Key objectives in conditional molecular generation include ensuring chemical validity, aligning generated molecules with target properties, promoting structural diversity, and enabling efficient sampling for discovery. Recent advances in computer vision introduced a range of new guidance strategies for generative models, many of which can be adapted to support these goals. In this work, we integrate state-of-the-art guidance methods─including classifier-free guidance, autoguidance, and model guidance─in a leading molecule generation framework built on an SE(3)-equivariant flow matching process. We propose a hybrid guidance strategy that separately guides continuous and discrete molecular modalities─operating on velocity fields and predicted denoising probabilities, respectively─while jointly optimizing their guidance scales via Bayesian optimization. Our implementation, benchmarked on the QM9 and QMe14S data sets, achieves new state-of-the-art performance in property alignment for de novo molecular generation. The generated molecules also exhibit high structural validity. Furthermore, we systematically compare the strengths and limitations of various guidance methods, offering insights into their broader applicability.
暂无摘要（点击查看详情）
Augmented reality (AR) visualization projects preoperative virtual three-dimensional (3D) models onto real surgical sites and can provide intuitive intraoperative guidance. This in vitro proof-of-concept study evaluated the feasibility of markerless AR-guided endodontic microsurgery by comparing objective outcomes between AR guidance (ARG) and traditional freehand (FH) procedures on customized 3D-printed mandibular models. Customized 3D dental models with artificial periapical lesions (APLs) were generated from cone beam computed tomography (CBCT) images obtained from one patient. A total of 20 dental models (80 mandibular molars and 160 APLs) were included, with 10 models assigned to the ARG group and 10 to the FH group. Surgical planning was performed on virtual models reconstructed from CBCT images. All procedures were performed by one endodontist with more than 10 years of clinical experience after standardized training in both workflows. Surgical time was recorded during each procedure, and postoperative CBCT images were acquired to evaluate bone window marking errors, osteotomy errors, and root resection angle error. The ARG group required less time than the FH group across all four molar positions. Median (IQR) surgical times ranged from 3.72 (2.99-5.75) to 5.25 (4.58-6.56) min in the ARG group and from 7.02 (6.60-7.66) to 9.13 (8.28-9.75) min in the FH group (all P < 0.05). The ARG group also yielded lower median (IQR) values for bone window marking, osteotomy, and root-resection angle errors. Several tooth-specific comparisons reached statistical significance (P < 0.05). Within the limitations of an in vitro proof-of-concept study, markerless AR guidance was feasible and was associated with improved accuracy and time efficiency during simulated mandibular molar endodontic microsurgery. Further clinical studies are required before routine clinical application.
Objective: To analyze the clinical characteristics of breast cancer susceptibility gene (BRCA) germline mutation carriers with ovarian cancer, collect family history information, screen for potential BRCA mutation carriers among family members, and provide preventive guidance for high-risk populations of ovarian cancer. Methods: A total of 77 patients with ovarian cancer (including fallopian tube cancer and primary peritoneal cancer, hereinafter collectively referred to as ovarian cancer) who were treated at the Department of Obstetrics and Gynecology, Chinese PLA General Hospital between 2015 and 2024 and confirmed to carry germline mutations in the BRCA1/2 genes through genetic testing were selected. According to the test results, they were divided into the BRCA1 mutation group (48 cases) and the BRCA2 mutation group (29 cases). The clinical baseline data, pathological characteristics, treatment efficacy, and survival outcomes were compared between the two groups. Family history information was collected, and BRCA genetic testing was performed on 81 relatives from 37 families. Family characteristics were analyzed in combination with family history and genetic testing results, and preventive guidance was provided to high-risk populations. Results: The age at onset of the 77 patients ranged from 19 to 78 years, with a median age of 55 years. The age at onset in the BRCA1 mutation group ranged from 19 to 74 years, with a median age of 52 years, which was earlier than the median age of 56 years in the BRCA2 mutation group. 43.8% (21/48) of BRCA1 carriers had a family history of hereditary breast and ovarian cancer syndrome (HBOC), which was 1.5 times higher than that in the BRCA2 group (17.2%, 5/29, P＜0.05). There were no statistically significant differences in fertility status, body mass index (BMI), personal history of breast cancer, and pre-treatment carbohydrate antigen 125 (CA125) levels between the two groups (P＞0.05). The median progression-free survival (PFS) for initial treatment was 21.8 months in BRCA1 mutation patients and 20.7 months in BRCA2 mutation patients. Among the 81 relatives, 47 BRCA gene mutation carriers were detected, of whom 63.8% (30/47) were from families without a family history of HBOC. Among 31 female mutation carriers, only 2 underwent risk-reducing salpingo-oophorectomy (RRSO). A survey of the general population showed that 78.5% of non-carrier women would accept prophylactic surgery, while the average surgical intention score among carriers was only 2.6 (on a 5-point scale), with 75.0% preferring to delay RRSO until after natural menopause. Conclusions: Chinese BRCA1/2 mutation carriers have significant concerns regarding iatrogenic menopause caused by RRSO, creating a decision-making dilemma for surgical prevention of ovarian cancer in high-risk populations. The age at onset of ovarian cancer in Chinese BRCA1/2 mutation carriers is relatively late compared with international data, and the optimal timing of surgery for Chinese women still requires further investigation. Developing a localized surgical timing prediction model may help advance ovarian cancer prevention and treatment efforts. 目的： 分析乳腺癌相关基因（BRCA）胚系突变卵巢癌患者的临床特征，并进行家系信息采集，筛查家系亲属中潜在的BRCA突变携带者，针对卵巢癌患病高危人群予以预防指导。 方法： 选取2015—2024年在解放军总医院妇产医学部接受治疗，并通过基因检测确认携带BRCA1/2基因胚系突变的77例卵巢癌（包含输卵管癌、盆腔腹膜癌，后文统称卵巢癌）患者，根据检测结果分为BRCA1突变组（48例）和BRCA2突变组（29例），比较两组患者的临床基线资料、病理特征、治疗效果及生存结局。采集患者家系信息，对来自37个家系的81位患者亲属进行BRCA基因检测，结合家族史情况和基因检测结果分析家系特征，对高危人群进行预防指导。 结果： 77例患者发病年龄波动于19～78岁，中位发病年龄55岁。BRCA1突变组发病年龄为19~74岁，中位发病年龄52岁，早于BRCA2突变组的56（37~78）岁（P＜0.05）。43.8%（21/48）的BRCA1携带者具有遗传性乳腺癌-卵巢癌综合征（HBOC）家族史，较BRCA2组高1.5倍（17.2%，5/29，P＜0.05）。两组患者的生育情况、体质指数、乳腺癌个人史及治疗前糖类抗原125水平比较，差异无统计学意义（P＞0.05）。BRCA1突变患者初始治疗的中位无进展生存时间（PFS）为21.8个月，BRCA2突变患者初始治疗的中位PFS为20.7个月。81位患者亲属中检测出47位BRCA基因突变携带者，其中63.8%（30/47）来自无HBOC家族史的家系。31位女性突变携带者中仅2位接受预防性双侧卵巢-输卵管切除术（RRSO）。健康人群调查显示，78.5%（128/163）非携带女性可接受预防性手术，而8位BRCA1/2突变携带者群体手术意向平均仅2.6分（5分制），6位（6/8）倾向延迟至自然绝经后施行RRSO。 结论： 中国BRCA1/2突变携带者对RRSO手术带来的医源性绝经顾虑较重，高危人群卵巢癌的手术预防存在决策困境。国内BRCA1/2 突变卵巢癌患者卵巢癌发病年龄较晚，适宜国内女性的手术时机仍需进一步探讨，开发本土化手术时机判定模型有助于推动卵巢癌防治工作。.
Complementary and alternative medicine (CAM) is widely used in Saudi Arabia, yet nurses' readiness to provide safe, evidence-informed guidance remains unclear. This study assessed nurses' knowledge, information-seeking ability, attitudes, and practice related to CAM and identified demographic and professional predictors of competency in 2 Ministry of Health tertiary hospitals in the Western Region. A cross-sectional survey of 501 registered nurses used validated measures of CAM familiarity, access to information, attitudes, and practice behaviors. Overall familiarity was low to moderate, and 64.5% reported difficulty locating reliable information. Attitudes were generally positive (42.7% very high), while practice levels were mostly moderate (84.6%); only 7.6% had prior CAM training. Higher education and previous CAM training were significant predictors of better familiarity, information-seeking, and practice. Despite supportive attitudes, gaps in knowledge and training limit safe integration, underscoring the need for structured education and institutional guidance.
Hemodynamic variables may be unreliable indicators of intraoperative nociception in older patients. We evaluated whether a prespecified IoC2-based sufentanil dosing protocol reduces intraoperative sufentanil use compared with conventional hemodynamic guidance in older patients undergoing laparoscopic colorectal surgery. In this prospective, single-center, parallel-group, single-blind randomized trial, patients aged 65-90 years with ASA physical status II-III undergoing elective laparoscopic colorectal resection were randomized 1:1 to IoC2-guided or hemodynamic-guided analgesia. Anesthesia, antiemetic prophylaxis, neuromuscular blockade, and postoperative analgesia were standardized. The prespecified primary outcome was weight- and time-normalized intraoperative sufentanil consumption (μg/kg/h); total intraoperative sufentanil dose was also reported. The secondary outcomes included postoperative pain and sufentanil consumption, interleukin-6 concentrations, intraoperative hemodynamic safety events, vasoactive drug use, recovery outcomes, postoperative nausea and vomiting (PONV), and delirium. Fifty-eight patients were analyzed (IoC2, n = 28; control, n = 30). The prespecified primary endpoint, weight- and time-normalized intraoperative sufentanil consumption, was lower with the prespecified IoC2-based protocol than with hemodynamic guidance (median [IQR], 0.10 [0.09-0.13] vs 0.17 [0.14-0.22] μg/kg/h; p < 0.001). Total intraoperative sufentanil dose was also lower in the IoC2 group (20.0 [16.9-26.3] vs 36.0 [27.8-44.4] μg; p < 0.001). Postoperative pain scores and sufentanil requirements were similar between groups, with no significant differences in hypotension, bradycardia, vasoactive drug use, baseline-adjusted interleukin-6 concentrations, or delirium. PACU PONV was less frequent in the IoC2 group (3.6% vs 30.0%; p = 0.012). A prespecified IoC2-based sufentanil dosing protocol reduced weight- and time-normalized intraoperative sufentanil consumption without worsening early postoperative pain outcomes in older patients undergoing laparoscopic colorectal surgery. This finding should be interpreted as the effect of the tested dosing protocol rather than validation of the IoC2 target range or treatment threshold. The lower PACU PONV incidence was a secondary finding and requires confirmation in larger trials.
Lateralization of behavior, including motor control and sensory processing, is widespread across bilaterians. In visually guided tasks it often manifests as an axis aligning eye, appendage, and a target within a shared reference frame, such as eye-hand coordination in humans or eye-beak coordination in birds. While studied intensively in a few vertebrate systems, whether similar control principles apply to invertebrates, and more generally, how sensory and motor lateralization are linked mechanistically, remains unclear. Using the proboscis inspection behavior of hummingbird hawkmoth Macroglossum stellatarum as a model for visual appendage guidance, our study provides evidence for lateralized visuo-motor control in an invertebrate. Combining high-speed videography and markerless pose estimation, we establish the underlying control axis between the hawkmoths' unpaired appendage and its eye. We demonstrate that individuals displayed stable, idiosyncratic proboscis lateralization, which was tightly linked to their instantaneous viewing angle of visual targets, thus forming a persistent eye-proboscis-target axis. This axis also had functional consequences for feature-targeting. Assessing the sensory-motor plasticity using monocular occlusion, we found that moths preserved their lateralized visuo-motor geometry by adjusting body posture during flower inspection. Our findings suggest convergent control principles with vertebrate models of lateralized visual appendage guidance, while highlighting stark differences in sensory-motor plasticity, thus adding to our general understanding of how lateralization shapes control strategies across nervous systems.
The Centers for Disease Control and Prevention's (CDC) National Program of Cancer Registries (NPCR) supports the management and operations of central cancer registries (registries) across the United States through funding and technical assistance (TA). To examine barriers and facilitators to program evaluation among NPCR-funded cancer registries, assess registries' TA needs related to evaluation and implementation, and evaluate satisfaction with CDC-provided TA. We used a mixed-methods approach. Quantitative analysis examined 114 TA requests submitted between June 2022 and September 2023 through an administrative TA management platform. Qualitative data were collected during routine monthly check-in calls with 23 registries from October 2023 to January 2024, during which evaluators facilitated conversations on program evaluation experiences, TA needs, and satisfaction. TA requests submitted by 32 cancer registries and routine check-in calls with 23 registries, representing 38 unique registries across data sources. Cancer registry program evaluation barriers and facilitators, TA needs, and satisfaction with CDC-provided TA. Most TA requests addressed operations and reporting (69.3%), followed by data submission (15.8%), evaluation and data management plans (8.8%), education and training (5.3%), and registry software/informatics (0.9%). Among resolved requests, more than 75% were addressed within 7 days. Qualitative findings indicated that registries were generally satisfied with TA timeliness and quality. Barriers to program evaluation included limited resources, insufficient training, and leadership transitions. Facilitators included adequate staffing and funding, evaluation competency, strong partnerships, and effective registry operations. Registries identified overlapping TA needs related to organizational support, targeted expertise, guidance and expectations, training, technical infrastructure, and peer learning. Program evaluation capacity within cancer registries is shaped by resources, training, partnerships, and operational context. Findings highlight opportunities for TA providers to strengthen evaluation through targeted training, clearer guidance, and peer learning to support consistent program implementation across multisite public health programs.
Thitarodes xiaojinensis larvae, obligate hosts of Ophiocordyceps sinensis, feed on Polygonum viviparum roots rich in quercetin, a defensive flavonoid that is toxic to many herbivorous insects. However, the molecular mechanism underlying their quercetin tolerance remains unclear. Here, we show that T. xiaojinensis larvae tolerate high quercetin exposure and identify the cytochrome P450 gene Cyp6A14 as a key detoxification factor. Quercetin treatment strongly induced the Cyp6A14 expression. RNA interference reduced Cyp6A14 transcript levels by 85.1% and significantly increased larval mortality under quercetin stress. High-performance liquid chromatography further showed that Cyp6A14 silencing caused marked accumulation of quercetin in larval hemolymph, indicating impaired Phase I detoxification. Phylogenetic analyses suggest functional adaptation of Cyp6A14 toward efficient quercetin metabolism. These findings reveal a molecular basis for quercetin tolerance and provide guidance for developing chemically compatible artificial diets for T. xiaojinensis rearing.
As saliva-based genomic analyses expand, the effect of common pre-sampling behaviors on salivary genomic DNA (gDNA) recovery remains poorly characterized. In this single-donor pilot study, we tested eight pre-sampling conditions combining tooth brushing, gargling, and water intake. Saliva was collected in triplicate under each condition, cells were isolated, and gDNA was extracted using the Qiagen Kit. Three-way ANOVA showed that brushing was the dominant factor, accounting for 62.9% of total variation in DNA yield. Gargling had a smaller but significant effect (5.6%), while water intake had no significant effect. DNA purity, assessed by A260/280 ratio, remained stable across all conditions. To assess the human-to-bacterial DNA ratio, we performed qPCR using RPPH1 (human) and 16S rRNA (bacterial) markers. Brushing increased the human DNA fraction but reduced the absolute amount of human DNA recovered, indicating a purity-yield trade-off. These single-donor pilot findings offer preliminary, quantitative guidance for pre-sampling conditions in saliva-based genomic analyses, to be validated in multi-donor cohorts.
Spinal cord injury (SCI) causes severe and often permanent neurological deficits, including neurogenic lower urinary tract dysfunction. Although restoration of bladder function is a major clinical priority after SCI and would profoundly improve care and quality of life, it remains underrepresented in neurotrauma research. Central to this pathology is Repulsive Guidance Molecule a (RGMa), a potent inhibitor of axonal outgrowth and neuronal differentiation that is upregulated following central nervous system injury. In this study, we evaluated the therapeutic efficacy of elezanumab, a human anti-RGMa monoclonal antibody tested in clinical trial for acute SCI, on bladder function in a clinically relevant bilateral impact-compression model of traumatic thoracic SCI in female rats. Quantitative urodynamic and cystometric analyses demonstrated that elezanumab administered initially at 3 h post-SCI and then weekly for 6 weeks significantly reduced urinary retention, reflex bladder activity, and intravesical pressure in SCI rats. Morphological assessment revealed that RGMa neutralization limited pathological bladder hypertrophy, with reductions in bladder mass correlating with reduced urine retention. Neuroanatomical mapping via retrograde tracing, together with exploratory transsynaptic tracing, was consistent with increased supraspinal connectivity in pathways involved in micturition. Moreover, elezanumab promoted axonal plasticity of descending catecholaminergic and serotonergic fibers within the lumbosacral spinal cord. These structural changes were associated with reduced bladder pressure and improved neurological recovery. Together, these findings suggest that RGMa inhibition via elezanumab promotes recovery within key components of the micturition circuitry following traumatic SCI.
The indiscriminate and excessive application of nitrogen fertilizer, coupled with over-irrigation, represents a well-documented driver of reduced crop productivity and severe environmental degradation in agroecosystems. Although deficit drip fertigation is recognized for enhancing water and nutrient use efficiency, quantitative evidence regarding its optimal irrigation and nitrogen fertigation levels for sesame remains critically lacking. Therefore, this study was conducted to quantitatively assess the effectiveness of deficit drip irrigation regimes (I50: 50, I80: 80, and I100: 100% of ETc) and nitrogen fertigation rates (N25: 25, N75: 75, and N100: 100% of the recommended nitrogen dose) on the morpho-physiological, agronomic, and quality attributes of sesame over two growing seasons of 2024 and 2025. ANOVA revealed that irrigation level, nitrogen fertigation rate, and their interaction had highly significant effects (p < 0.001) on leaf number, dry weight of capsules, chlorophyll b, capsule number, and seed yield. Full irrigation (100% ETc) substantially improved plant height, leaf number, and SPAD value of sesame. The maximum capsule dry weight and capsule number were observed under the 75% nitrogen treatment, suggesting that excessive nitrogen may promote vegetative growth at the expense of reproductive development. The application of N100 under well-watered conditions (I100) significantly enhanced chlorophyll a, chlorophyll b, and relative water content (1.98 mg·g⁻¹ FW, 0.827 mg·g⁻¹ FW, and 89.03%, respectively) compared to other treatments. Notably, the highest capsule number per plant (93.33) and 1000-seed weight (3.80 g) were documented under the interactive effects of full irrigation and a 75% nitrogen fertigation, which consequently maximized seed yield (1570.51 kg·ha⁻¹). Conversely, water stress (I50) considerably reduced nitrogen and oil content, especially at 25% nitrogen fertigation, indicating a decrease in the nutritional quality of sesame seeds. Furthermore, multivariate analyses substantiated that the application of N75 under full irrigation achieved an optimal balance among crop productivity and quality. These outcomes provide practical guidance for farmers seeking to maximize both sesame productivity and its potential profitability.
Atomically dispersed catalysts (ADCs), including single-atom catalysts (SACs), dual-atom catalysts (DACs), and metal cluster catalysts, have revolutionized the design of oxygen evolution reaction (OER) electrocatalysts by achieving precise atomic-level control over active sites. This review summarizes the structural evolution, interfacial electronic coupling mechanisms, and synergistic effects that enhance OER efficiency. SACs maximize atomic utilization and offer tunable coordination environments; DACs introduce bimetallic electronic synergy to optimize intermediate adsorption, and clusters provide multicenter cooperative catalysis with molecular-like delocalization. Strategies such as dynamic coordination reconstruction, heterostructure engineering, and interfacial electric field modulation are discussed for improving intrinsic activity and stability. Insights from in situ characterizations and theoretical simulations elucidate the relationships between structure and performance, providing design guidance for next-generation catalysts. This work highlights the potential of atomically engineered systems to achieve scalable, cost-effective, and high-efficiency OER catalysis for sustainable energy conversion.
Virtual healthcare has developed rapidly and become an important part of medical care. Shoulder complaints are a common reason for seeking care and require thorough examination. Studies indicate that musculoskeletal examinations can be performed via video with good validity, but the evidence is limited. There is a need to explore, identify and map current research on the topic. The aim of this scoping review was to map and compile the existing literature on real-time video-based examination of the shoulder, to identify knowledge gaps in this area, and to describe procedures used in shoulder examinations. A literature search was conducted in November 2024 on PubMed, CINAHL and Scopus, and updated in June 2026. Grey literature was excluded. Selection of literature was performed independently by two authors. Conduct and reporting of the review followed established guidance for scoping reviews. Twenty articles were included in the review. Seven were designed as guidelines, 12 were validity or reliability studies, and one article was a case report. A result was compiled that describes the different parts of a video-based examination of the shoulder. The result also includes a description of investigated validity and reliability for individual examination components, and overall clinical assessment and diagnosis. This scoping review identified multiple studies outlining examination components and practical procedures for video-based assessment of the shoulder, suggesting the usefulness of this mode. Nevertheless, more research is necessary to establish a robust evidence base. Further research is needed to determine best practices and the appropriate role of video-based shoulder examination in musculoskeletal care. . Not applicable. This study is not a clinical trial. Not applicable. The scoping review was preregistered on 8 Nov 2024 on Open Science Framework Registry (Identifier: https://doi.org/10.17605/OSF.IO/B4C8S).
To evaluate gynecologic cancer survivors' preferences regarding the organization of sexual health counseling, with a focus on timing, frequency, responsible healthcare professionals, and preferred counseling content and formats. This cross-sectional, questionnaire-based online study included cancer survivors aged 18 years or older, with Eastern Cooperative Oncology Group performance status of 2 or lower, who had completed treatment for ovarian, endometrial, or cervical neoplasia and were recruited nationwide in Poland. Participants were recruited through online patient forums, social media, and patient advocacy platforms; therefore, the sample was self-selected and may not be representative of all gynecologic cancer survivors. The survey addressed sexual activity status, sexual counseling, and preferences for when and by whom sexual health should be discussed. Sexual activity was defined as any genital stimulation with or without a partner for sexual pleasure. Comparative analyses were conducted between survivors who returned to sexual activity and those who did not. The final sample comprised 201 survivors. Sexual counseling was reported as having been offered to 15 of 201 respondents (7.4%), and 7 of 201 (3.4%) had visited a sexual medicine specialist. Among respondents who completed the sexual health counseling preference module and post-treatment sexual activity status (n = 156), 42 (26.9%) did not return to sexual activity. Most respondents indicated that sexual health should be addressed at diagnosis and reassessed during follow-up (55.1%, n = 87/156). Overall, 62.3% (n = 98/156) expressed a need to discuss sexual health at every follow-up visit, with a substantial preference for counseling delivered by gynecologic oncologists or gynecologists (63.4%, n = 99/156). Survivors most requested practical guidance on resuming sexual activity and managing treatment-related sexual problems (93.6%, n = 146/156), and most expressed interest in receiving written and/or digital educational materials. In this online cohort of gynecologic cancer survivors, sexual health counseling was infrequently reported, while many respondents expressed a preference for structured, repeated discussions from diagnosis through survivorship. Implementation of a structured, patient-centered counseling pathway may improve survivorship care quality and access. ClinicalTrials.gov NCT06958068.
Motor skills during early childhood are shaped by biological maturation, environmental opportunities, and cultural contexts. However, most reference data on motor skills derive from high-income countries, limiting global comparability. The SUNRISE International Study was developed to address this gap by generating cross-cultural evidence on early child development. This study aimed to develop age- and sex-specific percentile curves for gross and fine motor skills, based on a cross-cultural and income-diverse sample of 3-4-year-old children included in the SUNRISE Study. In 6 countries, 3027 children completed the supine-timed up and go and the 9-hole pegboard test, as measures of gross and fine motor skills, respectively. The Generalized Additive Models for Location, Scale and Shape model, with the Box-Cox Power Exponential adjusted method was used to construct percentile curves within each 3-month age category, according to sex. Percentile curves were generated to offer a foundational reference for interpreting gross and fine motor skills development within the scope of the SUNRISE. The proposed curves may support tracking children's motor skills and inform context-specific strategies aimed at identifying and addressing potential motor skills delays, while maintaining comparability across countries using the harmonized protocols. Regular updates based on broader and representative datasets are encouraged to maintain their relevance and applicability across populations and countries. What is Known: • Motor competence (MC) assessment is essential for identifying developmental delays and guiding interventions in early childhood. • Existing reference values for gross and fine MC often have limited applicability across diverse populations due to cultural and contextual differences. What is New: • The percentile curves developed provide a robust framework for comparing gross and fine MC across different samples within the scope of the Sunrise International Study. • These curves, capturing a broader range of variability, offer guidance for comparing children´s motor development, supporting teachers, health professionals, and policy makers at promoting motor skill development.
Psychedelics that target serotonin 2A receptors (5-HT2ARs) hold therapeutic promise for neuropsychiatric disorders but are often hindered by off-target actions. The 5-HT2AR agonist quipazine also activates 5-HT3R, which contributes to undesirable side effects. Here, we developed VCU-1012, a quipazine-based, structurally distinct 5-HT2AR agonist devoid of 5-HT3R activity. VCU-1012 was developed by applying a strategic chemical design that combined deconstruction to pinpoint the nitrogen atom critical for 5-HT2AR activation with structure-activity relationship studies to minimize 5-HT3R agonism. We showed that VCU-1012 modulated dendritic spine structural plasticity in the frontal cortex and produced antidepressant-like effects in mice through 5-HT2AR without activating 5-HT3R, thereby avoiding the gastrointestinal side effects of quipazine. In addition, our molecular modeling and mutant analysis suggested that VCU-1012 interacted in the canonical orthosteric binding pocket of 5-HT2AR. Together, these findings establish VCU-1012 as a potential therapeutic agent with reduced gastrointestinal impact, emphasize how differences in ligand-receptor interactions influence ligand positioning in the receptor binding pocket, and provide guidance for designing psychedelics with targeted therapeutic benefits.
Global data demonstrate that women have worse outcomes following acute coronary syndromes (ACS) compared to men. Routine follow-up care for ACS involves optimal medical therapy (OMT) to reduce the risk of future adverse cardiovascular outcomes; however, women are both less likely to receive OMT and underrepresented in cardiovascular clinical trials; thus, a sex bias exists in the evidence for many OMT drugs. In this review we examine sex-specific data for OMT, exploring sex differences in the pharmacology and clinical efficacy of these drugs. We outline various sex differences in the pharmacodynamics and pharmacokinetics of OMT drugs, which do not appear to result in convincing differences in efficacy. However, women are at increased risk of drug-related side effects, which has important implications for adherence and discontinuation. Sex-specific guidance is needed for current OMT medications to address differences in prescribing and side effect profiles. Understanding the sex-specific pharmacology of OMT is key to providing more personalized care.
Prioritizing defense responses often restricts growth and yield, forming a growth-defense conflict that limits crop productivity and threatens global food security. Traditionally attributed to resource allocation constraints, this trade-off is governed by sophisticated signaling regulatory networks. Plant G proteins act as pivotal molecular switches that initiate cellular signal transduction, and they extensively integrate plant growth, development, and stress adaptation. Recent studies have uncovered their multifaceted coordination roles in regulating crop yield and stress resistance, and elite alleles of G proteins have been identified and applied in molecular design breeding. However, the pleiotropy of most G proteins hinders the concerted control of yield and stress resilience, leading to trait divergence, which represents a key bottleneck for breeding high-yield and stress-tolerant crops. Here, we summarize the regulatory networks of G protein subunits in yield and quality traits and stress responses, dissect the mechanisms underlying G protein-mediated growth-resistance decoupling, and propose precision strategies to simultaneously enhance these agronomic traits. This review provides theoretical and practical guidance for developing high-performance crop varieties.