ConspectusThe innovative exploration of non-fullerene acceptors (NFAs) such as ITIC, Y6, and others, has boosted the power conversion efficiencies (PCEs) of organic solar cells (OSCs) surpassing 21%. However, organic photovoltaics still suffer from significant efficiency gaps compared to inorganic photovoltaics, particularly in open-circuit voltage under similar bandgaps. This notable disparity is largely driven by the stark difference in nonradiative recombination energy losses: OSCs typically incur losses exceeding 0.2 eV, whereas their inorganic counterparts suffer only minimal losses, ranging from a mere 0.03 to 0.04 eV. This insurmountable nonradiative recombination is closely associated with some intrinsic features of organic photovoltaic light-harvesting materials: relatively flexible molecular frameworks, loose and disordered molecular aggregates, large exciton binding energies, etc. Therefore, a multiscale regulation spanning single-molecular properties and aggregation behaviors in further molecular design is required, if a remarkable PCE improvement is expected.In this Account, we first present a brief review of the development of electron acceptor materials, with a focus on analyzing the prominent merits of current high-efficiency acceptor molecular skeletons (especially Y6 analogs) in terms of intermolecular packing modes, photodynamic, etc. Meanwhile, great challenges for further material design also arises from the quite limited structural optimization room for Y-series backbones. In order to break through the dilemma of molecular design, we developed CH-series NFAs with multi-functionalized central units and an "acceptor-donor-acceptor" architecture. Subsequently, a systematic discussion about CH-series NFAs will be made to reveal their advantages in (1) inducing a directional transformation of molecular packing mode toward a more favorable one, through multiple intermolecular weak interactions such as fluorine-hydrogen/sulfur/π bonds, thus rendering multidimensional long-range ordered molecular stacking to minimize energy loss pathways in OSCs; (2) breaking through the limitations of traditional dimeric/trimeric/polymeric acceptor design by pioneering the construction of relatively rigid central-units-linked dimeric/trimeric NFAs with multiple free terminals to enhance intermolecular packings; (3) proposing a novel "functional reconfiguration" strategy for the central units, aiming to explore new photoelectric conversion mechanisms in organic photovoltaic materials.Thus far, CH-series NFAs based binary OSCs have achieved the highest PCE of approaching 21%, ranking among the best NFAs. If further considering their great structural modification possibilities, CH-series NFAs hold exceptional promise as a versatile platform for developing OSCs with record-breaking PCEs. Therefore, we further propose some perspectives for CH-series NFAs, for example, more precise structural and packing optimization to reduce exciton binding energies and improve molecular packing ordering; further in-depth exploration of a "functional reconfiguration" strategy to apply new photoelectric conversion mechanisms, such as triplet excitons, singlet fission, etc.; extending the absorption edge of NFAs to near-infrared II region to harvest more low-energy photons, especially for tandem OSCs. These strategies may have the potential to overcome the critical challenge existing in OSCs and shrink the PCE gap comparing to inorganic platforms.
Solid polymer electrolytes are promising for lithium metal batteries, yet achieving both high ionic conductivity and interfacial stability remains a major challenge. Here, we report a molecular rotor strategy that addresses this trade-off by incorporating 3-(1-Pyridinio)-1-propanesulfonate zwitterions (PP-Z) into a polyvinylidene difluoride electrolyte. This design establishes a dipole-rotation-assisted ion transport mechanism distinct from conventional polymer relaxation-dependent conduction. Molecular dynamics simulations and experiments reveal that the anchored cationic group of PP-Z serves as a pivot, while the mobile anionic end creates a dynamic coulombic field. This configuration facilitates rapid Li+ migration through coordinated intrachain transport and interchain hopping, significantly enhancing ionic conductivity (5.1 × 10-4 S cm-1 at 25°C and 1.5 × 10-4 S cm-1 at 0°C) and the Li+ transference number (0.52). The anionic terminals further participate in Li+ solvation and promote formation of a LiF-rich solid electrolyte interphase, enabling stable cycling for 1200 h in Li||Li cells at 0.3 mA cm-2 and >  500 cycles in Li||LiFePO4 cells at 1C (25°C). Even at 0°C, the Li||LiNi0.8Co0.1Mn0.1O2 (1.8 mAh cm-2) pouch cell retains 85.1% capacity over 50 cycles while delivering 78.3% of its room-temperature capacity initially.
Formation of the activated human spliceosome (Bact) involves major structural rearrangements, leading to the catalytically active U2/U6 RNA core. This process involves at least two intermediates, pre-Bact-1 and pre-Bact-2, and is regulated by CDK11-mediated phosphorylation of the U2 snRNP protein SF3B1. However, the mechanisms of this essential step are poorly understood. Here we present the cryo-EM structure of a spliceosome stalled - by the CDK11 inhibitor OTS964 - in a previously undescribed early-activated state, termed pre-Bact-OTS, shortly after dissociation of U4 snRNP. In pre-Bact-OTS, the U2-SF3B6 protein is retained in a C-terminal region of the super-helical U2-SF3B1 HEAT domain (SF3B1HEAT) that clamps the U2/branch-site helix. In contrast, in pre-Bact-1, SF3B6 is repositioned to SF3B1's N-terminal HEAT repeats, thereby preventing a steric clash of SF3B6 with PRP8 during the pre-Bact-OTS-to-pre-Bact-1 transition. We infer that the CDK11-mediated phosphorylation of SF3B1 drives the relocation of SF3B6, gating progression to Bact formation. In pre-Bact-OTS, we also located the RNA helicase DHX15 at the N-terminal region of SF3B1HEAT, assisted by the SR140/SPF45/CHERP/SUGP1 protein complex. These results suggest the involvement of DHX15 in kinase-mediated proofreading of the early-activated spliceosome, by competing with CDK11's phosphorylation of SF3B1, and thus with relocation of SF3B6 at SF3B1HEAT.
Metastasis contributes to treatment failure and poor prognosis of esophageal squamous cell carcinoma (ESCC) patients. The 5'-3' exoribonuclease 2 (XRN2) is related to the pathogenesis and progression of various malignancies through its roles in transcription termination and metastasis promotion, but its function in ESCC remains unclear. Bioinformatic analysis showed that XRN2 was significantly overexpressed in ESCC tissues and was identified as a risk factor for ESCC patients. The analysis of our own cohort confirmed that XRN2 expression was overexpressed and significantly correlated with cancer stage in patients (P = 0.0100). Gain- and loss- of function analyses revealed that XRN2 promoted ESCC cell growth, migration and invasion capabilities, as well as experimental lung colonization foci. Interestingly, we found that the RNA level of XRN2 was upregulated by the RNA-binding protein polypyrimidine tract binding protein 3 (PTBP3). Specifically, PTBP3 bound to CUUUC motifs of the 3'UTR of XRN2, prolonging the half-life of XRN2 RNA. PTBP3 was found to be significantly overexpressed in ESCC, where its expression level correlated with tumor stage (P = 0.0164) and tumor size (P = 0.0495), positioning it as a risk factor for ESCC patients. PTBP3 upregulation promoted ESCC cell growth, migration, and invasion in vitro and in vivo. Notably, knockdown of XRN2 reversed the tumor promotion effects induced by PTBP3 overexpression. Collectively, our data reveal a novel function of XRN2 in ESCC metastasis and the critical roles of the PTBP3/XRN2 axis in ESCC metastasis, highlighting its promise as a novel therapeutic target in ESCC.
Adjacent vessel geometry may affect focal hemodynamics and plaque features in intracranial atherosclerotic disease. To investigate the correlations of upstream (internal carotid artery (ICA) bifurcation) and focal arterial geometry of M1 middle cerebral artery (MCA-M1) with location of MCA-M1 plaques and focal hemodynamics, particularly wall shear stress (WSS) metrics. In patients with symptomatic atherosclerotic stenosis (50-99%) of MCA-M1, we assessed vessel geometry at ICA bifurcation and MCA-M1, including diameters and diameter ratios of different arterial segments, angles between arteries, and MCA-M1 tortuosity. The MCA-M1 plaque was defined as in proximal or distal halves of MCA-M1. Computational fluid dynamics (CFD) modeling was conducted to simulate adjacent blood flow and quantify relative wall shear stress (relative WSS, rWSS) across the MCA-M1 plaque (as relative to mean WSS at proximal normal segment). We investigated the associations of vessel geometry with the plaque location and rWSS metrics. Among 132 patients (median age 62 years), smaller diameter of MCA-M1 origin (adjusted odds ratio = 0.19, 95%CI 0.08-0.43, p < 0.001), smaller diameter ratio of MCA-M1 origin and terminal (0.04, 0.01-0.17, p < 0.001), and larger MCA-M1 tortuosity (1.03, 1.00-1.05, p = 0.045) were associated with proximal (versus distal) MCA-M1 plaques, independent of patient characteristics. These geometric parameters were associated with higher rWSS and larger area of high-rWSS region, throughout the MCA-M1 plaque and in upstream and downstream plaque segments, in patients with proximal MCA-M1 plaques (most p < 0.05), but not in those with distal MCA-M1 plaques. CFD models also revealed different velocity profiles and flow patterns in cases with different ICA bifurcation and MCA-M1 geometry. Adjacent arterial geometry may affect plaque distribution in MCA-M1. Focal hemodynamics e.g., WSS and velocity profiles, may play a role underlying the associations.
While there is a growing body of evidence on end-of-life (EOL) care preferences such as place of death, research remains limited in key areas. This includes gaps in understanding preferred and actual places of EOL care and death (dying places), potential shifts of preferences over time, and their (non-)alignment with reality. We aimed to explore how preferred and actual dying places unfold for adults with life-threatening illness and their family caregivers in different socio-cultural settings. A qualitative longitudinal study in the Netherlands, Portugal, Uganda, and the United States (June 2023-August 2025) in adults (≥ 18 y) with cancer, dementia, neuromuscular or heart and cerebrovascular disease and their family caregivers. We conducted a semi-structured interview at inclusion, followed by at least 2 interviews (between 3 weeks to 18 months after), including post-death with the family caregiver. Fieldnotes of informal conversations and observations complemented the transcripts. Analysis was based on principles of applied qualitative ethnography, combining applied thematic analysis with thematic network analysis. Fourteen patients participated, eight of whom were followed until death. Home was the most preferred dying place. We identified 3 themes: (1) Beyond the preferred: choosing otherwise highlighted how factors (the burden of receiving care, anticipated trauma of death at home, and urgent care needs) drove decisions around place; (2) Family caregiver commitment and burden affecting realisation of patient preferences illustrated the critical role of family caregivers; and (3) Navigating care shapes dying places showed how the healthcare system and skills to navigate it, influenced dying places. Preferences and decisions were influenced by a complex interplay of personal, relational, and contextual considerations. The prominence of these considerations may vary by country, but their interaction and the way they shape preferred and actual dying places appear to be a shared phenomenon. Clinicians, policymakers, educators, and researchers must consider patients' and family caregivers' preferences along with influencing drivers that can support or limit choice. Patient and public involvement and engagement (PPIE) was embedded in this international project from the start, through formal partnerships established with two international organisations representing patients and informal carers, namely the International Alliance of Patients' Organisations (IAPO) and Eurocarers. Representatives of both organisations worked closely with the research team and are members of the project advisory board. They contributed to the development of the study design and materials, to the training of researchers helping ensure interviews with patients and family caregivers were conducted in a sensitive and appropriate manner, and to the interpretation of findings through various meetings. They will also help to disseminate the findings to engage patients, informal carers and the wider public.
RAG1/2 catalyzes V(D)J recombination to assemble antigen receptor genes, but the RAG1 N-terminal zinc-coordinating domain (NZD) has remained structurally and functionally uncharacterized. Here, we determine the NMR structure of mouse RAG1 NZD, revealing a compact, zinc-dependent fold composed of four α-helices and two short β-strands. This architecture is organized into two interdigitated zinc-coordinating modules, ZMa and ZMb. Structural similarity searches identify no close homolog with the same overall architecture, suggesting that NZD represents a previously undescribed zinc-coordinating fold. Comparative analyses show that NZD is broadly conserved across RAG1 and RAG1-like proteins, while also displaying lineage-specific remodeling, including acquisition of the H2 helix in jawed vertebrates. Guided by structure prediction, we further identify putative NZD-like domains in Chapaev transposases, supporting a possible evolutionary link between RAG1/RAG1L NZDs and Chapa domains. Together, these findings provide a structural framework for mechanistic and evolutionary analyses of RAG1.
Timely and accurate diagnosis of mild traumatic brain injury (mTBI) remains challenging in acute care. In the Asia-Pacific (APAC) region, marked heterogeneity in healthcare infrastructure, computed tomography (CT) utilization, and diagnostic pathways underscores the need for practical, standardized approaches to assessment. Blood-based biomarkers, particularly glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), have shown promising diagnostic performance and have been incorporated into clinical pathways in other regions. However, their role in APAC emergency care workflows has not been systematically addressed. This study aimed to develop expert consensus on the definition, diagnosis, and clinical integration of these biomarkers into mTBI assessment across APAC. A structured modified Delphi process was employed, involving ten expert panelists representing emergency medicine, neurosurgery, and neurology from APAC countries including Australia, India, Indonesia, the Philippines, Singapore, Taiwan, and Thailand. A targeted literature review informed the development of 34 preliminary statements, consolidated into 11 statements covering mTBI definition, diagnostic approach, and biomarker integration. Panelists rated each statement using a 4-point Likert scale across two anonymous online voting rounds, with consensus defined as ≥ 70% agreement. Voting results were reviewed at a face-to-face meeting in Bangkok in May 2025, where statements were refined before Round 2 voting. All 11 final consensus statements achieved agreement ratings of 90% to 100% following Round 2 voting. Seven statements reached 100% agreement and four achieved 90% agreement. Statements addressed definitions of TBI and mTBI, the adjunctive diagnostic role of GFAP and UCH-L1 within a 12-hour post-injury window, their utility in diagnostically challenging subgroups such as anticoagulated and intoxicated patients, and the continued primacy of clinical assessment and local imaging pathways in guiding triage, imaging, discharge, and follow-up decisions. This modified Delphi study produced 11 high-consensus statements that provide a regional framework for the diagnosis of mTBI and for integration of GFAP and UCH-L1 into biomarker-supported assessment pathways across APAC. These biomarkers may help reduce avoidable CT imaging and support triage in selected patients when used as adjuncts to clinical assessment and established imaging decision-making. The statements are intended to support locally adapted protocols and future APAC-specific implementation and validation studies.
In this study, we developed two classes of metformin-based organic catalysts that efficiently promote the formation of high-value cyclic carbonates and oxazolidinone derivatives from CO2 and epoxides. Three bifunctional metforminium halide salts-chloride, bromide, and iodide (Met-I)-were prepared and evaluated in CO2 cycloaddition reactions. Met-I exhibited the highest activity, affording 14 mono-substituted cyclic carbonates under mild conditions. It also enabled the synthesis of di- and three-substituted cyclic carbonates. A second catalyst library comprising 12 halide-free metformin-derived organic salts containing pyridinolate and phenolate anions was developed. Among these, metforminium 2-pyridin-1-olate delivered the highest performance, providing cyclic carbonates in high yields under metal-free and solvent-free reaction conditions. Furthermore, the synthesis of 5-hydroxymethyl oxazolidinone derivatives was achieved using metforminium 2-pyridin-1-olate. The simple preparation, low cost, commercial availability, nontoxicity, easy purification, and low environmental footprint of these catalysts highlight metformin-based systems as practical and sustainable platforms for efficient CO2 utilization.
The plant endoplasmic reticulum (ER) forms a highly dynamic tubular network whose architecture depends on ER-shaping proteins and its interaction with the cytoskeleton. While actin is well known to drive ER movement in plants, how the ER associates with microtubules and how this affects ER network architecture remain poorly understood. Here, we identify Arabidopsis thaliana reticulon 17 (RTN17) as an atypical reticulon that links the ER to the microtubule cytoskeleton. RTN17 features extended, intrinsically disordered N- and C-terminal domains enriched in low-complexity regions, consistent with a scaffolding or hub function. Topology analysis using redox-sensitive roGFP2 constructs shows that both termini face the cytosol, yet RTN17 lacks the amphipathic helix typical of ER-shaping reticulons and does not induce membrane constriction. Instead, RTN17 localises to punctate foci on curved ER membranes, recruits the ER fusogen ROOT HAIR DEFECTIVE3 (RHD3), and co-expression alters ER architecture and dynamics. RTN17 puncta preferentially co-localise with microtubules, and its over-expression promotes ER alignment with the microtubule network. We propose that RTN17 acts as a multifunctional scaffold linking curved ER domains with the microtubule cytoskeleton and localising RHD3 to these sites to regulate ER fusion events. By integrating curvature sensing, cytoskeletal attachment and fusion regulation, RTN17 represents a new class of plant reticulons with scaffolding rather than shaping functions. This work highlights an unrecognised mechanism coordinating ER organisation with the cytoskeleton, providing insights into how plants achieve spatial control of endomembrane architecture and potentially adapt membrane dynamics to developmental or stress cues.
Heart failure (HF) represents the terminal clinical stage of a broad spectrum of cardiac disorders, distinguished by notably high rates of incidence and mortality. Extensive clinical investigations have proved that monitoring of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels can reliably forecast HF and inform targeted clinical decision-making. Current detections for NT-proBNP depend on centralized laboratory instrumentation, which frequently creates delays that hinder the delivery of timely clinical care and decision-making. Here, we present a wearable microneedle-based electrochemical aptamer sensor (MEAS) for real-time, dynamic monitoring detection of NT-proBNP. Furthermore, this MEAS integrates real-time signal processing with wireless communication capabilities (e.g., Bluetooth to smartphones), enabling dynamic data analysis and visual reading out of the NT-proBNP level. In vitro characterization demonstrated high analytical performance, including a wide linear range (10-2000 pg/mL), a low detection limit (8.61 pg/mL), excellent selectivity against common interferents, and stable responses over repeated measurements. The microneedle biosensor exhibited favorable biosafety and enabled reliable in vivo NT-proBNP monitoring, with good agreement between sensor readouts and ELISA measurements. Together, these results position the proposed microneedle aptasensor as a promising alternative to conventional blood-based testing, with the potential to support real-time, patient-centered monitoring and advance next-generation HF management strategies.
Cranioectodermal dysplasia (CED) (OMIM #218330) is an autosomal recessive multisystemic disorder. While many studies have diagnosed this condition postnatally, few cases have been identified during the prenatal period. This study aimed to investigate genetic mutations in a Han Chinese fetus and conduct a literature review, integrating ultrasonographic findings with molecular analysis to expand the genotype-phenotype spectrum of this ciliopathy. A 22-year-old Han Chinese woman conceived naturally. Prenatal ultrasound revealed multiple fetal congenital anomalies, including limb shortening, generalized fetal edema, cystic hygroma, and bilateral echogenic kidneys. Whole-exome sequencing revealed two bi-parental inherited compound heterozygous variants in WDR35: [c.1600C > T (p.Arg534Cys)] and [c.2375_2383del (p.Asn792_ Ala794del)]. The couple ultimately opted to terminate the pregnancy. The WDR35 mutations are associated with CED and exhibit a complex prenatal phenotype. Comprehensive prenatal ultrasound, whole-exome sequencing, and multidisciplinary genetic counseling are essential for accurate diagnosis and informed reproductive counseling.
The complement system is crucial in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) pathogenesis. Extracellular vesicles (EVs) serve as carriers of bioactive substances, influencing the immune system. We aimed to investigate myeloperoxidase-positive EVs (MPO+EVs) exposing complement components (C3a, C4d), terminal complement complex (TCC) and complement factor B (CFB) in relation to disease activity and kidney involvement. Plasma MPO+EVs carrying complement products, C3a, C4d, TCC or CFB, were analysed by flow cytometry. Clinical data, including kidney biopsy findings, were retrieved. Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). Eighty-one patients with AAV with granulomatosis with polyangiitis (n=59) or microscopic polyangiitis (n=22) were included. Active disease was noted in 73 (90.1%) patients and 50 (68.5%) had kidney involvement. Patients with kidney involvement had higher concentrations of MPO+, MPO+C3a+, MPO+C4d+ and MPO+TCC+EVs compared to patients without, and concentrations correlated positively with BVAS (p<0.05), respectively. Levels of EVs showed a negative correlation with estimated glomerular filtration rate, and a positive correlation with the proportions of necrosis and crescents in kidney biopsies. ROC curve analysis indicated that MPO+EVs could distinguish patients with kidney involvement from non-renal AAV. A binary multivariable logistic regression confirmed an independent association between levels of EV subsets and kidney involvement. Elevated levels of MPO+EVs exposing complement components in patients with kidney involvement indicate activation of the classical or lectin and common complement pathways in renal AAV. Furthermore, the association between levels of MPO+EVs with the presence of crescents and necrotic lesions in kidney tissue supports a role in renal inflammatory activity.
Hemorrhagic shock (HS) remains a leading cause of trauma-related mortality, primarily due to severe hypovolemia and systemic hypoperfusion. These pathophysiological changes may profoundly affect the pharmacokinetics of fentanyl, an opioid widely used for analgesia in trauma care. Previous studies, predominantly based on fixed-pressure shock models, may not adequately reflect clinically relevant hemodynamic conditions. Therefore, we employed a fixed-volume HS model as an alternative approach to reflect hypovolemia-associated perfusion deficits influencing fentanyl disposition. This study aimed to evaluate the pharmacokinetics of fentanyl and its primary metabolite, norfentanyl, in an experimental model of fixed-volume HS. Male Wistar rats were randomly divided into two groups: a control group (C; n = 6) and a fixed-volume hemorrhagic shock group (HS; n = 6). In the HS group, hemorrhage was induced by withdrawal of 30% of the estimated blood volume (EBV) following vascular cannulation. Fentanyl (10 µg/kg) was administered intravenously, and serial blood samples were collected over 60 min. The concentrations of plasma fentanyl and norfentanyl were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Pharmacokinetic parameters were calculated using Phoenix WinNonlin software. Non-compartmental analysis demonstrated significantly increased systemic exposure to fentanyl in the HS group, reflected by higher area under the concentration-time curve (AUC0-∞ and AUC0-t) values, accompanied by a marked reduction in systemic clearance (CL). Mean residence time (MRT) and terminal elimination half-life (t½λz) were significantly prolonged. Compartmental analysis confirmed a more than two-fold increase in fentanyl exposure, driven primarily by reduced clearance and prolonged elimination. In contrast, peak plasma concentrations (Cmax) showed only a borderline increase, and no statistically significant differences were detected in distribution-related parameters. These findings suggest that the major detectable pharmacokinetic changes associated with HS were primarily related to impaired fentanyl elimination. The metabolic conversion ratio (MCR), defined as the ratio of norfentanyl AUC0-t to fentanyl AUC0-t, was lower in the HS group (0.117) compared with controls (0.197). HS significantly alters fentanyl pharmacokinetics in rats by reducing clearance and increasing systemic exposure. The lower norfentanyl-to-fentanyl AUC0-t ratio suggests that HS may also affect metabolite formation or disposition.
P. falciparum (Pf) malaria is a major cause of morbidity and mortality in sub-Saharan Africa. Recently introduced malaria vaccines, RTS,S/AS01 and R21/Matrix-M, are effective in preventing infection, but their efficacy declines over time. To address this challenge, next-generation vaccine candidates have been designed to improve the functional immunogenicity to the circumsporozoite protein (PfCSP). In this study, we tested multiple hypotheses for improved vaccine design. Immunogens were constructed to target regions containing functional epitopes, and these were displayed on a well-characterized clinically relevant particle display platform. These candidate vaccines were tested in the established infection mouse model in which P. berghei sporozoites have been engineered to contain PfCSP instead of the native PbCSP protein. Our results show that induction of antibodies to the junctional region and the minor and major repeats are all effective at reducing parasite infection of the liver, while antibodies to the C-terminal domain did not contribute to protective immunity. None of the domains showed evidence of antigenic competition when co-administered on separate particles or when expressed on the surface of a single particle. Immunogens expected to allow bivalent antibody binding were potently immunogenic while those with shorter structures permitting only 1-2 Fab binding interactions exhibited poor immunogenicity. No construct was found to be superior to the clinical benchmark RTS,S/AS01 in the mouse model. These results can inform approaches to malaria vaccine design and direct future research.
Lineage plasticity has emerged as a fundamental mechanism of adaptive therapy resistance in prostate and bladder cancers, enabling malignant cells to bypass lineage-restricted dependencies through non-genetic reprogramming. However, plasticity is often studied as a terminal phenotype rather than as a dynamic process that unfolds over time. The endpoint-centered view can obscure the early and potentially reversible events that initiate identity loss, as well as the intermediate states through which resistant phenotypes emerge. In this review, we propose a phse-based framework for modeling lineage plasticity in genitourinary cancers. We conceptualize plasticity as a temporally ordered trajectory comprising three phases: priming, transition, and stabilization. We examine how commonly used near-patient experimental and computational platforms, including patient-derived organoids (PDOs), patient-derived xenografts (PDXs), genetically engineered mouse models (GEMMs), and artificial intelligence-based approaches, tend to sample different portions of this trajectory. By mapping these model systems to the phases, they are best equipped to simulate, we demonstrate how a phase-aware approach can resolve long-standing discrepancies in the literature and clarify the gene-regulatory logic underlying tumor identity shifts. Ultimately, this framework provides a roadmap for integrating cross-platform insights to identify critical "windows of vulnerability," informing novel strategies for the early therapeutic interception of lineage-driven resistance before it reaches a terminal, irreversible state.
Pseudorabies virus (PRV) reprograms host inflammatory responses and epitranscriptomics, yet how these processes are connected remains unclear. Here, we report a JNK-WTAP-m⁶A-DUSP5 regulatory circuit that coordinates viral replication and inflammatory responses. PRV infection activated c-Jun N-terminal kinase (JNK), which phosphorylated wilms tumor-associated protein (WTAP) to drive its nuclear export and disrupt the activity of the m⁶A methyltransferase complex. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and biochemical analyses revealed a global reduction of N6-methyladenosine (m⁶A) on host transcripts, particularly on proinflammatory cytokines, alongside widespread m⁶A modification sites on viral transcripts. Consequently, reduced m⁶A prolonged the half-lives of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-18 (IL-18) mRNAs, as well as viral transcripts, thereby synergistically promoting PRV replication. Inhibition of JNK activity or restoration of m⁶A modification suppressed PRV replication in vitro and in vivo. Moreover, the m⁶A hypomethylation stabilized dual-specificity phosphatase 5 (DUSP5) transcripts at early infection, transiently restraining JNK activation and forming a negative feedback loop. These findings demonstrate that PRV reprograms the m⁶A machinery via JNK-mediated WTAP phosphorylation and highlights RNA methylation restoration as a promising antiviral strategy.
Electrocardiographic (ECG) artifacts mimicking acute coronary syndrome (ACS) pose a risk of misdiagnosis and unnecessary procedures. While arterial pulsation artifacts are known to cause limb-lead ST-T changes adhering to the "single-limb lead exemption principle," their potential to induce specific repolarization abnormalities in precordial leads remains unreported. A 66-year-old woman presented with chest tightness. The initial ECG showed ST-segment elevation in leads III and aVF, depression in I and aVL, and a previously undescribed pattern of isolated mid-portion T-wave inversions in precordial leads V2-V6, with preserved initial T-wave morphology. Suspected ACS was reconsidered after a senior physician noted atypical features. The diagnosis of radial artery pulsation artifact was confirmed after repositioning the limb electrodes away from the radial pulse, which normalized all ECG abnormalities Coronary computed tomography angiography revealed only mild atherosclerosis, ruling out acute ischemia. To our knowledge, this case is the first to describe a previously unreported variant manifestation of arterial pulsation artifact featuring isolated mid-portion T-wave inversions in precordial leads. We propose a potential mechanism via propagation of limb-derived interference currents through the Wilson Central Terminal, combined with an electromechanical hypothesis. This pattern, especially when combined with the limb lead exemption principle (spared lead II localizing the source to the left arm), suggests a potential electrocardiographic sign for differentiating artifact from true pathology. We also propose a practical bedside approach integrating lead-specific analysis and electrode repositioning to prevent misdiagnosis.
To evaluate whether baseline bone turnover markers (BTMs), particularly plasma β-C-terminal telopeptide of type I collagen (β-CTX), and body mass index (BMI) predict the feasibility and short-term safety of deferring zoledronic acid redosing beyond 12 months in postmenopausal Indian women with osteoporosis. In this prospective observational study, 50 treatment-naïve postmenopausal women with DXA-confirmed osteoporosis received intravenous zoledronic acid (5 mg). At the 12-month visit, β-CTX guided repeat dosing: women with β-CTX ≥300 pg/mL were redosed, whereas those with β-CTX <300 pg/mL underwent 12-weekly biochemical surveillance, with redosing deferred until β-CTX recovery or a maximum of 24 months. Multivariable logistic regression identified baseline predictors of delayed redosing (>12 months). Twenty-five women underwent delayed redosing (median interval 18.5 months). Compared with standard dosing, the delayed group had lower baseline β-CTX (582 vs 866 pg/mL; p < 0.001) and lower BMI (23.4 ± 5.5 vs 25.7 ± 2.0 kg/m2; p = 0.008). On multivariable analysis, lower baseline β-CTX (adjusted OR per 100 pg/mL 0.48; 95% CI 0.31-0.73; p = 0.001) and lower BMI (adjusted OR per kg/m2 0.81; 95% CI 0.67-0.98; p = 0.031) independently predicted delayed redosing. BMD gains were comparable between groups and no new vertebral fractures occurred during 2-year follow-up. Lower baseline bone turnover and lower BMI were associated with delayed zoledronic acid redosing, supporting a biomarker-guided approach to individualized treatment intervals.
Gram-negative bacteria pose a threat to global healthcare mainly because their outer membrane (OM) provides an intrinsic barrier to many antimicrobials. Key to this barrier function is the asymmetric structure of the OM, with phospholipids constituting the inner leaflet and lipopolysaccharides, the outer leaflet. Although the mechanism of phospholipid transport between the inner membrane (IM) and OM remains poorly understood, recent studies implicate TamB, YhdP, and YdbH as functionally redundant proteins mediating this process in Escherichia coli. Accordingly, the collective loss of these three paralogs is lethal, and any one of them is sufficient for growth. YdbH is anchored to the IM, and its periplasmic repeating β-sheet groove domain interacts with the OM lipoprotein YnbE via β-strand augmentation to form an intermembrane bridge. Additionally, YnbE multimerizes, and the periplasmic protein YdbL is proposed to modulate YnbE multimerization to facilitate its stacking on the C-terminus of YdbH. Here, we demonstrate that excess YdbL specifically inhibits the function of the YdbH-YnbE complex since overexpression of ydbL causes lethality in the ΔyhdP ΔtamB double mutant, but the presence of both ydbH and ynbE in trans abrogates this lethality. We resolve high-resolution structural data for YdbL and ascertain its interaction site with the YnbE C-terminal α-helix, with residues mediating this interface highly conserved and critical for YdbL function. Finally, we show that YdbL is protected from degradation by the protease DegP when complexed with YnbE. Overall, our data support a model in which YdbL ensures proper YdbH-YnbE intermembrane bridge formation by directly interacting with YnbE. The mechanism underlying phospholipid transport between the inner and outer membranes of gram-negative bacteria remains enigmatic. Bacterial bridge-like protein systems such as the YdbH-YnbE complex resemble proteins found at membrane contact sites between eukaryotic organelles. These proteins are proposed to mediate intermembrane phospholipid transport, which is essential for growth of the outer membrane (OM). Here, we define the role of YdbL, a periplasmic protein that specifically modulates the YdbH-YnbE system. YdbL directly interacts with YnbE and controls the formation of the YdbH-YnbE complex. Additionally, we reveal that YdbL is selectively degraded by the periplasmic protease DegP. We propose a regulatory model that connects the YdbH-YnbE complex assembly and controls the levels of YdbL, providing new insight into OM homeostasis in gram-negative bacteria.