搜索结果：Expanding

Headache disorders represent a major global health burden that is highly prevalent across the continent of Africa; however, they remain underdiagnosed and inadequately managed. The objective of this study was to evaluate the availability, accessibility, and organizational structure of headache care services across African countries and to detect major challenges and barriers to optimal care from the perspective of headache-treating clinicians. Countries were chosen using a stratified sampling strategy based on World Bank income classification [low-income countries (LICs), lower-middle-income countries (LMICs), and upper-middle-income countries (UMICs)] to ensure balanced representation across economic strata. Within each stratum, eligible neurologists were identified through national neurology societies and indexed publications. Of 120 invited clinicians from 40 countries, 73 neurologists from 28 countries responded (response rate 60.8%). Participants were invited to fill out a structured online questionnaire to assess the healthcare system structure (including workforce capacity, healthcare system characteristics, and diagnostic infrastructure), availability of the essential and newer headache medications, and perceived barriers to optimal care in their countries. Significant discrepancies were observed in workforce capacity, defined as the reported number of neurologists per country ranging from 10 (IQR: 4.75-34.5) in LICs to 200 (IQR: 97-700) in UMICs (p&#x202f;<&#x202f;0.001). Access to headache care was limited in LICs, where 50.0% (6/12) of respondents reported a 3-4&#x202f;week waiting list for elective neurological consultations, while 41.7% (5/12) reported a similar 3-4&#x202f;week waiting time for imaging (p&#x202f;=&#x202f;0.028, 0.012). Self-medication was universal (100%). Structural barriers were highest in LICs, including limited neuroimaging (91.7%) and financial constraints (83.3%). Essential medications (according to WHO (World Health Organization) and International Headache Society (IHS) practice recommendations) were relatively more reimbursed in LMICs/UMICs; however, innovative therapies (gepants, ditans, and calcitonin gene-related peptide (CGRP) mAbs) were not reimbursed across all settings. Headache care across African countries is facing substantial inequities in human resources, workforce capabilities, and access to proper care. Addressing these challenges requires fostering the healthcare systems, training of non-specialist healthcare providers, expanding insurance coverage, and increasing awareness of headache disorders in health policy to enhance patient outcomes.

The efficiency of electrocatalysis, a key factor in integrating renewable electricity into energy systems, is fundamentally influenced by the distribution of ions within the electric double layer. While the effects of specifically adsorbed ions (SAIs) at the inner Helmholtz plane (IHP) and nonspecifically adsorbed ions at the outer Helmholtz plane (OHP) are well-established, the role of OHP-located SAIs has remains unexplored. In this study, we probe the unknown by constructing a model Pt(111) interface where sulfate anions are exclusively confined to the OHP within the oxygen reduction reaction (ORR) potential region, achieved through their distinct pH dependencies. Strikingly, these OHP-located sulfates exert an asymmetric influence on the *O/*OH redox, which impedes the reduction of *O to *OH but not its reverse oxidation. This asymmetry is explained via a place-exchange model for the *O/*OH redox, in which the OHP-located sulfates primarily influence the electron-transfer-free process. The established OHP-anion behaviors are further correlated with ORR rates on Pt(111) in various electrolytes. Our study elucidates the effects of OHP-residing SAIs, expanding the knowledge boundary of ion effects on electrocatalysis.

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed or refractory large B-cell lymphoma, with overall response rates in real-world practice broadly comparable to those in pivotal clinical trials. However, progression-free survival is consistently shorter in real-world cohorts, suggesting that baseline disease characteristics may influence long-term outcomes more than initial treatment sensitivity. This review examines the role of baseline Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) features as predictors of response and survival after CAR T-cell therapy in lymphoma. We synthesize the evidence on established imaging predictors, including total metabolic tumor volume, extranodal disease distribution and site-specific organ involvement, and bulky disease, and discuss emerging biomarkers such as body composition metrics. Despite a growing body of evidence linking these imaging features to outcomes, clinical adoption has been limited by heterogeneous measurement methodologies, inconsistent definitions, and a lack of prospective validation. We propose practical considerations for structured baseline imaging assessment, including a reporting checklist designed to ensure systematic documentation of the imaging features with demonstrated or emerging prognostic relevance. By moving beyond descriptive staging toward structured, predictive baseline imaging evaluation, radiologists and lymphoma clinicians may improve pretreatment risk stratification and facilitate more informed therapeutic decision-making in the expanding landscape of CAR T-cell therapy.

Eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) is a type-2 inflammatory endotype characterised by tissue eosinophilia and mucosal remodelling. &#x3b3;&#x3b4; T cells are tissue-resident lymphocytes involved in barrier immunity, yet their subset composition and relationship to inflammatory remodelling in eCRSwNP remain incompletely defined. &#x3b3;&#x3b4; T cell subsets were analysed in nasal mucosa and polyp tissue from patients with eCRSwNP (n=21) and control subjects (n=10). Mononuclear cells isolated from nasal polyps and middle turbinate mucosa were examined by flow cytometry to quantify V&#x3b4;1+V&#x3b4;2-, V&#x3b4;1-V&#x3b4;2+ and V&#x3b4;1-V&#x3b4;2- subsets. Targeted transcriptional analyses using RT-qPCR assessed expression of TRDV1, TRDV2 and type-2 inflammatory markers. Clinical indices included symptom scores, radiologic disease severity and histological eosinophilia. eCRSwNP was associated with marked numerical and compositional remodelling of mucosal &#x3b3;&#x3b4; T cells. Diseased tissue showed expansion of V&#x3b4;1-V&#x3b4;2+ and V&#x3b4;1-V&#x3b4;2- subsets, whereas V&#x3b4;1+V&#x3b4;2- cell numbers remained stable but declined proportionally within the expanding &#x3b3;&#x3b4; compartment. These shifts followed a gradient from healthy mucosa to non-lesional tissue and nasal polyps and correlated with increasing disease severity, tissue eosinophilia and tissue-level type-2 inflammatory signatures. Progressive &#x3b3;&#x3b4; T cell remodeling across the sinonasal mucosa in eCRSwNP is associated with type-2 inflammatory activity, tissue eosinophilia and disease severity.

Although understanding real-world treatment patterns for inflammatory bowel disease (IBD) from initial diagnosis across age groups is essential, most studies focus on adult populations and advanced therapies. We conducted a descriptive study using a national healthcare database. Patients newly diagnosed with IBD between January 2014, and December 2022 were identified and classified into two groups by disease subtype: ulcerative colitis (UC) or Crohn's disease (CD). They were further stratified by age at the index date (pediatrics: <19 years, adults: &#x2265;19 years). Then we examined patients' characteristics and overall treatment patterns. A total of 60,181 individuals were identified as IBD patients with related medication use. Primarily, a younger age at diagnosis was observed among patients with CD, contributing to the predominance of CD within the pediatric population (proportion of CD patients: 71.6% in pediatrics and 24.8% in adults). Furthermore, pediatric-onset IBD was marked by a substantial burden of comorbidities (proportion of patients with &#x2265;2 pediatric comorbidity index score: 41.7% in UC and 46.4% in CD) and a tendency toward earlier use of advanced therapies [median time to advanced treatment initiation, months (IQR): pediatrics vs. adults; 8.1 (2.7-18.9) vs. 16.9 (6.0-36.5) in UC; 4.2 (1.6-11.6) vs. 9.6 (3.0-27.3) in CD]. Secondarily, among restricted adult population with at least 1 year follow-up since first advanced agent prescription, cumulative persistence at 12 months was 76.9%-88.5% across the most recently approved agents (vedolizumab and ustekinumab). This study provides a comprehensive nationwide evaluation of patient characteristics and treatment patterns in adult and pediatric IBD patients in South Korea. These findings underscore the importance of tailoring treatment strategies according to disease subtype and age at diagnosis. Given that only tumor necrosis factor (TNF)-alpha inhibitors are currently approved for pediatric use and considering the emerging evidence regarding treatment persistence with newer agents, these findings may support consideration of expanding therapeutic options for pediatric patients.

Selective C-H functionalization of small molecule leads is a powerful approach for efficient chemical space exploration and medicinal chemistry optimization. Here, we report a screening strategy for early- and late-stage chemoenzymatic oxidation of steroid-inspired compounds using a panel of P450BM3 variants. Late-stage oxidation of sterol transport protein inhibitors and their intermediates revealed enzyme- and substrate-dependent regioselectivity, which was rationalized by docking studies, and yielded hydroxylated analogues that provided rapid structure-activity relationship insights into the spirooxepinoindole as a privileged scaffold and its potential metabolic products. Early-stage functionalization of steroidal building blocks, including the Wieland-Miescher ketone and acetyl-cis-decalone, furnished hydroxylated derivatives with high diastereoselectivity. Notably, both enantiomers of both diastereoisomers of the C6-hydroxylated Wieland-Miescher ketone were obtained in preparative quantities, providing access to valuable early-stage building blocks for further derivatization. This work highlights the potential of chemoenzymatic approaches to deliver regio- and stereoselective oxidations of challenging steroid-like scaffolds, complementing classical synthetic methods and expanding opportunities in medicinal chemistry and natural product synthesis.

Protein S-palmitoylation, and more broadly protein S-acylation when acyl donors other than palmitoyl-CoA are involved, is an emerging post-translational mechanism in cancer that dynamically regulates protein stability, membrane localization, trafficking, and signaling output. Among the zinc finger DHHC-type palmitoyl acyltransferases, ZDHHC9 has attracted increasing attention because of its expanding roles across multiple malignancies. Accumulating evidence indicates that ZDHHC9 is frequently dysregulated in cancer and contributes to tumor progression through palmitoylation-dependent regulation of proteins involved in oncogenic signaling, stress adaptation, metabolic rewiring, and immune evasion. Functionally, ZDHHC9 has been linked to the modulation of substrates such as BiP/GRP78, CD38, STAT1, PD-L1, and PCBP1, thereby influencing unfolded protein response signaling, checkpoint-related immune suppression, ferroptosis-associated pathways, and tumor cell survival. Beyond its tumor-intrinsic effects, ZDHHC9 is increasingly recognized as a regulator of the tumor immune microenvironment, with emerging evidence showing that it can suppress effector CD8+ T-cell responses and reduce sensitivity to immune checkpoint blockade in selected cancer contexts. In this review, we summarize the molecular basis of ZDHHC9, discuss its roles in tumor progression and immune regulation, and highlight current advances and challenges in therapeutic targeting. A deeper understanding of ZDHHC9-dependent palmitoylation networks may support the development of new biomarkers and precision anticancer strategies.

Temporal dynamics, such as cell-cycle oscillations, transcriptional bursting, and the regulated assembly and disassembly of phase-separated condensates, constitute an important layer of regulation in biology. Yet, existing technologies, including DNA sequencing, plate readers, and fluorescence microscopy, face a fundamental trade-off between temporal resolution, single-cell and subcellular information, and experimental throughput. This trade-off not only fragments our understanding of fundamental cellular processes but also impedes large-scale screening for dynamic phenotypes. Efforts to mitigate such limitations are beginning to emerge. One promising approach combines live-cell time-lapse imaging of pooled bacterial libraries in microfluidic chips with sequential fluorescence in situ hybridization (seqFISH) to connect dynamic phenotypes exhibited by individual cells with their corresponding genotypes. However, widespread adoption of this strategy has been constrained by two technical challenges: (1) compromised in situ genotyping efficiency due to nonspecific fluorescent probe aggregation in confined microfluidic growth chambers, and (2) the reliance on high-copy-number plasmids to ensure genotyping sensitivity, which often distorts dynamic phenotypes and perturbs normal physiology during live-cell imaging. Here, we address both limitations with an integrated and physiologically compatible solution. We introduce a simple surface-modification strategy to suppress fluorescent probe aggregation in microfluidic chips, enabling robust in situ genotyping to be completed overnight. In parallel, we implement barcoded copy-number-tunable plasmids to decouple the conflicting requirements of live-cell imaging and post hoc genotyping, thereby preserving delicate subcellular dynamics while maintaining genotyping sensitivity. Together, these improvements transform image-based bacterial screening into a faster and minimally perturbative workflow, expanding the scalability and versatility of high-throughput single-cell and subcellular dynamics screening for both fundamental and synthetic biology research.

Work-related mental disorders comprise conditions of psychological distress in which causal factors are associated with elements of the work environment. These disorders impose substantial economic and social burdens on affected workers and are frequently associated with alcohol consumption and the use of other psychoactive substances. To conduct an epidemiological analysis of reported cases of work-related mental disorders in Brazil between 2012 and 2021, investigating their association with alcohol and other drug misuse. This analytical, quantitative study was based on notification data obtained from the Department of Informatics of the Brazilian Unified Health System. Sociodemographic characteristics, work-related conditions, and information on alcohol consumption and the use of other drugs were collected. Data were analyzed using statistical tests and multivariate analytical techniques. Work-related mental disorders predominantly affected women, individuals with higher educational attainment, and those who self-identified as White or Brown. Alcohol consumption and the use of other drugs showed limited statistical significance as factors associated with the reported cases. Strategies aimed at improving working conditions, expanding access to psychological support, and preventing substance misuse are essential to address work-related mental disorders, a major public health concern in Brazil. Identifying risk factors associated with these disorders may inform more effective interventions and promote improved work organization, thereby reducing their impact on the health of the working population and on the national economy.

Offshore wind farms are expanding rapidly as part of global climate mitigation efforts, but their effects on seabird movement behavior remain incompletely understood. While collision risk has received substantial attention, less is known about how turbines may alter flight routes through evasive behavior and meso-avoidance, particularly near breeding colonies where repeated commuting flights may accumulate energetic costs. We investigated flight responses of breeding Bridled Terns (Onychoprion anaethetus) to offshore wind turbines near their colony using high-resolution satellite tracking data collected at 1-s intervals and lower-resolution data collected at 1-h intervals. We quantified within-trajectory flight traits, including mean redirection, number of turns, flight speed, and flight altitude, in relation to turbine exposure. We assessed avoidance using both proximity-based and direction-sensitive metrics. At the near-colony scale, we tested whether flight behavior changed with increasing alignment between the trajectory bearing and turbine bearing from the colony. At the broader breeding-range scale, we tested whether behavior differed inside and outside wind farms or with distance to turbines, while accounting for colony distance, wind, and landscape variables. Bridled Terns showed increased mean redirection and lower flight altitude when trajectories were more closely aligned with turbine directions from the colony, suggesting localized route alteration in obstacle-facing directions. However, flight behavior was not significantly associated with turbine proximity, nor did it differ significantly inside and outside wind farms. These findings suggest that offshore wind farms may influence seabird movement through localized, direction-dependent route alteration rather than simple distance-dependent responses, highlighting the value of movement-context metrics and within-trajectory traits in wind farm impact assessments.

Schizophrenia is associated with substantial disability, persistent symptoms, and significant unmet treatment needs. The ketogenic diet has emerged as a metabolic intervention of growing interest for serious mental illness. This study reports quantitative and qualitative findings from a large international Change.org petition advocating for the resumption of a halted randomized blinded inpatient study investigating a ketogenic diet intervention for individuals with schizophrenia. The petition received 21,637 signatures and 1,105 comments from individuals across 151 countries. Participant comments were analyzed using top-down theme consensus coding and Latent Dirichlet Allocation (LDA) topic modeling. Results revealed widespread interest in nutritional and metabolic approaches to mental health, concerns regarding the limitations of current treatment options, and support for further investigation of ketogenic interventions in schizophrenia. Many petitioners described personal or observed experiences with ketogenic diets and emphasized the need for additional research. As this was a self-selected advocacy-driven sample, findings may overrepresent individuals supportive of ketogenic diet research and are not representative of the broader population. These findings provide insight into the perspectives and experiences of petitioners and highlight interest in expanding research on novel treatment approaches for schizophrenia, such as ketogenic dietary interventions.

Mosquito-borne viruses are expanding their geographic range in Europe, increasingly affecting wildlife and human health. Usutu virus (USUV), a zoonotic mosquito-borne Orthoflavivirus with birds as amplifying hosts, has caused large-scale avian mortality in Europe, particularly among Eurasian Blackbirds (Turdus merula). Although USUV is not considered a major human health threat, it is closely related to other human-pathogenic arboviruses. Its emergence in northwestern Europe may indicate increasingly suitable conditions for other arboviruses that could follow similar transmission dynamics upon emergence in this setting. In the Netherlands, USUV was first detected in 2016, caused major outbreaks in birds until 2018, and resurged in 2022. Here, we conduct phylodynamic and phylogeographic analyses to reconstruct the emergence and persistence dynamics of USUV in the Netherlands. We analyse 298 near-full-length viral genomes obtained from birds and mosquitoes from the Netherlands, combined with publicly available USUV genomes. We identify multiple independent USUV introductions into the Netherlands region, leading to the apparent enzootic establishment of two predominant clades from lineage Africa 3 in this broader region. For these two clades, our analyses show a temporal pattern consistent with invasion followed by local persistence, associated with a substantial spatial intermixing of viral lineages circulating in the region. Landscape phylogeographic analyses further suggest a possible tendency for USUV lineages to circulate in urbanized areas and regions with higher human population density, though future work should assess whether this pattern reflects true ecological preference or reporting bias. In a context with recurrent outbreaks of West Nile virus in northwestern Europe, this study provides insight into the dynamics of emergence and establishment of a closely related mosquito-borne virus in a previously nonendemic temperate region.

Bergenia ciliata (Haw.) Sternb. is an important Himalayan medicinal plant with diverse pharmacological properties owing to its rich repertoire of bioactive phytochemicals. Despite its medicinal importance, genomic and transcriptomic resources for this non-model species remain scarce, limiting the identification of functional genes and the elucidation of biosynthetic pathways underlying the production of therapeutically important metabolites. To address this knowledge gap, we generated a de novo leaf transcriptome using Illumina RNA sequencing and performed comprehensive functional annotation of the assembled unigenes. A total of 21,490,725 raw paired-end reads were generated, resulting in 65,010 assembled unigenes with an average length of 1,024&#xa0;bp. Of these, 54,732 (84.19%) unigenes were successfully annotated in at least one public database, including Nr (82.41%), Nt (68.14%), Swiss-Prot (65.05%), GO (45.34%), KEGG (34.67%), Pfam (31.70%), and KOG (23.11%). Functional annotation revealed that a large proportion of unigenes are involved in metabolic processes, catalytic activity, protein turnover, and signal transduction, indicating active metabolic and regulatory networks in B. ciliata. This study provides the comprehensive transcriptomic resource for B. ciliata, substantially expanding the genomic resources available for this medicinal species. The generated dataset provides a valuable foundation for functional gene discovery, molecular marker development, comparative transcriptomic studies, and future investigations of the biosynthetic pathways and regulatory mechanisms underlying the production of therapeutically important phytoconstituents.

Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disorder caused by mevalonate kinase (MVK) gene mutations, with phenotypes ranging from mild hyper-IgD syndrome (HIDS) to severe mevalonic aciduria (MA). Here, we report a 7-month-old Chinese male infant presenting with neonatal-onset MA. The proband presented with growth retardation, intractable diarrhea, recurrent fever, generalized rash, progressive hepatosplenomegaly, and persistent systemic inflammation. Laboratory tests revealed marked leukocytosis, elevated C-reactive protein, hyper-IgD and increased urinary mevalonic acid. Whole-exome sequencing identified two novel compound heterozygous MVK variants: c.64G&#x2009;>&#x2009;A (p.Val22Met) and c.1063G&#x2009;>&#x2009;C (p.Ala355Pro). Both variants were absent in global population databases. In silico analyses, including cross-species conservation, structural modeling, and pathogenicity prediction, confirmed significant structural perturbations. The patient achieved sustained remission with canakinumab. This is the first worldwide report of the MVK c.1063G&#x2009;>&#x2009;C variant causing severe MA, expanding the MVK mutational spectrum in Chinese populations.

Primary aldosteronism (PA) is a common cause of secondary hypertension. Bilateral macronodular adrenocortical disease (BMAD) with ARMC5 mutations is classically associated with hypercortisolism. This report describes a 54-year-old female with hypertension and hypokalemia, biochemically confirmed as PA, and imaging showing bilateral adrenal macronodules. Postoperative peripheral blood genetic testing identified a germline ARMC5 frameshift insertion (c.337dup). Whole-exome sequencing of the resected adrenal tissue revealed an additional somatic frameshift deletion (c.277_316del, p. P93fs, VAF 43.1%) absent in blood, demonstrating biallelic ARMC5 inactivation. Following unilateral adrenalectomy, the patient's aldosterone levels normalized. This case shows that ARMC5 mutations can cause isolated mineralocorticoid excess without hypercortisolism, expanding the known phenotypic spectrum. Genetic testing for ARMC5 should be considered in patients with bilateral adrenal enlargement regardless of steroid hormone profile.

Alopecia universalis (AU) is a severe autoimmune disorder characterized by complete loss of scalp and body hair. The introduction of Janus kinase (JAK) inhibitors has expanded therapeutic options for patients with severe disease; however, treatment responses remain variable, particularly among individuals with extensive and longstanding hair loss. Reporting cases with atypical or limited responses to therapy remains important for understanding the spectrum of clinical outcomes observed in practice. We describe a 30-year-old man with a 23-year history of AU who demonstrated minimal response to multiple prior therapies, including tofacitinib (pan-JAK inhibitor) and ritlecitinib (JAK3/TEC inhibitor), without meaningful scalp, eyebrow, or eyelash regrowth. Following six months of treatment with deuruxolitinib, the patient experienced his first clinically significant regrowth, limited to the eyebrows and eyelashes, while scalp involvement remained largely unchanged. This case highlights the potential for site-specific hair regrowth in longstanding, treatment-refractory AU and suggests that eyebrow and eyelash regrowth may occur even in the absence of substantial scalp hair recovery.

Biarylitides are a group of bacterial ribosomally synthesized and post-translationally modified peptides (RiPPs) that contain a biaryl bridge formed by dedicated cytochrome P450 enzymes that can introduce different cross-links. The biarylitides are produced via a five-amino-acid precursor peptide, encoded by a minimal 18 bp gene that evades automatic detection. Previous genome mining approaches for biarylitides do not capture their full biosynthetic space. We therefore repurposed a machine learning algorithm to comprehensively chart the biosynthetic space of the biarylitides, including variation of precursor motifs, P450, and additional modifying enzymes, which yielded 277 biarylitide biosynthetic gene clusters (BGCs). We experimentally investigated biaryl formation with previously uninvestigated core peptide motifs, including YWH, YVH, and YWY, and elucidated the nature of these cross-links. This study significantly expands the biarylitide precursor and BGC diversity and provides directions for the systematic exploration of other RiPP families.