together, these findings reveal that nocturnal rehydration triggers an anticipatory transcriptional program that primes PE synthesis, enabling desert cyanobacteria to maximize light harvesting at dawn. More broadly, our results provide insight into how desiccation-tolerant photosynthetic organisms dynamically optimize their light-harvesting apparatus in response to transient environmental cues.
Impact of culture dimensionality and matrix composition on morphology, phenotype and drug response in pancreatic cancer models
Abstract Patient-derived in vitro systems are powerful preclinical models that replicate key features of human tumors and enable investigation of cancer biology and drug response. They are particularly promising for pancreatic cancer research. We examined whether culture dimensionality and basement membrane extract (BME) composition affect establishment rates, morphology, proliferation, marker expression, and drug response in patient-derived models of pancreatic ductal adenocarcinoma (PDAC). From 12 PDAC samples, matched two-dimensional primary cell lines (PDCLs) and three-dimensional organoids were established in Cultrex (PDOCs) and Matrigel (PDOMs). PDCLs formed monolayers, while PDOCs and PDOMs developed cystic or dense organoids, independent of BME type. Immunohistochemistry showed no differences in key diagnostic markers between culture systems, and Ki-67 levels were consistently higher in vitro compared to original tumors. Pharmacological testing with five standard chemotherapeutics revealed no significant differences in drug response between dimensionalities or BMEs, although 3D models were detected to be slightly more chemoresistant. In two patients treated with gemcitabine monotherapy, in vitro therapy response correlated with clinical relapse. Our findings indicate that while drug responses are largely patient-specific and independent of dimensionality and matrix composition, 3D models more realistically recapitulate tumor architecture and phenotypes, supporting their value for translational PDAC research. Trial registration: The study was conducted according to the guidelines of the Declaration of Helsinki. Ethical approval was requested and granted by the ethics committee of the Charité Universitätsmedizin Berlin (EA1/157/21) on 26th May 2021.
Simulation-based inference captures non-Markovian effects as exemplified in protein production kinetics through cell division
Inferring protein production kinetics in dividing cells is complicated by protein inheritance from the mother cell. For instance, fluorescence measurements commonly used to assess gene activation may reflect not only newly produced proteins but also those inherited through successive cell divisions. In such cases, observed protein levels in any given cell are shaped by its division history. As a case study, we examine the activation of the glc3 gene in yeast involved in glycogen synthesis and expressed under nutrient-limiting conditions. We monitor this activity using snapshot fluorescence measurements via flow cytometry, where green fluorescent protein (GFP) expression reflects glc3 promoter activity. A naïve analysis of flow cytometry data ignoring cell division suggests many cells are active at low expression levels. Explicitly accounting for the (inherently non-Markovian) effects of cell division and protein inheritance makes it impossible to write down a tractable likelihood, namely the probability of observing data given a model—a key ingredient in physics-inspired inference. The dependence on a cell’s division history breaks the assumptions of standard (Markovian) master equations, rendering traditional likelihood-based approaches inapplicable. In order to generate a method for inference in arbitrary non-Markovian dynamics, we adapt conditional normalizing flows (a class of neural network models designed to learn probability distributions) to approximate otherwise intractable likelihoods from simulated data. In doing so, we find that glc3 is mostly inactive under stress, showing that while cells occasionally activate the gene, expression is brief and transient.
Channel estimation strategies for STAR-RIS-Aided NOMA: robustness to imperfections and complexity trade-offs for 6G wireless systems
Selective depletion of virus-specific CD8 T cells from the liver after PD-1 therapy with Fc-intact antibody during chronic infection
Anti-programmed cell death 1 (PD-1) antibody therapy is now widely used in various cancers. However, the role of the antibody Fc region in PD-1 directed immunotherapy is not well understood. Preclinical studies commonly use species-mismatched rat anti-mouse antibodies, which may not accurately reflect antibody-Fc gamma receptor (FcγR) interactions. Here, we used mouse anti-mouse PD-1 antibodies to investigate how the Fc region influences therapeutic efficacy for enhancing CD8 T cell responses using mouse models of chronic lymphocytic choriomeningitis virus infection and CT26 tumors. Treatment with these mouse anti-mouse PD-1 antibodies caused preferential depletion of PD-1+ virus-specific CD8 T cells in the liver, resulting in increased viral titers. These effects of mouse anti-PD-1 antibodies were Fc dependent since mutating the Fc region to block FcγR interaction prevented PD-1+ CD8 T cell depletion and resulted in effective immunotherapy. Using mice lacking activating FcγR III or inhibitory FcγR IIb, we found that depletion of PD-1+ CD8 T cells was mediated via activating FcγR III. Furthermore, we determined that phagocytic cells, not natural killer cells, were the in vivo effectors that mediated depletion of PD-1+ CD8 T cells. Similar depletion of tumor-specific CD8 T cells and reduced tumor control were observed in the CT26 model with Fc-intact mouse anti-mouse PD-1 treatment. These findings highlight potential negative effects of Fc-functional anti-PD-1 antibodies in therapies for liver cancer, liver metastases, and chronic hepatotropic viral infections. Conversely, FcγR-mediated depletion could benefit “agonistic” anti-PD-1 antibodies for treatment of autoimmunity. Our research emphasizes the importance of Fc region in tailoring PD-1 therapies for diverse clinical applications.
Clean energy storage devices in electricity market under dual carbon goals: assembly and performance of supercapacitors
Hypoxia inducible factors regulate pneumovirus replication by enhancing innate immune sensing
The immune mechanisms responsible for protection and pathogenesis in pneumoviral infection are not well defined. We demonstrated that pharmacological activation of the hypoxic inducible factor (HIF) signaling axis using daprodustat limited viral replication through enhanced immune signaling. Transcriptomic analysis revealed HIF augmented activation of innate immune response genes, including interferon-stimulated gene 15 ( Isg15 ), in the lung and spleen of mice infected with pneumonia virus of mice (PVM). In human respiratory syncytial virus (hRSV)-infected airway epithelial cells, daprodustat inhibited viral replication and enhanced ISG15 expression in a HIF-dependent manner. Importantly, inhibition of type I interferon signaling or the RIG-I sensing pathway abrogated the antiviral activity of HIF. Moreover, daprodustat increased interferon signaling in response to viral RNA, suggesting that HIF inhibits pneumovirus replication through enhancing viral RNA sensing. Mechanistically, daprodustat reduced N 6 -methyladenosine modification of viral RNA through upregulation of RNA demethylases, promoting detection by innate immune sensors. This study highlights the intricate interplay between hypoxia and antiviral immunity and offers valuable insights into pneumovirus–host interactions and potential therapeutic interventions.
WHO exclusive breastfeeding recommendation and cognitive development in Germany
RIPK1 ubiquitination regulates its kinase-independent function in development and inflammation
Receptor-interacting protein kinase 1 (RIPK1) is a key regulator of cell death and inflammation, with its activation modulated by diverse posttranslational modifications. While ubiquitination of RIPK1 at lysine 376 (K376) has been shown to inhibit apoptosis and necroptosis both in vitro and in vivo, its role in inflammation remains undefined. In this study, we introduced a kinase-dead D138N mutation into Ripk1 K376R/K376R mice. Notably, Ripk1 K376R,D138N/K376R,D138N mice rescued the embryonic lethality observed in Ripk1 K376R/K376R mice, but developed systemic inflammation. Remarkably, this inflammation was significantly alleviated by codeletion of Caspase-1/11 , but not Trif , indicating a critical role for inflammasome activation. Mechanistically, loss of ubiquitination at the K376 residue of RIPK1 promotes kinase activity-dependent cell death, which underlies the lethality of Ripk1 K376R/K376R mice. Importantly, the K376R mutation also drives RIPK1 kinase–independent inflammatory responses by triggering intrinsic NLRP3 inflammasome activation and downstream IL-1β secretion. Furthermore, we found that RIPK1 promotes this process through a RIPK3-dependent mechanism. Consistently, deletion of Ripk3 —but not Mlkl —ameliorated this inflammation, highlighting a necroptosis-independent inflammatory axis. Together, our findings demonstrate that the RIPK1 K376R mutant not only induces kinase activity-dependent cell death during embryogenesis but also promotes kinase-independent, scaffold-driven inflammation in adults via RIPK3-mediated metabolic reprogramming that activates the NLRP3 inflammasome.
Prediction of filter clotting using longitudinal trends of circuit pressure parameters during continuous renal replacement therapy (CRRT): an exploratory study
Transient ion-mediated interactions regulate subunit rotation in a eukaryotic ribosome
While it is well known that ion binding can stabilize RNA structure, little is known about how transient/probabilistic ionic interactions facilitate biologically relevant conformational rearrangements. To address this, we developed a theoretical model that employs all-atom resolution with a simplified representation of biomolecular energetics (i.e., a structure-based “SMOG” model), explicit electrostatics, and ions (K + , Cl − , Mg 2+ ). For well-studied RNA systems, the model accurately describes the concentration-dependent ionic environment, which includes chelated and hydrated/diffuse ions. With this foundation, we applied the model to simulate the yeast ribosome and quantified the ion-dependent energy landscape of intersubunit rotation. These calculations show how millimolar increases in [MgCl 2 ] shift the energetics to favor the unrotated state. The free-energy barrier is also increased, leading to an order-of-magnitude reduction in kinetics that is correlated with formation of ion-mediated interactions between the subunits. This provides a physical description for how transient ionic interactions can contribute to large-scale biomolecular dynamics.
Multicriteria site suitability for solar-powered green hydrogen production plants along the Northwestern coast of Egypt
Abstract An integrated geospatial, hydrogeochemical framework for identifying environmentally suitable locations for solar-powered green hydrogen production along Egypt’s northwestern Mediterranean coast is applied. The methodology combines environmental stable isotope of groundwater (δ 1 ⁸O and δ 2 H) for quaternary, upper miocene, and lower miocene aquifers with multi-criteria spatial analysis in geographic information system (GIS). Isotopic signatures are used to evaluate groundwater recharge sources, salinization processes, and the extent of seawater intrusion providing a quantitative basis for assessing aquifers vulnerability. Eight spatial criteria, elevation, slope, aspect, land use/land cover, proximity to roads, proximity to the shoreline, hydraulic head, and seawater intrusion index, are weighted using fuzzy-analytic hierarchy process (AHP) and integrated to generate site suitability map for hydrogen infrastructure development. The results classify the study area into five suitability zones, with central and northeastern sectors emerging as the most favorable due to high solar potential, lower groundwater vulnerability, and adequate accessibility. Environmentally constrained zones are primarily associated with low hydraulic heads and pronounced seawater intrusion near the coast. At the regional scale, the framework supports informed decision-making for sustainable hydrogen deployment while minimizing impacts on fragile coastal aquifers. More broadly, the study demonstrates the value of coupling isotope hydrology, hydrochemistry and environmental parameters with GIS-based decision analysis, offering a transferable approach for siting renewable hydrogen projects in arid and semi-arid coastal regions worldwide.
Elucidation of the aragonite nanofiber formation mechanism of LICP contained in the hinge ligament of <i>Pinctada fucata</i>
The hinge ligament of bivalves exhibits remarkable flexibility and compressive strength due to its composite structure of aragonite nanofibers embedded in an organic matrix. While these nanofibers are crucial for shell mechanics, the molecular mechanisms underlying their formation remain unclear. We investigated the function of a 10-residue intracrystalline peptide, ligament intracrystalline peptide (LICP), in regulating aragonite crystal growth. Using a solution-state NMR technique optimized for biomineral systems with dispersive calcium carbonate particles, we showed that LICP adopted a planar, elongated conformation in binding to aragonite. This structure features a coplanar arrangement of carboxyl and aromatic side chains—particularly tyrosines—that enables selective interaction with the aragonite {110}. Saturation transfer difference NMR and dose-dependent structural analyses confirmed that this conformational change is triggered by solid-phase contact, rather than free calcium ions. Molecular dynamics simulations revealed enhanced binding stability of LICP to the {110} surface through multiple carboxyl and aromatic residues. Furthermore, in vitro crystallization assays showed that LICP promoted elongation of aragonite crystals along the c -axis, consistent with its selective surface binding. These findings demonstrated that conformational plasticity in short, disordered peptides enabled specific recognition of crystal faces and directed modulation of mineral growth. LICP serves as a minimal yet powerful model for exploring protein–mineral interfaces, offering broader insights into the structural principles by which intrinsically disordered peptides function in solid-phase biological systems.
Baseline vitamin D status and clinical outcomes in advanced non-small cell lung cancer patients treated with nivolumab
Targeted degradation of c-Myc through the midnolin–proteasome pathway
Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy; however, most TPD technologies employ either the ubiquitin–proteasome system or the lysosomal degradation system. Here, we report the development of midnolin-based targeting chimeras (MbTACs), a ubiquitin-independent TPD that degrades target proteins. We designed and synthesized peptide-based MbTACs, which are multifunctional molecules containing c-Myc-recognition moieties and midnolin binding moieties. MbTACs promote the formation of a ternary complex consisting of the target protein, MbTACs, and midnolin via chemically induced proximity; subsequently, midnolin recruits the proteasome to degrade the target protein. Biological evaluations demonstrated that the MbTACs could degrade c-Myc effectively through the midnolin–proteasome pathway. The antitumor effects of MbTACs were further validated in vitro and in vivo. Collectively, our results provide a ubiquitin-independent TPD tool. MbTACs represent a conveniently developed modular peptide degradation chimera and have the potential to be widely used in disease therapy. We expect the MbTACs to provide a dimension for TPD design.