To explore how algorithmic recommendation experiences shape media consumption intentions across different cultures based on the Stimulus-Organism-Response (S-O-R) framework and Self-Determination Theory (SDT). Survey data collected from social media users in China and South Korea were analyzed using partial least squares structural equation modeling and multi-group analysis (MGA). Perceived autonomy significantly mediates the relationship between algorithmic stimuli (personalized perception and forced exposure) and viewing intentions in both nations. However, forced exposure exhibits a distinct cultural polarity reversal. It enhances perceived autonomy among Chinese users due to platform-led convenience. Conversely, it directly threatens autonomy among South Korean users who prioritize decision-making independence. Electronic word of mouth (eWOM) shows a non-significant moderating effect in both groups. In highly automated media environments, direct machine-user cognitive processing eclipses traditional external social signaling. The psychological impacts of algorithmic interventions are heavily bound by national culture rather than being universal.
Queer youth in Egypt navigate a carceral ecosystem characterized by systematic state surveillance, medical pathologization, and societal exclusion. Despite the severity of these conditions, empirical data on their lived experiences remains scarce. This study addresses this gap through a web-based, cross-sectional quantitative survey (N = 165) designed specifically to bypass Western clinical pathologization. The findings reveal a catastrophic mental health crisis: 70.3% of respondents reported self-harm, and 56.4% reported at least one suicide attempt. A three-step hierarchical multiple regression model demonstrated that perceived public safety (B = 0.281, p < .001) eclipses family acceptance as the primary driver of psychological deterioration. Furthermore, a Chi-Square analysis empirically validated the lethality of the visibility trap, revealing that suicide attempts surge from 39% to 66% (p = .001) among youth who experience public discrimination. While psychological distress is pervasive across the cohort, transgender women face distinct, statistically significant intersections of structural violence. We conclude that these elevated rates of suicidality represent rational responses to conditional citizenship-a framework where survival is predicated on identity erasure or migration. This challenges Western applications of the Minority Stress model by highlighting state-level spatial violence, rather than interpersonal rejection, as the primary catalyst of psychosocial collapse.
Adaptive immune responses to primary Kaposi sarcoma-associated herpesvirus (KSHV) infection are poorly defined. To develop better small-animal models for understanding KSHV pathogenesis and immunity, we previously generated a chimeric virus in which the KSHV latency-associated nuclear antigen (kLANA), a conserved multifunctional protein critical for viral latency, was exchanged for the LANA homolog in murine gammaherpesvirus 68 (MHV68). Despite supporting comparable levels of latent infection between wild-type (WT) and KLKI MHV68, kLANA directly repressed MHV68 lytic replication and reactivation. We therefore hypothesized that suppression of lytic replication by kLANA dampens adaptive immune responses. To test this, mice were infected with equivalent doses of either WT or KLKI MHV68, and adaptive immune responses were evaluated over time. Compared to the WT virus, polyclonal B and T cell activation was starkly reduced following KLKI MHV68 infection, which correlated with reduced virus-specific humoral immunity and effector CD4+ and CD8+ T cell activation. Immune activation phenotypes were independent of the inoculating dose, as a high-dose infection with KLKI MHV68 still resulted in comparatively reduced adaptive immune activation. In contrast, infection of Ifnar1-/- mice, which support enhanced KLKI MHV68 lytic replication, led to potent adaptive cellular and humoral immune activation by both WT and KLKI viruses, suggesting that a lytic replication threshold must be passed for viral antigen-driven adaptive immune engagement. Collectively, these data support the hypothesis that kLANA-mediated suppression of lytic replication limits polyclonal lymphocyte activation and facilitates adaptive immune evasion by holding viral replication below an antigenic activation threshold.IMPORTANCEKSHV is a gammaherpesvirus that establishes lifelong, chronic infections in humans and increases the risk of virus-associated cancers. Currently, there is little information on how primary KSHV infection influences adaptive immune development in healthy individuals. Rodent models, such as murine gammaherpesvirus 68 (MHV68), provide a valuable laboratory system for studying gammaherpesvirus pathogenesis in vivo. In this study, we report that infection with a previously characterized chimeric KSHV-MHV68 virus expressing KSHV LANA represses lytic viral replication and elicits weak adaptive immune responses following primary infection, despite efficient latency establishment. By enhancing KLKI MHV68 replication in vivo, we restore adaptive immune activation, providing evidence that a viral replication threshold must be eclipsed for potent adaptive immune engagement. We propose that KSHV, through LANA, evades detection by repressing lytic viral replication to remain "below the radar" of adaptive immune defenses during host colonization.
Chronic obstructive pulmonary disease (COPD) is a major public health problem. Research over the past few years has shown that COPD is the result of dynamic and cumulative gene-environment interactions starting early in life. This opens new opportunities for the Prediction, Prevention, Personalized and Precise management (P4) of COPD in young adults. The P4COPD study sought to: (1) investigate the genomic and environmental/lifestyle determinants of COPD in young adults (18-50 years); (2) contrast them with those determined in children, adolescent and older individuals; and (3) explore the feasibility and cost of implementing a P4 strategy for COPD in young adults in clinical practice. The P4COPD study leverages from already existing cohorts (EarlyCOPD, INMA, LEVANTE, Aduheart) of young subjects (18-50 years) and de novo recruitment from primary care centers, in whom we: (1) analyzed demographic, epidemiological, clinical and physiologic information; (2) measured genetic, epigenetic and proteomic markers; (3) used analytical methods to identify endotypes, biomarkers and potential therapeutic targets associated with the presence of COPD, pre-COPD and/or low peak lung function. Results in young individuals: (4) were contrasted with healthy controls from the general population (IMPACT cohort) and COPD cohorts in older patients (BIOMEPOC, CHAIN and ECLIPSE). Besides, we (5) explored how to implement results in clinical practice; and (6) estimated its potential health cost implications. First results are expected in the third and fourth quarters of 2026. Identifying young individuals at risk of COPD, in whom to establish a P4 strategy is highly relevant to promote healthy aging. La enfermedad pulmonar obstructiva crónica (EPOC) es un problema mayor de salud pública. La investigación de los últimos años ha demostrado que la EPOC es el resultado de interacciones dinámicas y acumulativas entre los genes y el medio ambiente que comienzan en la vida temprana. Esto abre nuevas oportunidades para la predicción, prevención y el manejo personalizado y preciso (P4) de la EPOC en adultos jóvenes. El estudio P4COPD tuvo como objetivos: (1) investigar los determinantes genómicos y ambientales/de estilo de vida de la EPOC en adultos jóvenes (20–50 años); (2) compararlos con los determinados en niños, adolescentes y personas de mayor edad; y (3) explorar la viabilidad y el coste de implementar una estrategia P4 para la EPOC en adultos jóvenes en la práctica clínica. El estudio P4COPD aprovecha cohortes ya existentes (EarlyCOPD, INMA, LEVANTE, Aduheart) de sujetos jóvenes (18–50 años), así como un reclutamiento de novo desde centros de atención primaria, en los que: (1) analizaremos información demográfica, epidemiológica, clínica y fisiológica; (2) mediremos marcadores genéticos, epigenéticos y proteómicos; (3) utilizaremos métodos analíticos para identificar endotipos, biomarcadores y posibles dianas terapéuticas asociadas con la presencia de EPOC, pre-EPOC y/o bajo pico de función pulmonar. Los resultados en individuos jóvenes (4) se contrastarán con controles sanos de la población general (cohorte IMPACT) y con cohortes de EPOC en pacientes de mayor edad (BIOMEPOC, CHAIN y ECLIPSE). Además, (5) exploraremos cómo implementar los resultados en la práctica clínica; y (6) estimaremos sus posibles implicaciones en costes sanitarios. Se espera que los primeros resultados estén disponibles en el tercer y cuarto trimestre de 2026. Identificar a individuos jóvenes en riesgo de EPOC, en quienes establecer una estrategia P4, es altamente relevante para promover un envejecimiento saludable.
The extension of transcatheter aortic valve replacement (TAVR) to younger patients with longer life expectancy has driven a shift in focus toward procedural optimization, with the goals of maximal clinical improvement, durable outcomes, maintained coronary access, and avoidance of permanent pacemaker implantation. A TAVR CODE framework including 4 key fluoroscopic parameters-coaxiality, orientation, depth, and expansion-has recently been proposed to standardize the intraprocedural evaluation of optimal transcatheter heart valve (THV) implantation. Systematic implementation of these concepts during TAVR is expected to improve valve performance and durability. This is hypothesized to improve afterload reduction, enhance left ventricular reverse remodeling, and confer increased and longer lasting clinical benefits. To date, procedural strategies to optimize TAVR outcomes have been largely based upon expert opinion, supported predominantly by mechanistic and retrospective studies. Ongoing randomized trials are evaluating the effects of systematic pre- and postdilatation during TAVR, the impact of same-volume double-tap techniques with balloon-expandable valves, and the effectiveness of different commissural alignment techniques. Meanwhile, intravascular ultrasound is under investigation as a tool to evaluate THV expansion to guide postdilatation, while technical consistency may be improved by innovative THV designs that promote symmetrical expansion, better fluoroscopic visualization, and robotic insertion systems using artificial intelligence. In this article, we detail the possible impact of implementing the TAVR CODE framework on THV function, durability, and clinical outcomes, and provide an expert perspective on procedural strategies to achieve optimal index TAVR outcomes, including management frameworks and position statements according to contemporary best practices.
Accurate prediction of CO2 injection profiles is essential for optimizing injection strategies in heterogeneous reservoirs. However, repeated compositional reservoir simulations under multiple geological and operational scenarios remain computationally prohibitive for rapid optimization and multi-scenario analysis. In addition, conventional machine learning models often struggle to jointly capture nonlinear temporal responses and static geological heterogeneity. This study proposes a deep learning surrogate framework for one-step-ahead prediction of layer-wise CO2 injection profiles. A large-scale dataset was generated using the ECLIPSE compositional simulator under multiple geological and operational scenarios and converted into supervised time-series samples. The proposed framework integrates Bidirectional Long Short-Term Memory (Bi-LSTM), a self-attention mechanism, and Feature-wise Linear Modulation (FiLM). Bi-LSTM extracts temporal dependencies from historical injection-rate sequences, attention adaptively weights influential historical time steps, and FiLM incorporates static geological attributes by modulating learned temporal representations. Quantitative evaluations over five independent runs demonstrate that the proposed model outperforms conventional LSTM-based baselines, with an MAE of 14.28 ± 0.41 m3/d and an R2 of 0.9915 ± 0.0024. Ablation studies further verify the complementary predictive contributions of all three core modules. The model also maintains stable predictive performance under different injection regimes, including continuous gas injection, Water-Alternating-Gas injection, and shut-in operations. This framework provides an efficient data-driven surrogate for accelerating multi-scenario evaluation and supporting layer-wise injection allocation optimization in CO2-EOR and CCUS applications.
Spatially fractionated radiation therapy (SFRT) planning requires three coordinated tasks: generation of high-dose sphere structures, position-aware optimization, and peak-valley dose ratio evaluation. In practice, clinicians and researchers address these tasks with a combination of closed-source scripts, research codes, and manual calculation. The absence of a unified, commercially deployable toolkit remains a barrier to multi-institutional SFRT trials. We present MAAS-SFRThelper, a shared-source plugin that integrates structure generation, geometric-aware optimization, and peak-valley dose ratio evaluation for SFRT into a single workflow inside Varian's Eclipse treatment planning system. MAAS-SFRThelper is a Windows Presentation Foundation (WPF) application built on the Model-View-ViewModel (MVVM) pattern, implemented in C# against ESAPI for Eclipse 15.6 and later. The plugin currently contains five task-oriented tabs that share common services for sphere extraction and objective creation. The SphereLattice tab generates sphere lattices using five placement patterns: hexagonal close-packed, simple cubic, alternating cubic, centroidal Voronoi tessellation, and a constraint-based Monte Carlo method. The SCART tab creates contracted spindle-like boost volumes for stereotactic central ablative radiation therapy. The Optimization tab auto-populates structure list, searches over candidate lattice positions using a four-metric geometric surrogate score, and triggers Eclipse VMAT optimization along with dose calculation on the best candidate. The Evaluation tab implements four analysis modes including 1D, 2D, and 3D PVDR analysis. We validated all functionality on digital phantoms against analytic ground truth. In phantom testing, the optimized lattice achieved 22.5% higher PVDR. The plugin is distributed as source code that compiles to a single dynamic-link library (DLL); all third-party dependencies are bundled at build time. At first launch, users review the Varian Limited Use Software License Agreement (LUSLA) and enter an access code that is emailed upon request. The plugin accepts the patient structure set and, where applicable, a plan with calculated dose; outputs include new structures written directly to the structure set through ESAPI and summary statistics exported as comma-separated value (CSV) files. Source code and documentation are publicly available on GitHub under the LUSLA. MAAS-SFRThelper supports clinical lattice SFRT planning with consistent workflows across institutions and standardized peak-valley dose ratio reporting for multi-institutional trials. The shared-services architecture enables community contributions of new placement patterns, evaluation metrics, and validation datasets. These features represent a practical step toward the dosimetric consistency called for in the 2024 NRG Oncology/AAPM consensus on SFRT. The plugin also serves as a platform for research extensions to GRID therapy, minibeam radiation therapy, and other heterogeneous dose-delivery modalities.
This study aims to develop an automatic beam arrangement algorithm based on deep reinforcement learning (DRL) to explore DRL's clinical potential in radiotherapy. The Soft Actor-Critic (SAC) algorithm was used with planning data from brain tumor patients at our institution. A three-dimensional dose distribution incorporating target areas and isocenters was used as input. Data interaction with the ECLIPSE planning system was facilitated through ESAPI scripts. To enhance sampling efficiency, multi-agent parallel sampling was employed to generate beam distribution plans. A total of 236 brain tumor patients were included. In the validation set, the model achieved a score of 73.48±23.17, compared to an initial plan score of 66.16±26.76. A random selection of 48 cases from the training set revealed that the best beam arrangement plans generated during training scored 83.33±25.18, while the initial plans scored 64.43±24.37. Furthermore, 14 cases not conforming to clinical beam arrangement practices were manually arranged, with the DRL group scoring 87.25±16.67 and the manual group scoring 79.94±20.02. All P-values were less than 0.05, indicating statistical significance. In this investigated cohort of brain tumor cases and under the evaluated technical configuration, the proposed DRL framework generated beam arrangement plans with improved plan scores, supporting its feasibility and potential value for beam angle optimization.
Around the world, the lives of transgender and non-binary individuals have become ever more prominent in public discourse, as have the rights and lives of sex workers. To date, an extensive number of scoping reviews exist documenting the lives and issues faced by both vulnerable populations. However, few scoping studies exist at these intersections. This scoping review takes its starting point by looking at the intersections of these two populations - transgender and nonbinary sex workers. The review demonstrates that there is an overrepresentation of transfeminine sex workers in the literature, with far less research existing on transmasculine sex workers, and even less on non-binary sex workers falling under the trans umbrella. There is abundant research from public health scholars, which has helped advance knowledge, shaping policy and direct services and clinical support for trans women sex workers, especially regarding HIV prevention and harm reduction. The ongoing public health focus in studies has left wide gaps in the literature, eclipsing the much scarcer yet vital work in gender and labor studies. In this article, I synthesize these findings from studies in public health, labor studies, and gender studies and explore dominant, developing, and emerging themes across these three primary fields. In charting new developments in the latest studies, I pinpoint new directions for future lines of inquiry in research studies focused on transgender and non-binary sex workers of various identities.
Giant cell arteritis (GCA) is the most prevalent vasculitis in the elderly of Caucasian ancestry, with the risk of visual loss as the most serious complication if the glucocorticoid therapy does not succeed. While imaging and temporal artery biopsy (TAB) remain diagnostic gold standards, new laboratory tests are needed to assess disease activity and follow-up monitoring. We aimed to characterize distinct proteomic signatures for the classification of polymyalgia rheumatica (PMR) and GCA (independent of concurrent therapy) and to identify specific markers of disease activity and markers that differentiate the two diseases. The plasma of 15 PMR and 13 GCA patients was analysed via mass spectrometry with the UltiMate 3000 nano-HPLC system coupled to an Orbitrap Eclipse mass spectrometer. Immunofluorescence analyses in TABs were performed to confirm the elevated plasma expression of S100A12. We identified 50 protein signatures characteristic of active GCA patients, and 83 signatures altered only in active PMR samples. Strikingly, both groups shared only 13 proteins with altered protein expression levels. The newly identified proteins point to activation of biological pathways not yet linked to the diseases: mitochondrial membrane activity (ACACA, SLC25A31) and clotting cascade (VWF, TUBB) in active GCA; erythrocyte integrity (SLC4A1, SPTA1), muscle contraction (MYLK, MYL6B/12B), and glucocorticoid resistance (PTGES3) in active PMR. Importantly, S100A12 was increased not only in plasma (~ 1.6-fold), but also in PMR and GCA TABs. Active PMR and active GCA patients share an unexpectedly small plasma proteome signature related to immune activation (8.9%: 13 proteins). Instead, active PMR is characterized by distinct erythrocyte and muscle contraction proteome changes, whereas active GCA appears driven by mitochondrial and clotting cascade alterations. Prospective, longitudinal validation studies of the described proteomic signatures might support the clinical classification of both diseases.
Accurate dose deposition in superficial radiotherapy remains challenging due to the inherent skin-sparing effect of megavoltage photon beams and difficulties in ensuring bolus conformity. This study aims to comprehensively evaluate the dosimetric characteristics of the room-temperature-malleable high-density bolus, to evaluate the accuracy of dose calculation and to assess clinical outcomes in a clinical cohort of 55 patients. The dosimetric validation was performed through the use of dose measurements in a solid water phantom on top of which a 1.0 cm thick high-densitybolus was positioned. Absolute depth dose measurements beyond the bolus were obtained by combining an absolute point dose (ion chamber) measurement at 1.0 cm depth beyond the bolus with relative depth dose measurements by using a microDiamond detector. Measurements were performed using 6 megavoltage (MV) flattening-filter-free (FFF) photon beams on an Halcyon and on a TrueBeam treatment unit. Obtained data were compared to dose calculations with both photon dose calculations available in the Eclipse treatment planning system (TPS): Analytical Anisotropic Algorithm (AAA) and Acuros XB (AXB). The impact of non-conforming interfaces was assessed by introducing 0.5 to 2.0 cm thick air cavities between bolus and skin. Skin dose loss due to the air cavities was measured for static open fields and for dynamic sweeping gap fields. Clinical outcomes of 55 patients treated between October 2023 and March 2025 were retrospectively analyzed. Depth dose measurements confirm that a 1.0 cm high-density bolus was sufficient to effectively overcome the build-up region of the 6FFF photon beam. The AXB dose calculation algorithm provided the best agreement between measurements and calculations. Air gaps between the bolus and the skin resulted in clinically relevant skin dose reductions, ranging from approximately 1% to 20%, depending on field size and gap thickness, especially for clinical target volumes < 5.0 cm, large (> 1.0 cm) air gaps, or the use of large static fields. Among the 55 included patients, acute dermatitis toxicity was predominantly Grade 1 (49%) or Grade 2 (47.0%), with a low incidence of severe adverse events (Grade III: 4 %, Grade IV: 0%). The high-density bolus demonstrated satisfying dosimetric reliability, particularly when modeled with the Acuros XB algorithm. The bolus addressed the build-up challenge inherent to MV photons, even in the presence of small air gaps, without increased toxicity in a large cohort of patients. This strategy represents a viable and accessible solution for ensuring accurate and conformal dose delivery in superficial tumors.
The historical submersion of the State Career Plan agenda within the Brazilian Unified Health System (SUS) is directly linked to the diffusion of managerial principles structured by New Public Management. This article aims to document the theoretical reasons and practical effects of the weakening of labour rights in the construction of SUS. Drawing on data related to the process of precarious labour relations and outsourcing, as well as the increasing municipalization of health management, we identify three key areas where labour management is central to the historical challenges faced by SUS: the pressure of personnel expenses on municipal budgets; the expansion of the public-private hybrid model in public administration; and the limitations in implementing a Regionalized Health Care Network. In conclusion, we argue that the ideology and practices of 'management culture' undermine the central role of labour management in the realization of SUS. Strengthening the State Career Program for workers hinges on this critique of managerialism, from which it will be possible to restore the dignity of labour in public health. A submersão histórica da agenda da Carreira de Estado no Sistema Único de Saúde (SUS) está diretamente relacionada com a difusão dos princípios teóricos gerencialistas estruturados pela Nova Gestão Pública. A partir dessa problematização, o presente artigo procura fundamentar as razões teóricas e os efeitos práticos da fragilização dos direitos do trabalho na construção do SUS. Considerando dados que documentam o processo de precarização e terceirização dos vínculos de trabalho e a crescente municipalização da gestão na saúde, apontamos em três dimensões a centralidade da gestão do trabalho para impasses históricos do SUS: a pressão das despesas com pessoal sobre o orçamento municipal; a expansão do hibridismo público-privado na administração pública; a limitação da implementação de uma Rede Regionalizada de Atenção à Saúde. A título de conclusão, apontamos que o ideário e a prática da “cultura management” rebaixam a centralidade da gestão do trabalho na realização do SUS. O fortalecimento do Programa da Carreira de Estado para as trabalhadoras e trabalhadores depende dessa crítica ao gerencialismo, do qual se tornará possível recuperar a dignidade do trabalho na saúde pública. La sumersión histórica de la agenda de la Carrera de Estado en el Sistema Único de Salud (SUS) está directamente relacionada con la difusión de los principios teóricos gerencialistas estructurados por la Nueva Gestión Pública. A partir de esta problematización, el presente artículo busca fundamentar las razones teóricas y los efectos prácticos del debilitamiento de los derechos laborales en la construcción del SUS. Considerando datos que documentan el proceso de precarización y tercerización de los vínculos laborales, así como la creciente municipalización de la gestión en salud, señalamos, en tres dimensiones, la centralidad de la gestión del trabajo para los impases históricos del SUS: la presión del gasto en personal sobre el presupuesto municipal; la expansión del hibridismo público-privado en la administración pública; y la limitación de la implementación de una Red Regionalizada de Atención a la Salud. A modo de conclusión, sostenemos que el ideario y la práctica de la “cultura management” reducen la centralidad de la gestión del trabajo en la materialización del SUS. El fortalecimiento del Programa de la Carrera de Estado para las trabajadoras y los trabajadores depende de esta crítica al gerencialismo, a partir de la cual será posible recuperar la dignidad del trabajo en la salud pública.
This research compares the dosimetric characteristics of sequential boost (SB) and simultaneous integrated boost (SIB) techniques using intensity-modulated delivery techniques for breast radiotherapy in left-sided breast cancer patients following breast-conserving surgery (BCS). Twenty-seven left-sided breast cancer patients who underwent BCS were retrospectively analyzed. Two treatment plans per patient were generated using Eclipse Treatment Planning System. SB delivered 40 Gy/15 fractions (four-arc volumetric modulated arc therapy [VMAT]) to whole breast, then 12.5 Gy/5 fractions (six-field intensity-modulated radiotherapy [IMRT]) to tumor bed, totaling 52.5 Gy/20 fractions. SIB delivered 40 Gy to whole breast and 48 Gy to tumor bed simultaneously in 15 fractions through four-arc VMAT. Target coverage, dose homogeneity, conformity, and organ-at-risk doses were compared using paired t-tests (P < 0.05). Both techniques achieved adequate target coverage with comparable whole breast mean doses. SB demonstrated significantly superior V95% coverage (98.4% vs. 95.7%), while SIB significantly achieved superior dose homogeneity within the integrated plan (HI: 0.31 ± 0.025 vs. 0.14 ± 0.032). SIB showed 31% reduction in total monitor units (10669 ± 881 vs. 15450 ± 1374 MU, P < 0.001) and 25% shorter treatment duration. SIB achieved superior left anterior descending artery sparing (mean: 5.70 ± 1.78 vs. 6.54 ± 2.64 Gy, P = 0.003) and spinal cord protection (maximum: 15.3 ± 1.55 vs. 18.7 ± 4.51 Gy, P < 0.001). SB provided better ipsilateral lung sparing (mean: 11.8 ± 1.44 vs. 12.4 ± 1.04 Gy, P < 0.001). Both achieved mean heart doses <5 Gy. Both techniques achieved adequate target coverage, SIB offers superior treatment efficiency and coronary artery sparing, while SB provides better V95% coverage and lung sparing. Technique selection should be individualized based on patient factors and institutional priorities.
A new and precise single-isocratic reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for the simultaneous analysis of Temozolomide (TMZ) and Alpha-lipoic acid (ALA) in bulk and lipidic nanovesicles. The chromatographic separation of both drugs was carried out on an Eclipse Plus (C18) column (250 ×4.6 mm, 5 μm). An acetonitrile: acetate buffer (pH 4.5) mixture (60:40% v/v) was used as the mobile phase at a flow rate of 0.7 mL/min in isocratic mode. The eluted compounds were detected with a diode array detector at 328 nm (TMZ) and 332 nm (ALA). The retention times for TMZ and ALA were recorded as 3.63 min and 5.59 min, respectively. The developed method was subsequently validated for various parameters in accordance with ICH Q2(R1). The method showed linearity within the concentration range of 2-60 μg/mL for TMZ (r2 = 0.9998) and 15-750 μg/mL for ALA (r2 = 0.9999). The % recovery for both drugs was within acceptable limits with minimal variability. Moreover, the limit of detection and limit of quantitation were 1.0 µg/mL and 2.9 µg/mL for TMZ, and 5.0 µg/mL and 15.1 µg/mL for ALA, respectively. The validated method was found to be adequately sensitive and specific in simultaneously quantifying TMZ and ALA entrapped in liposomes [73.01 ± 3.96% entrapment efficiency for TMZ and 79.63 ± 0.24% for ALA (average ± SD, n = 3)]. Therefore, the proposed RP-HPLC method was found to be quick, precise, and specific for the simultaneous analysis of TMZ and ALA in bulk and in lipidic nanovesicles.
Reporting cumulative equivalent dose in 2 Gy fractions (EQD2) for combined external beam radiotherapy (EBRT) and gynecologic high-dose-rate brachytherapy (HDR-BT) typically requires manual transcription of dose-volume histogram (DVH) parameters from treatment planning system (TPS) into worksheets. This process is time-consuming and prone to transcription errors. This study aimed to develop and validate a standalone application for automated DVH-based EQD2 reporting in cervical cancer HDR-BT, eliminating manual transcription, improving efficiency, and supporting standardized reporting. A standalone application (Gy+) was developed in C# using Varian's Eclipse Scripting API (ESAPI v15.5). The application retrieved treatment plan's metadata and DVH data, calculated biologically effective dose (BED) and EQD2 using linear-quadratic model, and performed parameter-wise EQD2 summation across EBRT and HDR-BT plans. The output included a standardized PDF report, aligned with ICRU Report 89 (Level 2) and EMBRACE II objectives. Technical verification was performed against an ESAPI reference script, and clinical validation was conducted against the existing manual workflow for 40 patients (154 HDR-BT plans). Technical verification confirmed identical DVH parameter extraction at ±0.1 Gy, ±0.01 Gy, and ±0.001 Gy, and EQD2 calculations matched worksheet outputs at the clinical reporting resolution. Clinical validation at the patient level showed median differences of -0.061 Gy for bladder and -0.066 Gy for rectum, with 52.5% and 47.5% agreeing within ±0.1 Gy, respectively. Plan-level analysis showed median differences of -0.013 Gy for bladder and -0.012 Gy for rectum, with 87.0% and 89.6% agreeing within ±0.1 Gy. Reporting time was reduced from approximately 6 minutes to 35 seconds. Gy+ application provides accurate, efficient, and reproducible automated EQD2 reporting for cervical cancer brachytherapy, reducing manual transcription and operator-dependent variability, with reporting consistent with ICRU 89 and EMBRACE II guidelines.
Alternative polyadenylation (APA) generates transcript isoforms with distinct 3' ends, yet the repertoire of its protein regulators remains poorly defined. Using a large-scale tethered function screen, we profiled 879 human RNA-binding proteins (RBPs) and identified 63 high-confidence activators of poly(A) site (PAS) selection, most of which were not previously linked to APA. We validated these factors by knockdown PAS-seq, RNA sequencing (RNA-seq), and enhanced cross-linking and immunoprecipitation (eCLIP) analyses and developed a fine-tuned protein language model that predicts PAS selection activators and their key functional domains. We then mechanistically dissected two unexpected hits: GRB2, a signaling adaptor protein, and RNPS1, a peripheral component of the exon junction complex (EJC). Both regulate APA, at least in part, through direct interactions with distinct subunits of the cleavage and polyadenylation (CPA) machinery. Together, our study provides a comprehensive resource of APA-regulating RBPs and uncovers unexpected roles of signaling and EJC factors in APA regulation.
Carbone compounds are characterized by a zero oxidation state on divalent C, which contains two lone pairs, coupled with dative bonding to its two substituents. The ability of this carbone center to act as an electron donor is examined by pairing it with 29 different halogen-containing Lewis acids. DFT calculations show the binding to be quite strong, eclipsing that of a NH3 Lewis base, despite the similarity of their electrostatic potentials. Binding energies span a wide range from nearly zero up to more than 40 kcal mol-1; interaction energies are even larger. The more weakly bound dyads, with binding energies below 20 kcal mol-1, have all the characteristics of conventional halogen bonds, including an increase in binding energy in the usual Cl < Br < I sequence. For the more powerful Lewis acids, there is a progressively larger degree of displacement of the halogen atom from the Lewis acid to the carbone center, some essentially fully transferred. The dependence of the energetics on the halogen atom reverses for these complexes: Cl > Br > I.
Gotthelf "Carl" Huber, M.D. (1865-1934) was a professor of histology and embryology, and later professor of anatomy at the University of Michigan. His scientific contributions to the understanding of the peripheral nervous system, the blood supply of the kidney and the comparative anatomy of the central nervous system may be eclipsed in importance by his dedication to mentorship, education, and employment of underrepresented neuroanatomists. Under Huber's guidance, Lydia DeWitt, MD (1859-1928) published work on neuroanatomy and on the anatomy of the heart and the pancreas. In 1902, barred from both the Research Club and the Junior Research Club, DeWitt founded the University's Women's Research Club. Jeanne Solis, MD (1867-1947)-one of the earliest identified women faculty neurologists-joined the Women's Research Club and from 1921-1927 offered a prize of $25 for the best published research in medicine or science done during the year by a woman student. The Solis prize was won in 1926 by Elizabeth Crosby, PhD (1888-1983), another of Huber's mentees, who would co-write The Comparative Anatomy of the Nervous System of Vertebrates with Huber and become the first female full professor at the University of Michigan Medical School. By providing a space for underrepresented minorities, including Crosby's life partner Tryphena Humphrey, MD, PhD (1902-1971), and African American neuroanatomist M. Wharton Young, MD, PhD (1904-1986), to learn, publish and work, Huber set in motion a cascade of events leading to increased diversity in the world of research and medicine.
Pulmonary artery (PA) enlargement is a non-invasive imaging biomarker associated with pulmonary hypertension and mortality in COPD; however, its genetic determinants remain incompletely understood. To characterize the genetic architecture of PA size across COPD-enriched and population-based cohorts. We performed genome-wide association analyses of PA diameter using whole-genome sequencing in COPDGene (n=9,418) and ECLIPSE (n=1,859), and imputed-genotype data from the UK Biobank (n=37,073). We replicated lead variants in the Framingham Heart Study (FHS; n=3,289), incorporated all four studies into a joint meta-analysis, and identified independent signals through conditional analyses. Candidate effector genes were prioritized using coding variant annotation, colocalization, and integrative regulatory evidence. We identified 44 independent genome-wide significant PA diameter signals within 39 loci, including 8 variants replicated in FHS, novel associations near FRMD4B , SLC20A2 , BORCS7-ASMT , and KCNRG , and 5 signals in conditional analysis including multiple signals at ANO1 . Genetic effects were concordant across imaging modalities and cohorts of differing COPD burden. Effector-gene prioritization nominated ABCC8 , PDGFD , HMCN1 , CCNE1 , and TBX20 , implicating pathways in vascular remodeling, developmental regulation, smooth muscle and endothelial function, ion-channel signaling, and extracellular matrix organization. Colocalization with pulse pressure GWAS demonstrated substantial shared causal variation between pulmonary and systemic vascular biology. In this largest genetic study of pulmonary vascular imaging to date, PA diameter exhibits a polygenic architecture consistent across imaging modalities and cohorts of differing COPD burden. The prioritized effector genes bridge rare-variant pulmonary hypertension biology with common-variant systemic vascular biology.
Two-dimensional (2D) materials have emerged as versatile platforms for exploring novel physical phenomena, particularly in electronic and thermoelectric transport, where reduced dimensionality enables confinement effects that provide enhanced control over fundamental properties. In this context, van der Waals heterostructures offer a strategic route to engineering these properties via proximity effects. In this work, we investigate Graphene (G)/Bi2Se3 heterostructures, experimentally accessible monolayers, by means of density functional theory (DFT) calculations, including spin-orbit coupling (SOC) and van der Waals corrections. Two stacking configurations, eclipsed and staggered arrangements, are considered, both with favorable interlayer binding energies that confirm the stability of the interface. Our results, globally similar for both configurations, show that the physical response is dominated by interfacial coupling, which induces significant charge transfer resulting from the competition between the work functions of the individual components and the formation of an interface dipole. This charge transfer results in a metallic character in the heterostructures with an upward Dirac cone shift. Furthermore, SOC and band hybridization increase the complexity of the electronic structure, leading to features such as band splittings and avoided crossings due to proximity interactions. These combined effects give rise to an enhancement of both electrical and electronic thermal conductivities; however, they reduce the Seebeck coefficient and the electronic figure of merit ZT(e), revealing a thermoelectric trade-off. Overall, we find that these heterostructures are better suited for efficient charge transport and heat dissipation than for thermoelectric energy conversion, underscoring how proximity effects can be exploited to tailor the functional limits of 2D systems.