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During epithelial morphogenesis, cell polarity aligns individual cell behaviors into collective motions that shape developing tissues. Here, we combine experiments with computational modeling to investigate how cell-scale forces oriented by planar cell polarity (PCP) direct the collective, counter-rotational cell flows that occur during hair placode morphogenesis. Unexpectedly, we find that junctional myosin and PCP protein localization are not co-correlated with junction shrinkage, indicating the role of PCP during placode polarization is not to direct apical neighbor exchanges. Instead, we find that PCP directs anterior-directed crawling of placode cells along the basal surface of the tissue through a mechanism that requires integrins and the cell-crawling regulator Rac1. Modeling the placode as a three-dimensional continuum viscoelastic fluid, we find that active forces from cell crawling at the basal surface are sufficient to generate the experimentally observed counter-rotational cell motion at the apical surface. Our results show an unexpected role for PCP in epithelial morphogenesis, centering the basal surface as the site of force generation.

Fish is widely recognized as a valuable source of high-quality proteins, omega-3 fatty acids, and essential micronutrients. However, these nutritional benefits are increasingly compromised by marine pollution, particularly plastics and microplastics (MPs), particles smaller than 5 mm that enter the food chain after ingestion by marine organisms. These emerging pollutants represent a growing threat to both marine ecosystems and human health. In this study, laser direct infrared microscopy (LDIR) was used, an innovative technique based on a mid-infrared quantum cascade laser that enables precise and sensitive characterization of MPs. Samples from multiple species inhabiting the Mar Menor lagoon (Spain) were analysed, including muscle tissue, liver, and gastrointestinal contents. The muscle and liver samples were treated using acid digestion, while the gut contents were processed using oxidative digestion combined with density flotation. The results showed a predominance of particles between 50 and 100 microns (over 70%), primarily rounded in morphology. Polyethylene was the most frequently detected polymer, representing more than 45% of particles in all the samples. Statistical analyses demonstrated trend toward MP accumulation in gut contents, with no significant differences among marine species. Additionally, a cytotoxicity assay using marine fish cells (SAF-1 cell line) revealed a decrease in cell viability in response to polyamide MP, highlighting the urgent need for monitoring their environmental and food safety implications.

Autoimmune thyroiditis (AIT) is a chronic immune-mediated thyroid disorder characterized by lymphocytic infiltration, follicular epithelial injury, autoantibody production, and variable progression to thyroid dysfunction. Because current management is largely supportive or replacement based, there is growing interest in interventions that might modify inflammatory and immune processes before irreversible tissue damage develops. This narrative review critically evaluates the potential, but not yet established, role of Artemisia-derived and artemisinin-related compounds in AIT. The analysis focuses on chemokine-receptor networks, spatial organization of thyroid inflammation, and molecular mechanisms linking endoperoxide/redox chemistry, innate immune signaling, and immune-cell trafficking. Evidence was identified through targeted, non-systematic searches of PubMed and Google Scholar, supported by backward and forward citation tracking. Thyroid-specific evidence remains limited and predominantly preclinical. Dihydroartemisinin (DHA) has been reported to attenuate experimental autoimmune thyroiditis by reducing inflammatory infiltration, thyroid autoantibodies, Th1/Th17-associated responses, CXCL10/CXCR3-linked signaling, and oxidative stress. Evidence from non-thyroid autoimmune and inflammatory models suggests additional effects on NF-κB, MAPK, PI3K/Akt/mTOR, JAK/STAT, TLR/MyD88, NRF2/GPX4-related redox responses, inflammasome activity, regulatory T-cell balance, and possible epigenetic remodeling; however, these findings should be treated as mechanistic context rather than direct evidence for human AIT. Most available studies involve purified or semi-synthetic compounds rather than standardized botanical preparations, and robust clinical validation is absent. Artemisinin-related compounds are therefore framed as hypothesis-driven immunomodulatory candidates that require thyroid-specific replication, target validation, comparative pharmacology, safety assessment, formulation standardization, and carefully designed translational studies before clinical application can be considered.

RNA modifications have emerged as central regulators of cancer translational control. Unlike transcriptional reprogramming, which unfolds over hours, modification-dependent translational rewiring enables rapid proteomic adaptation to the nutrient-deprived, hypoxic, and immunologically hostile tumour microenvironment. Yet most existing reviews organize epitranscriptomic mechanisms by modification type or cancer hallmark, obscuring the mechanistic logic by which chemical marks collectively reshape the translational apparatus. This review adopts a translation-centric framework, examining how the most abundant modifications on mRNAs, tRNAs, and rRNAs regulate each stage of protein synthesis in malignant cells. We survey the epitranscriptomic toolkit, including modification chemistries, enzymatic writers, readers, and erasers, and detection technologies including nanopore direct RNA sequencing. We then trace how modifications control initiation (m6A-driven mRNA circularization, cap-independent translation via eIF3 and eIF4G2, rRNA 2'-O-methylation-directed cap-to-IRES switching), elongation (m6A-induced ribosome stalling coupled to mRNA decay, tRNA mcm5s2U-mediated codon-biased translation, YTHDF1-dependent elongation factor recruitment), and termination (pseudouridine-mediated stop codon readthrough, NMD evasion). Crucially, we show that mRNA, tRNA, and rRNA modifications do not act in isolation but form integrated networks. For example, mRNA m6A and tRNA mcm5s2U operate on opposing arms of the same regulatory axis, with direct implications for therapeutic design. We assess the expanding drug pipeline, from the METTL3 inhibitor STC-15 now in Phase 1b/2 trials and METTL3-targeting PROTACs to FTO and ADAR1 inhibitors, and argue that biology-informed combination strategies targeting multiple modification axes will be essential for durable clinical responses.

Mucinous adenocarcinoma (MAC) represents a subtype of colorectal cancer (CRC) characterized by insensitivity to chemoradiotherapy, necessitating urgent development of novel therapeutic strategies specifically targeting tumor biology of MAC. Integrated analysis of ATAC-seq and RNA-seq data was performed to identify pivotal targets mediating treatment resistance in MAC. Subsequently, clinical specimens were collected for immunohistochemistry, RT-qPCR, and Kaplan-Meier survival analysis. Functional validation of the target was conducted through in vitro experiments encompassing colony formation, drug sensitivity assessments, synergy testing, and immunofluorescence. The translational potential of the target was evaluated in vivo. Integrated ATAC-seq and RNA-seq analyses identified hypoxia and dysregulated ferroptosis as critical features of MAC, screening carbonic anhydrase 9 (CA9) as a pivotal gene implicated in MAC treatment resistance. CA9-specific inhibitor synergized with 5-fluorouracil to exert enhanced antitumor effects. Additionally, CA9 knockdown or inhibition arrested tumor cell proliferation and migration, promoted intracellular reactive oxygen species generation, induced mitochondrial shrinkage, increased mitochondrial iron content, reduced glutathione levels, and triggered lipid peroxidation. Inhibitors of either ferroptosis or apoptosis antagonized CA9 inhibitor-mediated cell death. In vivo experiments demonstrated that CA9 knockdown or inhibition significantly delayed tumor growth. Co-immunoprecipitation revealed that CA9 interacts directly or indirectly with multiple ferroptosis-associated proteins. This study identifies the hypoxic tumor microenvironments and dysregulated ferroptosis as pivotal molecular characteristics of MAC, and proposes a novel mechanism underlying treatment resistance in MAC: Hypoxia remodels chromatin accessibility through epigenetic modifications, to dysregulate CA9 expression, which may subsequently modulate cellular susceptibility to ferroptosis, culminating in treatment resistance, and targeting CA9 may improve the therapeutic efficacy of MAC, although further studies are needed to establish direct causality.

Cancer immunotherapy, including immune checkpoint inhibitors (ICIs) and chimera-antigen receptor (CAR)-T cell therapy, has achieved substantial clinical success. However, response rates remain limited in many patients due to tumor-intrinsic immune evasion and immune cell dysfunction within the tumor microenvironment (TME). Rho family small GTPases are key signaling regulators of cytoskeletal dynamics, intracellular trafficking, transcription, and metabolism in cancers. Emerging evidence implicates Rho GTPase signaling in mediating immunotherapy efficiency through its context-dependent functions. Individual Rho GTPases modulate immunotherapy responses in tumor cells and various immune cells through actomyosin-mediated chemotaxis, cell junctions, cell polarity, and gene/epigenetic networks, among other pathways. The present review summarizes both the direct evidence linking Rho GTPases in tumor cells to immunotherapy responses and the indirect role of the selective Rho GTPase signaling network in various immune cells, with a focus on the recent progress in understanding the molecular mechanisms and associated outcomes of the ICIs and CAR-T cell therapies. We highlight current knowledge gaps at the intersection of Rho GTPase biology and cancer immunology and discuss therapeutic implications, proposing that selective modulation of specific Rho GTPase signaling pathways in tumor or TME immune cells represents a promising strategy to improve immunotherapy efficiency.

Hepatitis C virus (HCV) manipulates host cellular pathways to create favourable conditions that support its replication and persistence. Identifying virus-host interactions helps to prevent disease progression and supports the development of host-directed antiviral therapies (HDTs) with a reduced risk of drug resistance due to viral mutations. In this study, a proteomic approach using in vitro pulldown assay and mass spectrometry identified α- and β-tubulin as novel cellular proteins physically associated with the viral RNA-dependent RNA polymerase (NS5B). This association was validated in hepatic (Huh7) and non-hepatic (HEK293T) cells. Further analysis confirmed that the interaction between NS5B and α/β-tubulin is an indirect interaction mediated by unidentified protein(s). Domain mapping analysis using NS5B-deletion mutants localized the tubulin-interacting region of NS5B to its N-terminal domain. Nocodazole, a known inhibitor of α- and β-tubulin polymerization, significantly reduced the association between NS5B and α-tubulin in vitro and in vivo settings, but had no notable impact on the NS5B/β-tubulin interaction. Additionally, nocodazole treatment markedly inhibited RNA replication of HCV subgenomic replicon in Huh7 cells in a dose-dependent manner. These results suggest an association between tubulin proteins and HCV RNA replication, potentially involving the interaction with NS5B. In addition, NS5B expression was associated with increased cell proliferation, indicating a possible link between NS5B/tubulin interaction, microtubule dynamics, and cellular transformation. Further studies are required to determine whether these associations reflect direct functional roles in HCV RNA replication, trafficking, virus assembly and/or cellular transformation.

The lncRNAs Airn and Kcnq1ot1 recruit Polycomb Repressive Complexes (PRCs) and repress genes over multi-megabase genomic intervals, but how they interact with proteins to direct repression remains poorly understood. We conducted formaldehyde-linked RNA-immunoprecipitations (RIPs) of 27 proteins from mouse trophoblast stem cells (TSCs), using a protocol exhibiting similar signal-to-non-specific signal and post-lysis reassociation ratios as crosslinking immunoprecipitation (CLIP) and crosslinking affinity purification (CLAP). Patterns of protein associations across Airn and Kcnq1ot1 were more similar to each other than to nearly all other transcripts and partitioned to extents that mirrored the degree of repression each lncRNA induced, implying connections to mechanism. Indeed, HNRNPU, a factor essential for Xist's localization to chromatin, was enriched over Airn and Kcnq1ot1 and required to maintain normal levels of PRC1- and PRC2-directed chromatin modifications across the Airn and Kcnq1ot1 target domains, yet was dispensable for both lncRNAs' localization to chromatin and for their association with PRC1. HNRNPU depletion caused a greater reduction in PRC-directed chromatin modifications and gene repression across the inactive X and the ~ 15 Mb Airn target domain than across the ~ 3 Mb Kcnq1ot1 domain. Perhaps relatedly, HNRNPU depletion significantly reduced the overall levels of Xist and Airn but not Kcnq1ot1. Our study reports architectures of protein association along Airn and Kcnq1ot1 compared to the transcriptome at large, highlights shared and distinct features between the two lncRNAs, and provides new perspective on the role of HNRNPU in long-range chromatin regulation by lncRNAs.

Cerebral cavernous malformations (CCMs) are characterized by abnormal clusters of dilated, thin-walled capillaries in the brain that are prone to bleeding, which give rise to a range of neurological symptoms including seizures and stroke. Current therapeutic strategies are restricted to surgical resection, highlighting the requirement for effective and efficient treatments. In this study, we investigated the therapeutic potential of Compound Danshen Dripping Pills (CDDP) as a traditional Chinese medicine (TCM) against the progression of CCMs. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to characterize the chemical composition of CDDP and identify its brain-penetrating ingredients. Lesion burden was assessed by macroscopic observation, micro-computed tomography (microCT), and histological analysis. Vascular integrity and function were evaluated by immunofluorescence staining. Blood flow was assessed by laser speckle contrast imaging and permeability was examined using Evans blue dye and FITC-dextran. Multi-omics approaches, including RNA sequencing (RNA-seq), proteomics, and metabolomics, were conducted to decipher molecular mechanisms. Western blot and quantitative Real-time PCR (qPCR) were performed to detect key signaling pathways. Brain-penetrating components were identified by UPLC-MS/MS, followed by molecular docking and molecular dynamics simulations for target proteins (MEKK3 and NF-κB). Surface plasmon resonance (SPR) assay was performed to validate the direct binding affinity of the identified key components to their respective target proteins. The functional impacts of target binding were assessed in HEK293T cells overexpressing MEKK3 (HEK293T/MEKK3-OE) by examining the phosphorylation levels of downstream mediators. KRIT1-knockdown human cerebral microvascular endothelial cells (HCMEC/D3) stimulated by lipopolysaccharide (LPS) were treated with identified components (ginsenoside F3 and tanshinone I), and assessed for trans-endothelial electrical resistance (TEER) and expression of critical inflammatory cytokines. UPLC-MS/MS identified 36 ingredients in CDDP, including phenolic acids, alkaloids, and ginsenosides. CDDP treatment dose-dependently reduced CCM lesion burden in Krit1iECKO mice, with 0.2 g/kg demonstrating optimal efficacy comparable to propranolol. Immunofluorescence revealed that CDDP significantly enhanced vascular integrity by upregulating Claudin-5 and VE-cadherin expression, increasing pericyte coverage, and normalizing basement membrane support. Functional assays demonstrated that CDDP restored cerebral blood flow and reduced vascular permeability. Integrated transcriptomics, proteomics, and metabolomics analysis revealed that CDDP significantly downregulated the MEKK3-MEK5-ERK5-KLF2/4-p-MLC2 signaling axis and suppressed inflammatory networks involving NF-κB, ICAM1, VCAM1, IL-6, IL-1β, and neutrophil extracellular traps (CitH3). Diprovocim-induced exacerbation of CCM lesions was effectively reversed by CDDP, confirming the involvement of MAPK and NF-κB pathways. Brain tissue analysis identified 11 brain-penetrating components, including salvianolic acids and ginsenosides. Molecular docking and molecular dynamics simulations revealed that ginsenoside F3 exhibited optimal binding affinity with NF-κB, while tanshinone I strongly bound to MEKK3. SPR assay further confirmed the direct binding, with ginsenoside F3 binding to NF-κB and tanshinone I binding to MEKK3. Functional validation in HEK293T/MEKK3-OE cells demonstrated that tanshinone I markedly suppressed MEKK3-driven phosphorylation of MEK5 and ERK5, while ginsenoside F3 significantly attenuated NF-κB phosphorylation. Administration of ginsenoside F3, tanshinone I, or their combination in Krit1iECKO mice led to reductions in cerebellar hemorrhagic lesions and vascular leakage, with the combination group exhibiting the most prominent therapeutic effect. In vitro validation in KRIT1-knockdown HCMEC/D3 cells demonstrated that ginsenoside F3, tanshinone I, and their combination significantly restored TEER values and reduced IL-1β and IL-6 expression, with the combination showing synergistic effects. CDDP exerts therapeutic effects against CCM progression by strengthening vascular integrity, restoring endothelial barrier function, and suppressing inflammation through inhibition of the MEKK3-MEK5-ERK5-KLF2/4-p-MLC2 and NF-κB signaling pathways. Brain-penetrating components, particularly ginsenoside F3 and tanshinone I, directly targeted key proteins (NF-κB and MEKK3) and synergistically protected endothelial function. These findings provide preclinical evidence supporting CDDP as a promising multi-target therapeutic strategy for CCMs.

Monitoring floating marine debris (FMD) is a global priority, emphasized in international initiatives and increasingly incorporated into marine policy frameworks, including many Marine Strategy Framework Directives. Despite this relevance, systematic monitoring of FMD remains virtually absent across the South Atlantic Ocean basin. Throughout 2025, we monitored weekly FMD using a fixed and temporally consistent vessel-based transport route across Baía de Todos os Santos, Brazil, with high temporal granularity encompassing tidal stages, weeks, and months, based on standardized visual observations from the vessel deck. Plastic items accounted for over 99% of all recorded debris, and no transect yielded zero detections, indicating the pervasive occurrence of floating litter along the monitored route. Tidal phase, surface current direction, and velocity were associated with distinct patterns of FMD accumulation and transport throughout the year. The terminal sections of the route exhibited the highest cumulative densities, likely driven by retention under lower current velocities compared with the faster-flowing mid-route section. Both mean and maximum FMD densities per km2 were among the higher values reported in vessel-based observational studies, although direct comparisons should be interpreted cautiously due to methodological heterogeneity among monitoring designs. This study provides the first systematic application of this monitoring approach along the Brazilian coast and suggests fixed-route, high-frequency vessel monitoring may offer a replicable framework for improving floating marine debris assessment in other South Atlantic coastal systems.

Non-functioning pituitary adenomas (NFPAs) present a complex clinical challenge due to their indolent and invasive growth patterns, and critical anatomical location. Post-surgical tumor progression is frequent in patients with NFPAs, which often necessitates additional therapeutic interventions. The molecular mechanisms underlying post-surgical progression remain poorly understood and there are currently no reliable methods to stratify patients according to risk of tumor progression. The aim of this study was to comprehensively characterize the molecular alterations, together with an integrated understanding of their interactions, that could potentially uncover the biological processes driving post-surgical tumor progression of NFPAs. We performed an integrated analysis of genome-wide DNA methylation and proteomics in 25 progressive and 15 indolent NFPAs using hypernetwork modelling linking CpG sites to the differentially expressed proteins to identify functional alterations associated with tumor progression. In addition, we investigated cis-regulatory relationships by examining CpG sites located within or in close proximity to the genes encoding the corresponding proteins, allowing assessment of the direct impact of DNA methylation changes on protein expression levels. Hypernetwork analysis uncovered extensive indirect and higher-order associations, capturing coordinated epigenetic influences on protein networks in indolent and progressive NFPAs. Progressive NFPAs were characterized by a compact and highly interconnected hub network with proteins primarily involved in DNA replication and transcription regulation (MCM6 and HDGFL2), chromatin organization (SAFB, HDGFL2, KDM3B, and TAF7), and cytoskeleton organization and cell structure maintenance (AJM1 and SYNE2). In contrast, indolent adenomas exhibited a broader and more diffuse network architecture with hub proteins linked to protein processing and transport (PSMD6, APMAP, B4GAT1, and COPE), extracellular matrix organization (LAMB2), and oxidative stress response (CISD2). Hub proteins in progressive NFPAs were enriched for metabolic pathways including glycolysis and tricarboxylic acid cycle, while enriched pathways for hub proteins in the indolent group were associated with genome maintenance and cellular stress responses. Hypernetwork analysis highlighted distinct epigenetic-proteomic regulatory mechanisms linked to tumor behavior that were not detected through cis-acting correlation analysis. Collectively, this integrative approach provides insight beyond direct regulation effects and offers a framework for identifying network-informed candidate markers with mechanistic relevance in tumor progression.

Although their functions have long been disputed, pulmonary neuroepithelial bodies (NEBs) are now considered complex, multifunctional units implicated in vagal sensory signaling within the brain-lung axis. A widely proposed function of NEBs is that their neuroendocrine cells would be able to sense acute airway hypoxia, triggering Ca² ⁺ -dependent transmitter release and the subsequent activation of vagal afferents that transfer the hypoxic information to the central nervous system (CNS). However, physiological evidence for the latter well-documented hypothesis is so far inconclusive. Using a confocal live-cell imaging model, based on murine precision-cut lung slices (PCLSs), this study was designed to directly visualize hypoxia-induced activation of NEB cells, including associated Ca² ⁺ -mediated exocytotic events that would support CNS-directed signaling. In PCLSs from prenatal and postnatal C57BL/6 mice, including GAD67-GFP mice, we monitored changes in intracellular Ca²⁺ ([Ca²⁺]i), mitochondrial membrane potential, and reactive oxygen species (ROS) during acute and intermittent hypoxia, as well as after ROS scavenging. Whole-mount mouse carotid bodies served as positive controls. Carotid body glomus cells showed robust hypoxia-induced [Ca²⁺]i rises, confirming assay sensitivity. In contrast, neither acute (2 or 12% O₂) nor intermittent hypoxia elicited [Ca²⁺]i increases in NEBs or delayed activation of adjacent Clara-like cells at any developmental stage. NEBs remained responsive to K+-induced depolarization, though excitability appeared to decrease during hypoxia. Hypoxia caused rapid, reversible mitochondrial depolarization in NEBs and ciliated epithelial cells, accompanied by a modest ROS increase in all airway epithelial cells. Tempol did not uncover any [Ca²⁺]i responses. Whereas control airway epithelium and carotid body expressed all NADPH oxidase subunits, the NEB microenvironment appeared to lack clear expression of several components. We conclude that mouse NEBs do not exhibit Ca² ⁺ -mediated exocytotic responses to hypoxia and that NADPH oxidase is unlikely to function as their O₂ sensor. These findings challenge a direct NEB-to-brain signaling pathway for acute hypoxia, but support local, paracrine functions related to airway oxygenation.

SARS-CoV-2 endoribonuclease NSP15 (NendoU) requires tight regulation within the replication-transcription complex (RTC); however, no viral protein has been described to date that regulates its activity. We demonstrate here that NSP3 ADP-ribose phosphatase, also known as ADPRP (Mac1), binds directly to NSP15 and stimulates its endoribonuclease activity. Surface plasmon resonance revealed moderate-affinity binding (KD = 1.59 ± 0.4 µM), with Mn2+ significantly enhancing binding compared to metal-free conditions. FRET assays confirmed close molecular association between the fluorophore-labeled proteins, while pull-down experiments revealed a stable complex formation with ∼51% ADPRP retention. Functionally, ADPRP increased NSP15-mediated cleavage of an 18-mer RNA substrate from 51-52% to 90-98%, with Mn2+ further potentiating maximal catalytic efficiency. Kinetic analysis showed an increase in kcat with no significant change in Km, indicating increased catalytic turnover rather than altered substrate affinity. EMSA and Denaturing PAGE showed that ADPRP neither bound nor cleaved RNA, indicating an indirect mode of regulation. AlphaFold modeling predicted binding in the vicinity of the NSP15 N-terminal oligomerization region. Normal Mode Analysis of the AlphaFold Complex revealed a dominant low-frequency collective motion consistent with intrinsic conformational flexibility relevant to interactions and regulation. Molecular docking using the Surflex-Dock program available in SYBYL-X v2.1 identified AW00832 and HTS00094 as the two computationally predicted hits and candidate inhibitors of NSP15. Overall, our results identified ADPRP as the first putative viral regulator of NSP15 activity and established NSP15-ADPRP as a regulatory pathway that can be therapeutically exploited through direct inhibition of NSP15.

High mobility group box 1 protein (HMGB1) is a central mediator of inflammation and pain, but efforts to neutralize it therapeutically have had limited clinical success. This gap suggests that the essential problem is not simply the abundance of extracellular HMGB1, but its accessibility: its availability to assemble into pathogenic complexes, engage receptors such as the receptor for advanced glycation end products (RAGE), enter cells, and deliver inflammatory cargo to the cytosol. Here, a perspective is advanced that integrates HMGB1 biology with the inflammatory reflex and the cholinergic anti-inflammatory pathway. In this framework, HMGB1 promotes inflammatory entry and amplification, whereas acetylcholine, acting through the vagus nerve and alpha7 nicotinic acetylcholine receptors, limits HMGB1 release and uptake of HMGB1-containing complexes. Vagus nerve stimulation therefore emerges as a bioelectronic strategy to restrict upstream access of danger signals to intracellular inflammatory pathways, in addition to suppressing downstream cytokine signaling. This formulation does not alter the established biology of HMGB1; rather, it places existing observations into a unifying model with direct relevance to inflammation and pain.

This review's scientific value is to systematically review existing literature on B. sinuspersici ensuring a structure of exploiting such genetic adapt reactions to counter climate change impacts on agriculture. This work highlights the need for such interdisciplinarity to bring such discoveries into fruition of improved, salinity and drought, tolerant crops, providing novel tactics toward food production from saline and arid landscapes. This paper argues that Bienertia sinuspersici has revolutionary genes for enhancing crop varieties and global food security in regions that are affected by climate change, synthesises current knowledge of the molecular phylogenetics, evolution, adaptive physiology, and translational potential of Bienertia sinuspersici, with particular emphasis on its application to crop improvement. As one of the few known plants performing fully functional single-cell C4 photosynthesis in a halophytic context, B. sinuspersici provides a valuable genetic reservoir for enhancing salt and drought tolerance in staple cereals such as rice (Oryza sativa) and wheat (Triticum aestivum). We examine the physiological and molecular traits that enable B. sinuspersici to thrive under extreme abiotic stress including ion homeostasis, osmoprotectant biosynthesis, and photosynthetic efficiency and evaluate the prospects for transferring these traits into glycophytic crops through transgenic approaches and marker-assisted selection. Key findings centre on stress-responsive genes, notably high-affinity potassium transporters (HKT1) and sodium/hydrogen exchangers (NHX1), which are strongly associated with salinity tolerance. Recent advances in CRISPR-Cas9 genome editing and genome-wide association studies (GWAS) further expand the toolkit for introgressing B. sinuspersici-derived traits into food crops, with direct implications for global food security. However, significant gaps remain, particularly the absence of multi-year, multi-location field trials validating these traits under realistic agronomic conditions. The principal contribution of this review is a systematic integration of the available literature on B. sinuspersici, framed as a roadmap for harnessing its adaptive genetic resources to mitigate the agricultural impacts of climate change. We argue that realizing this potential will require sustained interdisciplinary collaboration spanning molecular biology, plant breeding, and agronomy, and that B. sinuspersici offers transformative genetic resources for developing salinity- and drought-tolerant cultivars suited to saline and arid production systems.

Olfactory dysfunction is one of the most common early features of Alzheimer's disease (AD), yet its underlying neural mechanisms remains unclear. The lateral entorhinal cortex (LEC), a central node in the olfactory network, is among the earliest regions affected by AD pathology. However, the direct evidence supporting a causal link between LEC dysfunction and olfactory disorders in early AD is limited. In the present study, we explored whether and how LEC dysfunction contributes to early AD olfactory dysfunction by injecting amyloid-β1-42 (Aβ1-42) oligomers into the LEC to induce localized Aβ oligomers accumulation in this region. Our data demonstrate that localized Aβ oligomers in the LEC impaired odor detection and discrimination in mice. In vivo recordings revealed that Aβ oligomers increased baseline firing and odor-evoked activity in LEC neurons, while also enhancing odor-evoked beta oscillations. This hyperactive state corresponded with disrupted population-level odor decoding. Furthermore, deficits in synaptic structure and impaired synaptic transmission likely underlie the observed behavioral dysfunctions. Overall, these findings indicate that LEC dysfunction is linked to olfactory deficits in early AD, providing direct evidence for the involvement of this region in AD-related olfactory impairment.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, characterized by rapid progression and exceptionally poor prognosis. Identifying novel molecular drivers and therapeutic targets is urgently needed. This study reports a previously unrecognized MET-YANK2 signaling axis that drives glioma progression. Analysis of glioma patient samples reveals that high co‑expression of MET and YANK2 is positively correlated and significantly associated with poor survival outcomes. Mechanistically, MET directly phosphorylates YANK2 at tyrosine 282 (Y282), a conserved residue critical for maintaining YANK2 protein stability. This phosphorylation event prevents SUMOylation mediated proteasomal degradation of YANK2, thereby enhancing its oncogenic function. Functional assays demonstrate that YANK2 phosphorylation promotes GBM cell proliferation and tumor growth both in vitro and in vivo. Conversely, loss of this phosphorylation or enhanced SUMOylation at lysine residues K8 and K148 markedly suppresses YANK2 oncogenic activity. Through structure based screening, rutin, a natural flavonoid compound, is identified as a potent direct binder of YANK2. Rutin treatment effectively inhibits YANK2 kinase activity, reduces downstream p70S6K phosphorylation, and selectively suppresses proliferation of YANK2 high GBM cells. Importantly, rutin exhibits synergistic effects with temozolomide (TMZ), significantly inhibiting tumor growth and prolonging survival in YANK2 overexpressing orthotopic glioma models. Collectively, these findings establish YANK2 as a novel prognostic biomarker and a promising therapeutic target, and highlight rutin as a potential chemosensitizer for biomarker driven combination therapy in glioma.

Cancer stem cells (CSCs) drive recurrence and drug resistance in hepatocellular carcinoma (HCC), but their origin remains controversial: are they tumour-initiating cells or late-stage dedifferentiation products? Direct human single-cell evidence linking bipotent progenitors (BPs) and CSCs has been lacking. We integrated single-cell RNA sequencing (scRNA-seq) data from 109 samples (44 patients; 410,608 cells) across five public cohorts and generated EpCAM-enriched scRNA-seq from two additional HCC patients. Single-cell somatic mutations were inferred from the transcriptomic data, yielding 384,867 high-confidence variants across 31,908 cells from 20 patients. Clonal evolution was reconstructed through copy number variation (CNV) phylogenies and transcription-coupled-repair-based cell-of-origin inference. CSC and non-CSC subpopulations from Huh7 cells were flow-sorted before and after two weeks of culture and profiled by targeted bisulfite sequencing. A core-imprint risk score was evaluated in multiple cohorts and validated on a 97-case tissue microarray by multiplex immunofluorescence. Unexpectedly, BPs harboured higher mutation burdens than other non-malignant parenchymal cells, and CSCs harboured higher mutation burdens than most other tumour cells, challenging their role as genomically quiescent ancestors. CNV phylogenies and evolutionary distances placed CSCs at the most distal branches of the tumour tree, while cell-of-origin analysis identified BPs as a pre-malignant precursor arising from hepatocyte dedifferentiation. RNA velocity, pseudotime and SNP-integrated lineage reconstruction converged on this directionality, with CSCs arising at the terminus of tumour evolution, reproduced at single-patient resolution in the EpCAM-enriched samples. Mechanistically, CSCs upregulated DNA methyltransferases (DNMTs), and ~78% of CSC-specific methylation changes were stably retained after CSC differentiation but not reproduced during de novo stemness acquisition, indicating locked-in epigenetic memory. A 16-gene core-imprint risk score specifically predicted early recurrence (≤2 years), and CD13+ CD133+ CSCs showed elevated 5-hydroxymethylcytosine correlating with poor prognosis. We propose a framework in which hepatocytes dedifferentiate into BPs as a pre-malignant state, undergo malignant transformation, and a subset acquires stemness through DNMT-mediated reprogramming stabilized by epigenetic memory. These findings challenge the classical stem cell origin hypothesis, showing that CSCs in established HCC are late-stage dedifferentiation products, provide a rationale for targeting CSC epigenetic stability, and offer a biomarker for early recurrence.

With over 27,100 papers currently written about Proliferating Cell Nuclear Antigen (PCNA) and more than 11,700 papers describing a role for the protein and its relationship to cancer, this chapter will just touch upon some of the important role's PCNA has within cells and what types of proteins might interact with PCNA. This chapter is not meant to provide a thorough review of the multitude of protein complexes utilizing PCNA as a cofactor but rather highlight only some of those direct or indirect interactions between PCNA and its binding partners which together are involved in maintaining the genome, regulating cytoplasmic activities, and participating in immune surveillance. Additionally, this chapter will provide a high-level overview of how the caPCNA isoform is being used as a platform for a new class of anticancer therapeutic agent that selectively kills cancer cells, while leaving non-cancer cells unharmed.