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Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of invasive infections, yet the genetic basis of its stress adaptation remains partially understood. This study investigates the role of the conserved membrane-associated gene ytrE in MRSA USA300 pathogenesis. While disruption of ytrE did not affect in vitro growth or biofilm formation, the ΔytrE mutant exhibited significant attenuation in a murine systemic infection model, characterized by increased host survival and reduced bacterial burdens in major organs. Phenotypic analyses revealed that loss of ytrE leads to compromised membrane integrity, impaired surface-associated motility, and heightened sensitivity to oxidative stress (H2O2). Furthermore, the mutant showed reduced levels of cell-associated phenol-soluble modulins (PSMs), which may contribute to the impaired colony spreading phenotype. Genetic complementation restored the major altered phenotypes observed in the ΔytrE mutant. These findings suggest that ytrE contributes to MRSA pathogenic fitness by supporting envelope homeostasis and resistance to oxidative stress. Non-essential factors involved in membrane stability may represent potential targets for future anti-virulence studies.
Periostin is a matricellular protein that binds to its receptors, which include several integrin molecules but mainly αvβ3 integrin on cell surfaces, thereby transducing its signals into cells. Almost 20 years have passed since we found that periostin is involved in the pathogenesis of asthma, which marked the first evidence of its involvement in allergic diseases. Over the past 2 decades, cumulative evidence has demonstrated that periostin plays important roles in the onset or progress of many allergic diseases such as chronic rhinitis with nasal polyp, atopic dermatitis (AD), allergic conjunctivitis, eosinophilic esophagitis, eosinophilic otitis media, allergic rhinitis, and eosinophilic granulomatosis with polyangiitis. Starting from the observation of highly expressed periostin in the lesions of these diseases, periostin studies have expanded to include how periostin contributes to the generation of allergic phenotypes, how measurement of periostin is useful as a biomarker for allergic diseases, and recently how periostin inhibitors can improve allergic diseases. Periostin contributes to the generation of allergic phenotypes by acting as a matricellular protein on many cells, including both non-immune and immune cells. Based on the characteristics of periostin as a surrogate biomarker of interleukin-13, a signature cytokine of type 2 inflammation, serum periostin has been used as a biomarker for stratifying endotypes, estimating disease severity, predicting or monitoring the efficacy of therapeutic drugs, and predicting disease relapse or recurrence. Moreover, a lot of attention is now being paid to periostin in body fluids such as tears and sputum as a biomarker directly reflecting type 2 inflammation. Since it has been shown that periostin evokes itch in AD, we hope to see the development of a novel therapeutic agent for AD targeting periostin/αvβ3 integrin. Here we summarize the discovery and characteristics of periostin, as well as questions and/or problems regarding periostin that remain to be resolved.
Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disease in which eosinophil (Eos) infiltration into polyp tissues is associated with disease prognosis. Our previous study found that linoleic acid is an important differential metabolite. However, lipid metabolism in nasal polyps has been insufficiently investigated. This study aimed to explore the characteristics of lipid metabolism in CRSwNP tissue. This study employed a multi-omics approach by integrating lipidomics and single-cell transcriptomics. The lipidomics analysis was performed using nasal mucosal tissues obtained from 32 patients with nasal polyps and 20 healthy controls. The sequencing findings were validated by using immunofluorescence staining and Western blotting. Phosphatidylethanolamine and phosphatidylcholine were the most abundant lipids expressed in the sinus mucosa, and lysophosphatidylinositol (LPI) was significantly increased in the eosinophilic CRSwNP group compared to the noneosinophilic CRSwNP and the control groups. The LPI levels showed significant positive correlations with the Eos counts and percentages in nasal polyp tissue. The expressions of membrane-bound O-acyltransferase 7 and receptor G-protein coupled receptor 55 in the LPI metabolic pathway were significantly elevated in eosinophilic nasal polyps, and their expression was mainly localized to Eos in polyp tissues. There are differences in the lipidomic patterns between healthy individuals and patients with CRSwNP. The LPI metabolic axis may be associated with Eos activation in polyp tissue. These findings could provide new insights into the pathogenesis and endotyping of CRSwNP.
The pathophysiology and natural course of childhood food allergies (FAs) remains largely elusive. Recent findings have implicated resolvins, omega-3 metabolites, in the pathogenesis and resolution of FAs, highlighting their potential clinical significance. This investigation aimed to elucidate the clinical implications of resolvins in the manifestation and resolution of childhood FAs. Serum samples were collected from a cohort of children diagnosed with FA and healthy controls upon their first visit to the Severance Children's Hospital (Seoul, Korea). FA persistence was assessed for each patient based on follow-up records. Resolvin D1 (RvD1) levels were measured and their correlation with total immunoglobulin E (IgE) and allergen-specific IgE levels were evaluated. This study included 278 children (mean age 3.28 ± 3.17 years; 62% male), consisting of 92 children with resolved FA (resolved FA group), 113 children with persistent FA (persistent FA group), and 73 children (control group). RvD1 levels were significantly higher in children with FA than in controls (P < 0.001), and were significantly higher in the persistent FA group than in the resolved FA group (P = 0.045). A positive correlation was found between total IgE and RvD1 levels (r = 0.32, P < 0.001), particularly in the persistent FA subgroup. Furthermore, the correlation between RvD1 and total IgE was stronger in children with multiple FAs (r = 0.367, P < 0.001). RvD1 levels were also positively correlated with egg- and milk-specific IgE levels, especially in the persistent FA group. Our findings suggest that RvD1 is a candidate metabolite associated with the persistence of childhood FA, across various food allergens and may provide complementary information to existing clinical features.
Dysmenorrhoea is one of the most frequent manifestations of chronic pelvic pain. Endometriosis and adenomyosis are among the most common pathological causes of secondary dysmenorrhoea. Symptoms often persist despite treatment, so individuals frequently engage in self-management strategies. One self-management approach that may have potential benefits for chronic pain is whole-body thermal therapy, which involves exposure to heat or cold stimuli inducing systemic physiological responses. The aim of this scoping review is to map and synthesise the available literature on the use and reported benefits of whole-body thermal therapies in individuals assigned female at birth (AFAB) with chronic pelvic pain, dysmenorrhoea, endometriosis and adenomyosis. The proposed scoping review will adhere to the PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analysis, Extension for Scoping Reviews) checklist. We will search the Embase, Scopus, Medline, American Psychological Association (APA) PsycINFO, Web of Science and CINAHL Ultimate electronic databases for primary studies published in English from the year 2000. All articles will be independently assessed by two reviewers for eligibility. Data will be synthesised using framework synthesis and findings will be presented descriptively in tabular and narrative format. The proposed study does not require ethical approval as it is a scoping review of the existing literature and will only describe and synthesise previously published data. We will consult with an established patient and public involvement (PPI) panel who will assist in interpreting and disseminating the findings. We will produce and disseminate creative outputs (eg, visual illustrations) that capture discussions during PPI panel meetings. Findings will be disseminated in a peer-reviewed journal, at conferences and via webinars with relevant networks. This protocol has been registered as a preprint on the Open Science Framework platform: https://osf.io/zxp3j.
Acute and chronic bacterial prostatitis are clinically significant entities that can be difficult to diagnose and appropriately treat. Herein, we review when to suspect these clinical conditions, how to diagnose them, and how to effectively treat them based on the extant literature. Our aim was to equip the practicing clinician with the ability to proficiently diagnose and manage acute and chronic bacterial prostatitis, particularly in older patients.
Objective: To investigate the value of shear wave elastography (SWE) in the early diagnosis of diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes mellitus. Methods: This study was a diagnostic case-control study. From May 2021 to October 2022, 68 patients with type 2 diabetes mellitus who met the inclusion criteria were admitted to the Department of Burns and Plastic Surgery of Affiliated Hospital of Zunyi Medical University, including 45 males and 23 females, aged (57±10) years. According to whether the DPN was present, the patients were divided into DPN group (38 patients) and non-DPN group (30 patients). During the same period, 30 healthy volunteers who underwent physical examinations at the health examination center of the hospital were recruited as healthy control group, including 19 males and 11 females, aged (56±10) years. Cross-sectional areas of the bilateral common peroneal nerves and tibial nerves measured by a color Doppler ultrasonography system in two-dimensional ultrasonography mode, and the stiffness of the bilateral common peroneal nerves and tibial nerves measured in SWE mode were compared between volunteers in healthy control group and two groups of patients at admission. Independent risk factors for the development of DPN were screened in the three groups of participants. Receiver operating characteristic curves were used to evaluate the diagnostic value of common peroneal nerve stiffness, common peroneal nerve cross-sectional area, tibial nerve stiffness, and tibial nerve cross-sectional area for DPN in two groups of patients. The correlations of common peroneal nerve stiffness and common peroneal nerve cross-sectional area with the Toronto clinical scoring system (TCSS) score were analyzed in patients of DPN group. Results: At admission, the cross-sectional areas of the bilateral common peroneal nerves of patients in DPN group were significantly larger than those of patients in non-DPN group and volunteers in healthy control group (P<0.05); there was no statistically significant difference in the cross-sectional area of the bilateral tibial nerves between volunteers in healthy control group and two groups of patients (P>0.05). At admission, the stiffness of the bilateral tibial nerves and common peroneal nerves of patients in both non-DPN group and DPN group was significantly greater than that of volunteers in healthy control group (P<0.05); the stiffness of the left tibial nerve and the bilateral common peroneal nerves of patients was significantly greater in DPN group than in non-DPN group (P<0.05). The results of multivariable ordinal logistic regression analysis showed that common peroneal nerve stiffness, tibial nerve stiffness, and common peroneal nerve cross-sectional area were all independent risk factors for the development of DPN among the participants in the three groups (with ORs of 0.91, 0.93, and 0.75, respectively, 95% CIs of 0.89 to 0.95, 0.89 to 0.97, and 0.58 to 0.96, respectively, P<0.05). In the two groups of patients, common peroneal nerve stiffness yielded the largest area under the curve for diagnosing DPN, which was 0.85 (with a 95% CI of 0.74 to 0.92). The optimal cutoff value was 75.29 kPa, with a sensitivity of 76.32% and a specificity of 90.00% at the optimal cutoff value. In DPN group, common peroneal nerve stiffness and common peroneal nerve cross-sectional area of patients were significantly positively correlated with the TCSS score (with rs values of 0.83 and 0.89, respectively, P<0.05). Conclusions: SWE demonstrates excellent performance in assessing peripheral nerve stiffness in patients with type 2 diabetes mellitus. In particular, common peroneal nerve stiffness measured by SWE has high diagnostic value for patients complicated with DPN and is correlated with clinical severity. It may serve as an auxiliary imaging marker for the early screening and severity assessment of DPN. 目的： 探讨剪切波弹性成像（SWE）对2型糖尿病患者并发糖尿病周围神经病变（DPN）的早期诊断价值。 方法： 该研究为诊断性病例对照研究。2021年5月—2022年10月，遵义医科大学附属医院烧伤整形外科收治68例符合入选标准的2型糖尿病患者，其中男45例、女23例，年龄（57±10）岁，根据是否并发DPN将患者分为DPN组（38例）和非DPN组（30例）；同期招募在该院体检中心体检的30名健康志愿者作为健康对照组，其中男19名、女11名，年龄（56±10）岁。比较健康对照组志愿者和2组患者入院时采用彩色多普勒超声诊断仪在二维超声模式下测量的双侧腓总神经和胫神经横截面积、在SWE模式下测量的双侧腓总神经和胫神经硬度。在3组受试者中，筛选DPN发病的独立危险因素。在2组患者中，采用受试者操作特征曲线评价腓总神经硬度、腓总神经横截面积、胫神经硬度和胫神经横截面积诊断DPN的价值。分析DPN组患者腓总神经硬度、腓总神经横截面积与多伦多临床评分系统（TCSS）评分的相关性。 结果： DPN组患者入院时双侧腓总神经横截面积均显著大于非DPN组患者和健康对照组志愿者（P<0.05）；但健康对照组志愿者与2组患者入院时双侧胫神经横截面积比较，差异均无统计学意义（P>0.05）。非DPN组与DPN组患者入院时双侧胫神经和腓总神经硬度均显著高于健康对照组志愿者（P<0.05），DPN组患者入院时左侧胫神经和双侧腓总神经硬度均显著高于非DPN组（P<0.05）。多因素有序logistic回归分析结果显示，在3组受试者中，腓总神经硬度、胫神经硬度、腓总神经横截面积均为DPN发病的独立危险因素（OR分别为0.91、0.93、0.75，95%CI分别为0.89~0.95、0.89~0.97、0.58~0.96，P<0.05）。在2组患者中，腓总神经硬度诊断DPN的曲线下面积最大，为0.85（95%CI为0.74~0.92），其最佳截断值为75.29 kPa，最佳截断值下的敏感度为76.32%、特异度为90.00%。在DPN组患者中，腓总神经硬度、腓总神经横截面积均与TCSS评分呈显著正相关（rs值分别为0.83、0.89，P<0.05）。 结论： SWE在评估2型糖尿病患者周围神经硬度方面表现优异，其中SWE测量的腓总神经硬度对患者并发DPN具有较高的诊断价值，并与临床严重程度相关，可作为DPN早期筛查和病情评估的辅助影像学指标。.
Objective: To investigate the clinicopathological, immunophenotypic, and molecular characteristics of gastrointestinal Langerhans cell histiocytosis (LCH). Methods: A total of 12 patients diagnosed with gastrointestinal LCH from July 2021 to September 2025 were retrieved from the pathological archive database of the First Affiliated Hospital, Zhejiang University School of Medicine, among whom 10 cases were external consultation specimens. Clinical data of these patients were collected, lesion locations, endoscopic findings, histopathologic features, treatment strategies, and follow-up outcomes were systematically analyzed for all cases. Immunohistochemical staining was performed to detect the expression of CD1a, Langerin, S-100, cyclin D1, BRAF V600E and so on, followed by a comprehensive review of relevant literatures. Results: A total of 12 patients were enrolled, including 9 males and 3 females, with an age of 34.5 (26.0, 51.0) years. Lesions predominantly involved the upper gastrointestinal tract (11 out of 12 cases, gastric involvement observed in 10 cases). Endoscopically, 6 of 12 cases presented as polypoid lesions, 3 of 12 cases were flat/depressed lesions and no obvious mucosal lesions were identified in the remaining 3 patients. The key histological findings were sheets of tumor cells displaying reniform or coffee bean-shaped nuclei, and the adjacent stroma was associated with mixed inflammatory cell infiltration, with eosinophils as a prominent constituent. Immunophenotypically, all 12 cases were positive for CD1a, Langerin and S-100; cyclin D1 was positive in 8 out of 10 cases, and BRAF V600E was positive in 6 out of 10 cases. One case showed BRAF V600E point mutation by ARMS-PCR. All patients were diagnosed via biopsy and subsequently received local treatment or regular follow-up observation. The follow-up duration ranged from 3 to 54 months. All patients remained disease-free during follow-up, except for one case that developed multifocal lesions within the same system. Conclusions: Gastrointestinal LCH follows an indolent clinical course with a favorable prognosis. Characteristic histopathologic features include tumor cells with reniform or coffee bean-shaped nuclei and stromal infiltration by eosinophils. The triple immunohistochemistry panel consisting of CD1a, Langerin and S-100 serves as the cornerstone for definitive diagnosis, whereas combined assessment of cyclin D1 and BRAF V600E help confirm the neoplastic nature of the lesion. 目的： 探讨消化道朗格汉斯细胞组织细胞增生症（LCH）的临床病理、免疫表型及分子特征。 方法： 回顾性分析浙江大学医学院附属第一医院病理科2021年7月至2025年9月确诊的消化道LCH病例共12例，其中10例为外院会诊病例。收集患者的临床资料，系统分析其病变部位、胃肠镜表现、病理形态、治疗方案及随访结局；采用免疫组织化学染色检测CD1a、Langerin、S-100蛋白、cyclin D1及BRAF V600E等的表达水平并复习相关文献。 结果： 12例患者中男性9例，女性3例，年龄34.5（26.0，51.0）岁，病变以累及上消化道为主（11/12，其中累及胃10例）。胃肠镜下6例表现为隆起性病变，3例为平坦/凹陷性病变，3例未见明显病灶。组织学特征为瘤细胞核呈肾形或咖啡豆样，片状生长，间质伴嗜酸性粒细胞浸润的混合性炎性细胞；免疫表型：瘤细胞CD1a、Langerin、S-100蛋白12例阳性表达，8例cyclin D1和6例BRAF V600E免疫组织化学染色阳性。扩增阻滞突变系统PCR检测显示1例BRAF V600E突变。12例患者均行活检确诊，予局部治疗或定期随访观察；随访3~54个月，除1例出现同系统多灶性病变外，均无进展、复发及其他系统病变。 结论： 消化道LCH呈惰性生长，预后较好。病理特征以肾形核和咖啡豆样核为显著特征，间质伴嗜酸性粒细胞浸润。CD1a、Langerin、S-100蛋白三联免疫组织化学检测可作为确诊核心手段，cyclin D1与BRAF V600E联合检测可辅助明确肿瘤性增生。.
Heyde syndrome (HS) is defined as the association between severe aortic valve stenosis and angiodysplasias (AD)-related bleeding. It is thought to occur as a consequence of an acquired type 2A von Willebrand disease, promoted by the high shear stress generated by the stenotic valve. It appears to be an underdiagnosed condition. We report a case of HS in which gastrointestinal (GI) bleeding was identified in duodenal and jejunal AD. Bleeding was successfully treated with argon plasma coagulation. Additionally, the patient underwent a transcatheter aortic valve implantation, after which he experienced improvement in heart failure symptoms and no further episodes of GI bleeding.
In the context of stalled progress in reducing malaria burden and ongoing efforts to develop novel vector control methods, there is ongoing debate about the impact of livestock on malaria transmission. Zooprophylaxis refers to the use of livestock as an alternate source of blood that diverts mosquito vectors away from humans, potentially reducing malaria transmission. However, conflicting evidence highlights the concept of zoopotentiation, where livestock may instead increase vector populations and enhance malaria transmission. Prior studies that explore these concepts have examined livestock as a household asset, which does not account for the geospatial effect of animals owned by neighbours around the home. We implemented a novel spatial approach to explore the impact of cattle on the risk of malarial infection in coastal Kenya. Using data with high granularity from a recent randomised controlled trial, we measured the presence of animals at increasing concentric areas around the household. We fit binomial regression models with generalised estimating equations to explore how cattle density and cattle-to-human-ratio measures were related to malaria prevalence in children 5-15 years old, accounting for relevant environmental and socio-economic variables. Our findings show that cattle density measured at 400, 500, and 600 m around the household (ORs: 1.63, 95% CI 1.20 to 2.21; 1.84, 95% CI 1.21 to 2.80 and 2.04, 95% CI 1.13 to 3.67, respectively) and cattle-to-human ratio at 500 and 600 m (ORs: 2.73, 95% CI 1.45 to 5.41 and 2.32, 95% CI 1.11 to 4.86, respectively) are significantly related to higher odds of testing positive for malaria. We did not find a significant association at closer distances (<400 m) or when cattle were evaluated only as a household asset. To better understand the impact of livestock on malaria transmission and potentially develop vector control strategies that account for these impacts, future research should consider animals as an environmental exposure and not only as a household asset.
This review analyzes the structure and content of the two-axis classification systems for hyperkinetic disorders. The first classification was developed for dystonia in 2013, a tremor classification appeared in 2018, and a myoclonus classification in 2025, together with a revision of the 2013 dystonia classification. In all these classifications, Axis I refers to clinical characteristics, and Axis II to etiology. However, for myoclonus there is also an Axis Ib dedicated to neurophysiology. The clinical features of dystonia are recognized by clinical assessment, whereas in the case of tremor, and particularly of myoclonus, neurophysiology plays a relevant role. In the tremor and myoclonus classifications, neurophysiology is included as an Axis I descriptor aside clinical assessment. The positioning of other laboratory tests differs among classifications. Neuroimaging is an etiological Axis II division in dystonia, whereas it is included aside other laboratory tests under Axis I in the tremor and myoclonus classifications. The results of genetic testing are included under Axis II in the dystonia and tremor classifications, instead under Axis I in the myoclonus classification. The positioning of functional movement disorders also differs, and for myoclonus a new Axis II etiology of "functional neurological disorders" has been added. These classification exercises highlight the specificity of different hyperkinetic disorders on the background of a comparable two-axis structure.
To compare the effectiveness and safety of interleukin 6 receptor inhibitors (IL-6Ris) and conventional synthetic immunomodulators (csIM) in patients with polymyalgia rheumatica (PMR) who received glucocorticoids (GC) and initiated a new therapy for PMR. We evaluated the effectiveness and safety of IL-6Ris in a retrospective comparative cohort created from the US Medicare fee-for-service medical and part D prescription claims data. Patients with PMR, on GC, without prior IL-6Ri exposure and initiating IL-6Ri/csIM therapy were identified. These patients were categorised into csIM-naïve and csIM-experienced cohorts and matched using direct methods and propensity score methods. Primary endpoints were time-to-GC discontinuation and time-to-minimal GC use (≤2 mg/day or stop GC) through year 1. Incidence rates (IRs) for adverse events of special interest were reported for IL-6Ri and csIM initiators through year 2. We included 415 matched treatment pairs (187/228, csIM-naïve/csIM-experienced). IL-6Ri initiators were more likely to discontinue GC (adjusted HR (aHR) 1.28, 95% CI 1.02 to 1.60; p=0.031) or achieve minimal GC use (aHR 1.28, 95% CI 1.03 to 1.58; p=0.025) by year 1 versus csIM initiators. At year 1, IR (95% CI)/100 patient-years for primary hospitalised infections was higher for IL-6Ri initiators versus csIM initiators (12.2 (95% CI 8.9 to 16.3) vs 5.7 (95% CI 3.6 to 8.6)); however, it was similar for year 2 (5.8 (95% CI 3.3 to 9.6) vs 6.4 (95% CI 3.8 to 10.1)). For other events of interest, the IRs were low and comparable in both groups. IL-6Ri therapy was more effective as a steroid-sparing agent than csIM for PMR with no new safety findings.
How the energy status of enteric progenitors controls neurogliogenesis and the subsequent formation of the complex enteric nervous system (ENS) remains poorly understood. We previously showed that the tumor suppressor kinase LKB1 is essential for postnatal ENS maintenance through amino acid homeostasis. Here, we investigated LKB1's functions during embryonic ENS formation using a genetically engineered mouse model with conditional Lkb1 inactivation in neural crest progenitors during gut colonization. Using advanced 3D imaging techniques on cleared tissue including light sheet microscopy and adaptive optics confocal microscopy, we found that Lkb1 loss impairs early neuronal differentiation followed by progressive glial degeneration, leading to hypoganglionosis and compromised digestive tissue integrity. Notably, Lkb1 inactivation induced a transient upregulation of the glial stress marker S100β during gestation, suggestive of a reactive glial state preceding glial loss. Consistent with this response, Lkb1 loss elevated oxidative stress in the digestive tract and in neural crest progenitors and their glial derivatives, triggering DNA damage and p53 activation. Although p53 ablation rescued glial specification in vitro and glial maintenance in vivo, it only partially restored ENS architecture in vivo without rescuing enteric neuron numbers. Together, these findings establish LKB1 as a critical metabolic checkpoint governing neuronal-glial balance during ENS development and suggest that dysregulated LKB1 signaling may contribute to human enteric neurogliopathies.
Condyloma acuminata is an uncommon epithelial proliferative and infiltrative growth associated with human papillomavirus (HPV) subtypes 6 and 11. Giant condyloma acuminata is a more aggressive variant characterised by extensive growth, anatomical disfigurement, psychosocial morbidity and a high recurrence rate. Extragenital involvement in an immunocompetent individual is uncommonly reported in the literature. We report a case of an immunocompetent young woman who developed a rapidly progressive verrucous growth involving the vulva, lower vagina, perianal region and also extragenital sites (inframammary fold and axilla). Pelvic MRI demonstrated a large exophytic lesion without underlying stromal involvement. Complete surgical excision with histopathological confirmation demonstrated condyloma acuminata with low-risk HPV type 11. Early recurrence occurred within 3 months, which was managed by topical medication. This case highlights the importance of clinical examination, the role of MRI followed by surgical excision with long-term follow-up even in immunocompetent patients.
The Jagged1 (JAG1) gene is essential for cardiac development, yet its tissue-specific transcriptional regulation remains poorly understood. In this study we used an integrative screening approach to identify 19 candidate enhancers within the ±100 kb region flanking the JAG1 locus, among which R7 exhibited the highest activity in dual-luciferase assays. CRISPR/Cas9-mediated deletion of R7 in AC16 cells significantly reduced JAG1 expression, decreased proliferative and migratory capacities, and increased apoptosis. Mechanistically, R7 deletion altered local chromatin contacts and reduced accessibility at CTCF-bound regions near the JAG1 promoter, accompanied by decreased H3K27ac, H3K4me3, RNA polymerase II, and SRF occupancy. These findings identify R7 as a cardiac-associated promoter-proximal regulatory element with enhancer-like activity that contributes to local chromatin organization and transcriptional activity at the JAG1 locus.
Enzalutamide is a cornerstone therapy for castration-resistant prostate cancer (CRPC), yet acquired resistance remains a major clinical challenge. Although metabolic enzymes are increasingly recognized as modulators of therapeutic response, their specific roles-particularly their non-enzymatic functions-in sustaining enzalutamide resistance remain incompletely understood. In this study, we performed an in vivo screen using a custom metabolic CRISPR library in enzalutamide-treated xenografts and identified the pentose phosphate pathway enzyme ribulose-5-phosphate 3-epimerase (RPE) as a critical driver of enzalutamide resistance. Silencing RPE markedly restored enzalutamide sensitivity, enhanced apoptosis in vitro, and significantly suppressed tumor growth in both cell line-derived and patient-derived xenograft models. Mechanistically, RPE promoted resistance independently of its canonical enzymatic activity. Instead, RPE physically interacted with FKBP5 and promoted its ubiquitin-proteasome-mediated degradation. Loss of FKBP5 subsequently hyperactivated AKT signaling, leading to increased p-BAD and BCL-xL levels and suppression of enzalutamide-induced cell death. Conversely, disrupting the RPE-FKBP5 interaction or silencing RPE in vivo using a PSMA-targeted lipid nanoparticle system effectively abrogated these resistance phenotypes. Together, these findings illustrate how CRPC cells hijack the non-enzymatic function of a metabolic enzyme to evade antiandrogen therapy, establishing the RPE-driven degradation of FKBP5 and consequent AKT hyperactivation as a targetable vulnerability for overcoming enzalutamide resistance.
目的： 探讨应用MYB分离探针进行荧光原位杂交（FISH）检测出现不典型信号模式在腺样囊性癌中的解读方法。 方法： 纳入2022年8月至2025年8月在苏州大学附属第一医院病理科使用MYB分离探针进行FISH检测且信号模式不典型的腺样囊性癌病例6例，同时使用MYB/NFIB融合探针及靶向RNA测序法验证MYB基因易位情况。 结果： 6例MYB不典型信号模式病例中，3例信号模式为1个融合信号和1个红色信号，其余3例信号模式为1个融合信号和1个绿色信号。使用MYB/NFIB融合探针FISH法验证，6例标本均为MYB/NFIB融合阳性；使用靶向RNA二代测序法验证，3例信号模式为1个融合信号和1个红色信号的病例均为MYB/NFIB融合阳性，3例信号模式为1个融合信号和1个绿色信号的病例均为MYB/NFIB融合阴性。 结论： MYB分离探针FISH检测信号模式为1个融合信号和1个红色信号的腺样囊性癌病例，MYB基因发生易位，形成MYB/NFIB融合基因；信号模式为1个融合信号和1个绿色信号的腺样囊性癌病例，MYB/NFIB融合探针检测结果为阳性、靶向RNA测序结果为阴性，可能与RNA测序试剂盒捕获探针覆盖范围外MYB基因罕见位点断裂或MYB基因邻近区域位点断裂有关。.
Beneficial plant-microbe associations (BMAs) offer a valuable opportunity to reduce dependence on synthetic inputs. However, traditional breeding has rarely targeted traits that enhance beneficial interactions, and conventional agricultural practices have often degraded soil health and microbial diversity. We present a framework that combines breeding for traits that facilitate BMA with soil management practices that enrich BMA. This approach integrates advanced breeding technologies with strategies for precise production and inoculation of microbes. Strengthening these complementary plant- and microbe-centered approaches and encouraging their adoption by farmers can foster more resilient and productive agricultural systems with reduced dependence on pesticides and fertilizers.
Protein-losing enteropathy (PLE) is a rare syndrome characterized by excessive, nonspecific loss of serum proteins through the gastrointestinal tract. More than 60 distinct conditions across organ systems have been associated with PLE. The presentation is often nonspecific-manifesting as edema, diarrhea, or malnutrition-leading to delayed recognition. Protein-losing enteropathy arises through mucosal injury or lymphatic dysfunction. Evaluation requires exclusion of hepatic, renal, and nutritional causes, followed by targeted testing with stool α1-antitrypsin and upper or lower endoscopy. Early identification enables prompt management of nutritional, immune, and thrombotic complications while also facilitating the detection of secondary causes that may be treatable or reversible. This review provides a practical overview of PLE's pathophysiologic mechanisms, clinical features, diagnostic approach, and indications for subspeciality referral.