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.
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.
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.
Controlling local chemical environments within porous crystalline materials is essential for selective adsorption and catalysis, yet remains difficult in stable frameworks with precisely oriented functional sites. Here we use reticular chemistry to programme tunable confinement in triazolate metal-organic frameworks constructed from Kuratowski-type Zn5Cl4 nodes. Linker geometry directs the formation of the ith-d topology, in which terminal Zn-bound groups point inwards to generate confined and chemically addressable pores. This strategy yields two isoreticular frameworks, NU-6000 and NU-6001, with distinct cage dimensions and apertures, while preserving the same topology. Post-synthetic chloride-to-hydroxide exchange installs dense arrays of inward-facing Zn-OH groups without loss of crystallinity, enabling reversible CO2 chemisorption through bicarbonate formation. Single-crystal analysis of a CO2 adduct reveals that confinement imposes a geometric accessibility limit on reactive hydroxyl sites within the smallest cage of NU-6000. Under this confinement regime, NU-6000 exhibits strong low-pressure CO2 capture, including at 30 ppm, and achieves 61.4% site utilization at 420 ppm, among the highest reported for metal-organic frameworks under comparable conditions.
Nociceptors detect damaging stimuli and evoke pain in healthy animals. We conducted an optogenetic activation screen to identify genetically defined nociceptor populations that elicit place aversion and nocifensive behaviors in response to stimulation. Smr2Cre- and Bmpr1bCre-labeled Aδ high-threshold mechanoreceptors (HTMRs) emerged as two of the few nociceptor populations, and we focused on investigating their physiological, morphological, functional, and synaptic properties. These neurons densely innervate skin and other organs, are activated only by intense, potentially damaging stimuli, and are necessary for protective responses to sharp mechanical stimuli. Centrally, Aδ-HTMR projections span multiple spinal segments and terminate across spinal cord laminae, forming strong, monosynaptic connections onto anterolateral tract projection neurons, including antenna cells of the deep dorsal horn. Aδ-HTMRs also engage a local spinal reflex circuit, enabling a remarkably rapid limb withdrawal. Thus, Aδ-HTMRs are myelinated nociceptors with unique properties that can be exploited for the development of new analgesics.
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.
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 investigate the expression level of hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway in elderly patients with acute myocardial infarction (AMI), and to analyze its relationship with the prognosis of AMI. A total of 160 elderly patients with AMI were selected from October 2023 to September 2024 in Nanjing Medical University Affiliated Wuxi People's Hospital as the study group, 160 individuals who underwent physical examination during the same period were selected as the control group according to the 1:1 matching principle. The levels of serum HIF-1α and VEGF were compared between the two groups. The study group was treated with percutaneous coronary intervention (PCI). According to the prognosis of patients at 12 months after operation, they were divided into good subgroup and poor subgroup. The clinical data, serum HIF-1α and VEGF levels of the two subgroups were compared. The effect of serum HIF-1α and VEGF on prognosis and its predictive value were analyzed. The accuracy-recall rate (PR) curve was drawn to evaluate the performance of combined prediction. The area under the curve (AUC) was calculated, the DeLong test was used to compare AUCs, and the precision-recall (PR) curve was drawn to evaluate the performance of combined prediction. The levels of serum HIF-1α and VEGF in the study group were higher than those in the control group (P < 0.05). The time from onset to admission, the proportion of Killip class IV, the proportion of multivessel disease, N-terminal pro-brain natriuretic peptide (NT-proBNP), HIF-1α and VEGF in the poor subgroup were higher than those in the good subgroup, while left ventricular ejection fraction was lower (P < 0.05). Before and after correction of multivessel disease and NT-proBNP, serum HIF-1α and VEGF levels were the influencing factors of prognosis in patients with AMI (P < 0.05). The AUC of serum HIF-1α and VEGF levels alone and combined prediction were 0.717,0.748 and 0.900, respectively, the AUC of combined prediction was significantly higher than that of the two alone (Z = 3.315,2.832, P = 0.001,0.005), and the best sensitivity and specificity were 83.33% and 84.87%. The DCA curve showed that the combined prediction of serum HIF-1α and VEGF levels in the probability range of 5%-70% could obtain significant positive net benefits. The PR curve showed that the PR-AUC value of serum HIF-1α and VEGF levels in evaluating prognosis was 0.767, which had a high recall rate and accuracy rate. Serum HIF-1α and VEGF levels are highly expressed in elderly patients with AMI, and are closely related to the prognosis of patients. The combination of the two can be used to predict the prognosis of patients, provide a reference for the assessment and prognosis of elderly patients with AMI, facilitate early identification of high-risk groups, and provide a reference for subsequent personalized program development.
Most of the transcription factors require a nuclear localization signal (NLS) to translocate to the nucleus via the nuclear import machinery. Initially, classical monopartite NLS with an arginine-lysine basic box was discovered, later less common bipartite NLS with two basic boxes separated with a spacer was found in certain nuclear proteins. Although both types of signals perform the same nuclear translocation function, it is not clear what role does the spacer play in the translocation and what benefits do two basic boxes give to a protein. We studied NRF1 - a transcription factor with a bipartite NLS. We dissected the function of the NLS of NRF1 and found that the spacer plays an auxiliary role in the transcriptional activity of NRF1, and phosphorylation inside the spacer regulates the nuclear translocation of NRF1 when combined with the posttranslational modifications of the NLS. We discovered that the spacer of NRF1 is not necessary for the translocation but it is indispensable for the transcriptional activation. We found that only a single basic box at the N-terminal of NLS is necessary for the nuclear translocation, while C-terminal basic box deletion shows no effect on the NRF1 subcellular localization. Additionally, we found a new downstream target of NRF1 - ZNF777.
Dysesthesia-such as tingling and numbness-remains refractory to pharmacological treatment and poses therapeutic challenges within neuropathic pain. Dysesthesia-matched transcutaneous electrical nerve stimulation (DM-TENS) is a perceptually guided neuromodulation approach in which stimulation parameters are iteratively adjusted to synchronize with the perceived temporal patterns and intensity of the patient's abnormal sensory experience. However, immediate responses to DM-TENS across heterogeneous neuropathic pain conditions, as well as the feasibility of both direct and indirect (remote-site) stimulation approaches have not been described. This retrospective observational case series included consecutive patients with refractory neuropathic pain referred from the pain clinic to the rehabilitation department at our university hospital between December 2024 and August 2025. Dysesthesia intensity was assessed before and during stimulation using the Numerical Rating Scale (NRS), and pain quality was evaluated using the Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2) as an exploratory measure. Within-session changes were examined using session-level linear mixed-effects models, with aggregated non-parametric analyses performed as sensitivity analyses. As an exploratory analysis, within-patient consistency of stimulation parameters (frequency, pulse width, and intensity) across repeated sessions was evaluated using intraclass correlation coefficients (ICCs). DM-TENS was well tolerated in all participants, with no stimulation-related adverse events requiring session termination. Fifteen patients underwent 66 DM-TENS sessions, of which 64 provided NRS data. A session-level linear mixed-effects model showed significantly lower NRS scores during stimulation (p < 1 × 10⁻8). Aggregated sensitivity analyses showed a median NRS change of - 2.0 (interquartile range - 2.75 to - 1.43). Indirect stimulation was applied only in trigeminal neuropathic presentations; lower within-session symptom scores were observed during palm stimulation, and these findings should be considered exploratory. SF-MPQ-2 total scores were also significantly lower during stimulation (p = 0.002). Stimulation parameters showed good to excellent within-patient consistency across repeated sessions (ICC range 0.78-0.85). In this retrospective observational case series, lower within-session symptom scores were observed during DM-TENS across heterogeneous neuropathic pain conditions, including trigeminal, spinal, and peripheral presentations. These findings raise the hypothesis that individualized, perceptually guided adjustment of stimulation parameters warrants prospective evaluation.
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.
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.
Intramyocardial injection of hiPSC-CMs is a promising cell replacement therapy for myocardial infarction, but EAs after transplantation hinder their clinical translation. This study aims to analyze the characteristics of EAs after hiPSC-CMs transplantation, and to identify risk factors associated with the occurrence of EAs. This study included patients undergoing CABG combined with hiPSC-CMs transplantation (experimental group) or isolated CABG (control group) at our hospital between November 2023 and November 2025. Patients in the experimental group were assigned to low- and high-dose groups (0.5×108 and 1.5×108 cells). EA characteristics were analyzed and compared between the two subgroups. Univariate logistic regression was performed to identify risk factors for EAs. A total of 24 patients in the experimental group were enrolled, 13 (54.2%) of whom developed EAs originating from the cell injection site (localized by ECG QRS morphology). Initially, EAs were paroxysmal (heart rate: 55-96 bpm, 72.15±9.77 bpm), progressing to sustained episodes over hours with increased heart rate (max 111-185 bpm, 146.00±21.02 bpm) and R-R interval variability. No hemodynamic abnormalities were detected in any patient during EA episodes. Atrial pacing, and electrical cardioversion reduced EA rate but failed to terminate EAs. EA incidence was significantly higher in the high-dose than low-dose group (10/12 [83.3%] vs 3/12 [25.0%], P=0.012). Univariate logistic regression showed hiPSC-CM dose was significantly associated with EA occurrence (OR=15.00, 95%CI: 2.02-111.17, P=0.008). The occurrence of EAs was likely driven by an automaticity mechanism, and hiPSC-CMs transplantation dose was significantly correlated with EA incidence.
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.
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.
R-loops and D-loops are three-stranded nucleic acid structures that have emerged as central regulators of genome stability, gene expression, and DNA metabolism. R-loops form co-transcriptionally or post-transcriptionally when nascent RNA re-anneals with the template DNA strand, generating an RNA: DNA hybrid that displaces the non-template strand into a single-stranded state. These structures are enriched at CpG island promoters, transcription termination sites, and immunoglobulin class-switch regions, where they coordinate transcription regulation, chromatin remodeling, and DNA damage signaling. D-loops are formed when a single-stranded DNA segment pairs with one strand of a duplex and displaces the other, arising through context-dependent mechanisms that include RAD51- or DMC1-mediated strand invasion in homologous recombination, shelterin-assisted invasion at telomeres, and replication-coupled strand displacement at the mitochondrial DNA origin. They serve as indispensable intermediates in double-strand break repair, telomere maintenance, and mitochondrial DNA replication. Recent cryo-electron microscopy studies have resolved the stepwise RAD51-mediated strand exchange mechanism at near-atomic resolution, substantially advancing structural understanding of D-loop biogenesis. Despite their differences in molecular composition, both structures remodel Watson-Crick base pairing and, when dysregulated, are associated with replication fork stalling, transcription-replication conflicts, and aberrant recombination. This review systematically compares the structural features, formation mechanisms, regulatory networks, and biological functions of R-loops and D-loops, with emphasis on their convergent roles in safeguarding genome integrity. We further discuss rapidly evolving detection technologies and emerging therapeutic strategies targeting these structures in cancer and neurodegeneration, identifying key unresolved questions for future investigation.
We report the case of a 30-year-old woman in the first trimester with a cesarean scar pregnancy (CSP) following a previous caesarean section, who wished to preserve the pregnancy. External advice had previously recommended termination, but an individualized, experimental approach was agreed upon. At 11th weeks' gestation, a mesh was placed over the scar dehiscence and secured in position. The uterus was strongly retroflexed, and the placenta prolapsed through the scar. Direct closure of the cranial and caudal myometrium surrounding the protruding placenta was not feasible; the defect measured approximately 4 cm, and the prolapsed placenta was the size of a mandarin. The patient was closely monitored until 32 weeks' gestation, when she presented with lower abdominal pain and mild vaginal bleeding. A hysterectomy was performed at the patient's request, although a focal resection had been offered. This case demonstrates that live birth can be achieved in extreme CSP and suggest that mesh coverage of large cesarean scar defects may represent a novel, pregnancy-preserving therapeutic option.
The direct removal of carbonyl groups from cyclic ketones offers a nonintuitive but straightforward route to access multisubstituted saturated structural motifs via late-stage modification. However, such transformations have been challenging to achieve, especially in a chemoselective manner. Here we report reductive and annulative carbonyl removal methods, enabled by the N'-alkyl hydrazonamide (NAHA) reagents, via sequential double C-C bond cleavage. These transformations efficiently convert diverse cyclic ketones to the corresponding ring-opened and ring-contracted analogues with broad functional group tolerance. Besides late-stage modification of complex bioactive compounds, this carbonyl-removal strategy can also be applied to the synthesis of all-carbon quaternary centers lacking polar functional groups, terminal deuteration, and iterative ring contraction.
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.
To assess efficacy and adverse outcomes of misoprostol 200mcg versus 400mcg every three hours buccal or vaginal for medication abortion (MAb) from 24-27 weeks' gestation. This retrospective cohort study included MAbs from 24 0/7-27 0/7 weeks' gestation at Bellevue Hospital from 7/2022-6/2025. All patients received digoxin 2mg intraamniotic injection and mifepristone 200mg oral followed at 24-48hrs by misoprostol 200mcg or 400mcg every three hours buccal or vaginal based on hospital policy at time of admission. The primary outcome was time from first misoprostol dose to placental expulsion. Secondary outcomes were procedural complications. Primary statistical analysis was performed with Fisher's exact and Wilcox rank-sum tests. Of 55 patients, 27 (49%) received 200mcg doses of misoprostol and 28 (51%) received 400mcg doses of misoprostol. Median time to expulsion was 13hrs in the 200mcg group versus 9.5hrs in the 400mcg group (p=0.144). More patients in the 200mcg group versus the 400mcg group had blood loss ≥500mL (11.1% vs 0%, p=0.11) and retained placenta at four hours (3.7% vs 0%, p=0.49). No patients in either group had uterine rupture. Misoprostol 200mcg versus 400mcg every three hours buccal or vaginal for MAb from 24-27 weeks' gestation had overall similar outcomes. Although this single site retrospective study is underpowered to significantly differentiate between the two regimens, we observe that 200mcg dosing may be associated with higher risk of complications. Larger studies are needed to clarify optimal misoprostol dosing for 24-27 week MAb. For medication abortion from 24-27 weeks' gestation, serial doses of misoprostol 200mcg versus 400mcg every three hours have similar rates of complications, though there is a signal that 200mcg dosing may be associated with longer time to expulsion, higher blood loss, and more incidences of retained placenta.