Aberrant Modular Segregation of Brain Networks in Patients with Diabetic Retinopathy.

Background: Diabetic retinopathy (DR) is a prevalent ocular manifestation of diabetic microvascular complications and a primary driver of irreversible blindness. Existing studies have illuminated the presence of aberrant brain activity in individuals affected by DR. However, the alterations in the modular segregation of brain networks among DR patients remain inadequately understood. The study aims to explore the modular segregation of brain networks in patients with DR. Methods: We examined the blood oxygen levels dependent (BOLD) signals using resting-state functional magnetic resonance imaging (R-fMRI) in a cohort of 46 DRpatients and 43 age-matched healthy controls (HC). Subsequently, Modular analysis utilizing graph theory method was applied to quantify the degree of brain network segregation by computing the participation coefficient (PC). Deviations from typical PC values were further elucidated through intra- and inter-module connectivity analyses. Results: The DR group demonstrated significantly lower mean PC in the frontoparietal network (FPN), sensorimotor network (SMN), and visual network (VN) compared to the HCgroup. Moreover, increased inter-module connections were observed between the default-mode network (DMN) and SMN, as well as between FPN and VN within the DR group. In terms of nodal analysis, higher PC values were detected in the left thalamus, right frontal lobe, and right precentral gyrus in the DR group compared to the HC group. Conclusion: Patients with DR show impairments in primary sensory networks and higher cognitive networks within their functional brain networks. These changes may provide essential insights into the neurobiological mechanisms of DR by identifying alterations in the brain networks of DR patients and pinpointing sensitive neurobiological markers that could serve as vital imaging references for future treatments of diabetic retinopathy.

Photoinduced Copper-Catalyzed Enantioselective Allylic C(sp3)-H Oxidation of Acyclic 1-Aryl-2-alkyl Alkenes as Limiting Substrates.

Herein, we disclose a simple copper-catalyzed method for enantioselective allylic C(sp3)-H oxidation of unsymmetrical acyclic alkenes, specifically 1-aryl-2-alkyl alkenes. The C-H substrates are used in limiting amounts, and the products are obtained with high enantioselectivity, E/Z-selectivity, and regioselectivity. The method exhibits broad functional group tolerance, and E/Z-alkene mixtures are suitable C-H substrates. The transformation is enabled by light irradiation, which sustains the enantioselective copper catalysis by photoinduced oxidant homolysis.

THBru attenuates diabetic cardiomyopathy by inhibiting RAGE-dependent inflammation.

Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus characterized by heart failure and cardiac remodeling. Previous studies show that tetrahydroberberrubine (THBru) retrogrades cardiac aging by promoting PHB2-mediated mitochondrial autophagy and prevents peritoneal adhesion by suppressing inflammation. In this study we investigated whether THBru exerted protective effect against DCM in db/db mice and potential mechanisms. Eight-week-old male db/db mice were administered THBru (25, 50 mg·kg-1·d-1, i.g.) for 12 weeks. Cardiac function was assessed using echocardiography. We showed that THBru administration significantly improved both cardiac systolic and diastolic function, as well as attenuated cardiac remodeling in db/db mice. In primary neonatal mouse cardiomyocytes (NMCMs), THBru (20, 40 µM) dose-dependently ameliorated high glucose (HG)-induced cell damage, hypertrophy, inflammatory cytokines release, and reactive oxygen species (ROS) production. Using Autodock, surface plasmon resonance (SPR) and DARTS analyses, we revealed that THBru bound to the domain of the receptor for advanced glycosylation end products (RAGE), subsequently leading to inactivation of the PI3K/AKT/NF-κB pathway. Importantly, overexpression of RAGE in NMCMs reversed HG-induced inactivation of the PI3K/AKT/NF-κB pathway and subsequently counteracted the beneficial effects mediated by THBru. We conclude that THBru acts as an inhibitor of RAGE, leading to inactivation of the PI3K/AKT/NF-κB pathway. This action effectively alleviates the inflammatory responses and oxidative stress in cardiomyocytes, ultimately leading to ameliorated DCM.

Outcomes Following Different Management of Mycotic Infrarenal Abdominal Aortic Aneurysms.

OBJECTIVE: The objective was to present our experience on managing mycotic infrarenal abdominal aortic aneurysm (MIAAA) through a retrospective cohort study. METHODS: Data of patients with MIAAA managed in our center from July 2016 to October 2022 were retrospectively analyzed. The diagnosis of MIAAA was made based on: (1) preoperative clinical signs of infection; (2) elevated serologic infection parameters; (3) para-aneurysmal infection features on enhanced computed tomography; and (4) positive blood or tissue cultures. All the patients received standard antibiotic therapy. Surgical management including endovascular aneurysm repair (EVAR), initial EVAR followed by open re-operation, and initial open surgical repair (OSR) were conducted according to disease seriosity, physical condition, and patient's will. Infection index and clinical outcome were evaluated during the follow-up time. RESULTS: A total of 23 patients (21 men; averaged=66.3 years, range=49-79 years) were included, with a mean follow-up time of 19.9 months (range=1-75 months). Bacteria culture from blood or tissue specimen was positive in 15 patients (Salmonella, n=8; Escherichia coli, n=3; methicillin-sensitive Staphylococcus aureus [MSSA], n=1; Klebsiella pneumoniae, n=1; Staphylococcus epidermidis, n=1; Mycobacterium tuberculosis, n=1). Seven patients received OSR as the initial surgical intervention, whereas 14 patients chose EVAR instead. The 2 conservatively managed patients (refused surgery) died within 30 days. The 7 patients who received initial OSR survived till now. Among the 14 patients who underwent initial EVAR, infection deteriorated without exception (14/14, 100%). Three of these patients refused re-operation and died within 6 months. Eleven patients received secondary surgical intervention (10 cases of aneurysm and endograft resection, thorough debridement, subclavian to bi-femoral artery bypass, or in situ aorta reconstruction; 1 case of laparoscopic debridement) and 7 survived the follow-up time. The overall mortality rate was 39.1% (9/23). The mortality rates differed greatly following different intervention methods (merely antibiotic management, 100%; initial open operation, 0%; initial EVAR without secondary operation, 100%; initial EVAR plus secondary operation, 36.4%). CONCLUSIONS: Open surgical repair is still the first choice for hemodynamically stable and low-risk patients. Merely EVAR is related with disastrous results, which should be reserved as a temporary alternative for patients with ruptured aneurysms, hemodynamic instability or high surgical risk, and followed by timely secondary OSR. CLINICAL IMPACT: The management of mycotic or primary-infected aortic aneurysm is challenging; treatment remains controversial. Our center has reviewed our experience over the past 6 years and found that open surgical repair is still the first choice for hemodynamically stable and low-risk patients. Merely endovascular aneurysm repair (EVAR) is related with disastrous results, which should be reserved as a temporary alternative for patients with ruptured aneurysms, hemodynamic instability or high surgical risk, and followed by timely secondary open surgical repair.

Recent developments for intermolecular enantioselective amination of non-acidic C(sp3)-H bonds.

Enantioenriched chiral amines are of exceptional importance in the pharmaceutical industry. Recently, several new methods for the installation of these functional groups directly from non-acidic C(sp3)-H bonds by catalytic intermolecular enantioselective amination have been reported. These methods represent significant advances of the field and most of them display high levels of enantioselectivity, utilize the C(sp3)-H substrate as the limiting reagent, feature good functional group tolerance, and show compatibility with late-stage C(sp3)-H amination of advanced substrates. This perspective provides an overview of the recent developments in this rapidly advancing field and outlines possibilities and limitations, which will help identify unsolved challenges and guide future research efforts.

Interpretable, predictive spatio-temporal models via enhanced pairwise directions estimation.

This article concerns predictive modeling for spatio-temporal data as well as model interpretation using data information in space and time. We develop a novel approach based on supervised dimension reduction for such data in order to capture nonlinear mean structures without requiring a prespecified parametric model. In addition to prediction as a common interest, this approach emphasizes the exploration of geometric information from the data. The method of Pairwise Directions Estimation (PDE) is implemented in our approach as a data-driven function searching for spatial patterns and temporal trends. The benefit of using geometric information from the method of PDE is highlighted, which aids effectively in exploring data structures. We further enhance PDE, referring to it as PDE+, by incorporating kriging to estimate the random effects not explained in the mean functions. Our proposal can not only increase prediction accuracy but also improve the interpretation for modeling. Two simulation examples are conducted and comparisons are made with several existing methods. The results demonstrate that the proposed PDE+ method is very useful for exploring and interpreting the patterns and trends for spatio-temporal data. Illustrative applications to two real datasets are also presented.

[Effects of Combined Stress of Polyethylene and Sulfamethazine on Seed Germination, Seedling Growth, and Physiological Characteristics of Soybean].

The combined pollution of antibiotics adsorption by microplastics has become inevitable in soil ecosystems; moreover, the plant biological effects under combined stress remain unclear. This study used soybean variety Jindou 21 as the material and conducted seed germination test and soil-potted seedling experiment to study the effects of different single and combined treatments of polyethylene (PE) and sulfamethazine (SMZ) on seed germination, seedling growth, photosynthetic parameters, chlorophyll fluorescence parameters, and nitrogen metabolism. The results showed that single PE treatment at low levels promoted soybean seed germination and seedling growth physiology; however, inhibited them at a high level. A lower-level PE treatment[10 mg·L-1 (or mg·kg-1)] could promote soybean seed germination, seedling growth, photosynthesis, and nitrogen metabolism, whereas a higher level PE treatment[100 mg·L-1 and 200 mg·L-1 (or mg·kg-1)] had significant inhibition. The single SMZ treatment had different degrees of inhibition on soybean seed germination and seedling growth physiology, and the inhibition degree increased with the increase in SMZ treatment level. Under the different levels of combined treatments of PE and SMZ, adding the lower level PE treatment could alleviate the inhibition of the single SMZ treatment on soybean, with 10 mg·L-1(or mg·kg-1) PE+1 mg·L-1(or mg·kg-1) SMZ treatment having the best comprehensive mitigation effect, which could increase soybean seed germination potential, germination rate, germination index, vigor index, plant height, root length, shoot and root fresh weight, Pn, Gs, Tr, chlorophyll contents, Fv/Fm, ΦPSⅡ, ETR, qP, and key enzyme activities for nitrogen metabolism such as NR and decrease the average germination time, Ci, NPQ, and NO3--N and NH4+-N contents compared with those in the single SMZ treatment. Adding the higher level PE treatment enhanced the inhibition of SMZ on soybean, and the inhibition degree increased with the increase in SMZ treatment level, in which 200 mg·L-1(or mg·kg-1) PE+50 mg·L-1(or mg·kg-1) SMZ treatment yielded the greatest inhibition. In summary, the lower level PE treatment could alleviate the inhibition of SMZ on soybean seeds and seedlings to a certain extent; however, the higher level PE treatment could produce a synergistic effect with SMZ, thus aggravating the toxic effect of the single stress treatment.

A core-shell structure ratiometric fluorescent probe based on carbon dots and Tb3+ for the detection of anthrax biomarker.

A novel core-shell structure ratiometric fluorescent probe was developed, which can selectively and sensitively detect 2,6-dipicolinic acid (DPA) as an anthrax biomarker. Carbon dots (CDs) was embedded into SiO2 nanoparticles, which was acted as an internal reference signal. Tb3+ with green emission was connected to the carboxyl functionalized SiO2, which was acted as a responsive signal. With the addition of DPA, the emission of CDs at 340 nm was unchanged, while the fluorescence of Tb3+ at 544 nm was enhanced by the antenna effect. In the concentration range of 0.1-2 µM, the fluorescence intensity ratio of I544/I340 showed a good linear relationship with the concentration of DPA, and the limit of detection (LOD) was 10.2 nM. In addition, the dual-emission probe showed an obvious fluorescence color change from colourless to green with increasing DPA under UV light, which enabled visual detection.

Fluorescence on and off sensing platform based on europium nanosheets for the detection of DPA and Cu2+ ions.

With the development of society, the modern environment has put forward higher requirements for analysis and detection. This work proposes a new strategy for the construction of fluorescent sensors based on rare-earth nanosheets. Organic/inorganic composites were obtained by the intercalation of 4,4'-stilbene dicarboxylic acid (SDC) into layered europium hydroxide, and then the composites were exfoliated to form nanosheets. Taking advantage of the fluorescence emission characteristics of SDC and Eu3+, a ratiometric fluorescent nanoprobe was constructed, which realized the detection of dipicolinic acid (DPA) and Cu2+ in the same system. With the addition of DPA, the blue emission of SDC gradually decreased and the red emission of Eu3+ gradually increased, when Cu2+ was added, the emission of SDC and Eu3+ were gradually weakened. The experimental results showed that the ratio of fluorescence emission intensity (I619/I394) of the probe had a positive linear relationship with the concentration of DPA, and a negative linear relationship with the concentration of Cu2+, thus realizing the high sensitivity detection of DPA and a wide detection range of Cu2+. In addition, this sensor also exhibits potential visual detection possibilities. This is a multifunctional fluorescent probe that provides a novel and efficient method for the detection of DPA and Cu2+, which broadens the application field of rare-earth nanosheets.

Surgical treatments of recurrent small intestine metastatic melanoma manifesting with gastrointestinal hemorrhage and intussusception: A case report.

BACKGROUND: Melanoma is the most aggressive form of skin cancer, with a tendency to metastasize to any organ. Malignant melanoma is the most frequent cause of skin cancer-related deaths worldwide. Small intestine cancers especially small intestine metastases are relatively rare. Small intestine metastases are seldom described and likely underdiagnosed. Intussusception is most common in pediatric age, and in adults are almost 5% of all cases. CASE SUMMARY: A 75-year-old man with a history of acral malignant melanoma was admitted to the Gastroenterology Department of our hospital, complaining of intermittent melena for 1 mo. Magnetic resonance enterography showed partial thickening of the jejunal wall and formation of a soft tissue mass, indicating a neoplastic lesion with jejunojejunal intussusception. The patient underwent partial small bowel resection. Pathological findings and immunohistochemical staining indicated small intestine metastatic melanoma. The patient refused further anti-tumor treatment after the surgery. Ten months after the first surgery, the patient presented with melena again. Computed tomography enterography showed the anastomotic stoma was normal without thickening of the intestinal wall, and routine conservative treatment was given. Three months later, the patient developed melena again. The patient underwent a second surgery, and multiple metastatic melanoma lesions were found. The patient refused adjuvant anti-tumor treatment and was alive at the latest follow-up. CONCLUSION: Small intestine metastatic melanoma should be suspected in any patient with a history of malignant melanoma and gastrointestinal symptoms.

Nitidine chloride induces cardiac hypertrophy in mice by targeting autophagy-related 4B cysteine peptidase.

Nitidine chloride (NC) is a standard active component from the traditional Chinese medicine Zanthoxylum nitidum (Roxb.) DC. (ZN). NC has shown a variety of pharmacological activities including anti-tumor activity. As a number of anti-tumor drugs cause cardiotoxicity, herein we investigated whether NC exerted a cardiotoxic effect and the underlying mechanism. Aqueous extract of ZN (ZNE) was intraperitoneally injected into rats, while NC was injected into beagles and mice once daily for 4 weeks. Cardiac function was assessed using echocardiography. We showed that both ZNE administered in rats and NC administered in mice induced dose-dependent cardiac hypertrophy and dysfunction, whereas administration of NC at the middle and high dose caused death in Beagles. Consistently, we observed a reduction of cardiac autophagy levels in NC-treated mice and neonatal mouse cardiomyocytes. Furthermore, we demonstrated that autophagy-related 4B cysteine peptidase (ATG4B) may be a potential target of NC, since overexpression of ATG4B reversed the cardiac hypertrophy and reduced autophagy levels observed in NC-treated mice. We conclude that NC induces cardiac hypertrophy via ATG4B-mediated downregulation of autophagy in mice. Thus, this study provides guidance for the safe clinical application of ZN and the use of NC as an anti-tumor drug.

Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy.

Heart aging is characterized by left ventricular hypertrophy and diastolic dysfunction, which in turn induces a variety of cardiovascular diseases. There is still no therapeutic drug to ameliorate cardiac abnormities in heart aging. In this study we investigated the protective effects of berberine (BBR) and its derivative tetrahydroberberrubine (THBru) against heart aging process. Heart aging was induced in mice by injection of D-galactose (D-gal, 120 mg · kg-1 · d-1, sc.) for 12 weeks. Meanwhile the mice were orally treated with berberine (50 mg · kg-1 · d-1) or THBru (25, 50 mg · kg-1 · d-1) for 12 weeks. We showed that BBR and THBru treatment significantly mitigated diastolic dysfunction and cardiac remodeling in D-gal-induced aging mice. Furthermore, treatment with BBR (40 µM) and THBru (20, 40 µM) inhibited D-gal-induced senescence in primary neonatal mouse cardiomyocytes in vitro. Overall, THBru exhibited higher efficacy than BBR at the same dose. We found that the levels of mitophagy were significantly decreased during the aging process in vivo and in vitro, THBru and BBR promoted mitophagy with different potencies. We demonstrated that the mitophagy-inducing effects of THBru resulted from increased mRNA stability of prohibitin 2 (PHB2), a pivotal factor during mitophagy, thereby upregulating PHB2 protein expression. Knockdown of PHB2 effectively reversed the antisenescence effects of THBru in D-gal-treated cardiomyocytes. On the contrary, overexpression of PHB2 promoted mitophagy and retarded cardiomyocyte senescence, as THBru did. In conclusion, this study identifies THBru as a potent antiaging medicine that induces PHB2-mediated mitophagy and suggests its clinical application prospects.

Duodenojejunostomy treatment of groove pancreatitis-induced stenosis and obstruction of the horizontal duodenum: A case report.

BACKGROUND: Groove pancreatitis (GP) is a rare condition affecting the pancreatic groove region within the dorsal-cranial part of the pancreatic head, duodenum, and common bile duct. As a rare form of chronic pancreatitis, GP poses a diagnostic and therapeutic challenge for clinicians. GP is frequently misdiagnosed or not considered; thus, the diagnosis is often delayed by weeks or months. The treatment of GP is complicated and often requires surgical intervention, especially pancreatoduodenectomy. CASE SUMMARY: A 66-year-old man with a history of long-term drinking was admitted to the gastroenterology department of our hospital, complaining of vomiting and acid reflux. Upper gastrointestinal endoscopy showed luminal stenosis in the descending part of the duodenum. Abdominal computed tomography showed slight exudation in the descending and horizontal parts of the duodenum with broadening of the groove region, indicating local pancreatitis. The symptoms of intestinal obstruction were not relieved with conservative therapy, and insertion of an enteral feeding tube was not successful. Exploratory laparoscopy was performed and revealed a hard mass with scarring in the horizontal part of the duodenum and stenosis. Intraoperative frozen section analysis showed no evidence of malignancy, and side-to-side duodenojejunostomy was performed. Routine pathologic examination showed massive proliferation of fibrous tissue, hyaline change, and the proliferation of spindle cells. Based on the radiologic and pathologic characteristics, a diagnosis of GP was made. The patient presented with anastomotic obstruction postoperatively and took a long time to recover, requiring supportive therapy. CONCLUSION: GP often involves the descending and horizontal parts of the duodenum and causes duodenal stenosis, impaired duodenal motility, and gastric emptying due to fibrosis.

PD-1/PD-L1 combined with LAG3 is associated with clinical activity of immune checkpoint inhibitors in metastatic primary pulmonary lymphoepithelioma-like carcinoma.

Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is an Epstein-Barr virus (EBV)-related, rare subtype of non-small-cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICI) show durable responses in advanced NSCLC. However, their effects and predictive biomarkers in PLELC remain poorly understood. We retrospectively analyzed the data of 48 metastatic PLELC patients treated with ICI. Pretreated paraffin-embedded specimens (n = 19) were stained for PD-1, PD-L1, LAG3, TIM3, CD3, CD4, CD8, CD68, FOXP3, and cytokeratin (CK) by multiple immunohistochemistry (mIHC). Next-generation sequencing was performed for 33 PLELC samples. Among patients treated with ICI monotherapy (n = 30), the objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and overall survival (mOS) were 13.3%, 80.0%, 7.7 months, and 24.9 months, respectively. Patients with PD-L1 ≥1% showed a longer PFS (8.4 vs. 2.1 months, p = 0.015) relative to those with PD-L1 <1%. Among patients treated with ICI combination therapy (n = 18), ORR, DCR, mPFS, and mOS were 27.8%, 100.0%, 10.1 months, and 19.7 months, respectively. Patients with PD-L1 ≥1% showed a significantly superior OS than those with PD-L1 <1% (NA versus 11.7 months, p = 0.001). Among the 19 mIHC patients, those with high PD-1/PD-L1 and LAG3 expression showed a longer PFS (19.0 vs. 3.9 months, p = 0.003). ICI also showed promising efficacy for treating metastatic PLELC. PD-L1 may be both predictive of ICI treatment efficacy and prognostic for survival in PLELC. PD-1/PD-L1 combined with LAG3 may serve as a predictor of ICI treatment effectiveness in PLELC. Larger and prospective trials are warranted to validate both ICI activity and predictive biomarkers in PLELC. This study was partly presented as a poster at the IASLC 20th World Conference on Lung Cancer 2019, 7-10 September 2019, Barcelona, Spain.

Long-term Follow-up of Patients With Hernia Using the Hernia-Specific Quality-of-Life Mobile App: Feasibility Questionnaire Study.

BACKGROUND: Hernia repair is one of the most common surgical procedures; however, the long-term outcomes are seldom reported due to incomplete follow-up. OBJECTIVE: The aim of this study was to examine the use of a mobile app for the long-term follow-up of hernia recurrence, complication, and quality-of-life perception. METHODS: A cloud-based corroborative system drove a mobile app with the HERQL (Hernia-Specific Quality-of-Life) questionnaire built in. Patients who underwent hernia repair were identified from medical records, and an invitation to participate in this study was sent through the post. RESULTS: The response rate was 11.89% (311/2615) during the 1-year study period, whereas the recurrence rate was 1.0% (3/311). Causal relationships between symptomatic and functional domains of the HERQL questionnaire were indicated by satisfactory model fit indices and significant regression coefficients derived from structural equational modeling. Regarding patients' last hernia surgeries, 88.7% (276/311) of the patients reported them to be satisfactory or very satisfactory, 68.5% (213/311) of patients reported no discomfort, and 61.1% (190/311) of patients never experienced mesh foreign body sensation. Subgroup analysis for the most commonly used mesh repairs found that mesh plug repair inevitably resulted in worse symptoms and quality-of-life perception from the group with groin hernias. CONCLUSIONS: The mobile app has the potential to enhance the quality of care for patients with hernia and facilitate outcomes research with more complete follow-up.

TSC/MTOR -associated Eosinophilic Renal Tumors Exhibit a Heterogeneous Clinicopathologic Spectrum : A Targeted Next-generation Sequencing and Gene Expression Profiling Study.

BACKGROUND: Several TSC1/2- or MTOR -mutated eosinophilic renal tumor subsets are emerging, including eosinophilic solid and cystic renal cell carcinoma (ESC RCC), eosinophilic vacuolated tumors (EVTs) and low-grade oncocytic tumors (LOTs). "Unclassified renal tumors with TSC/MTOR mutations" ( TSC -mt RCC-NOS) do not meet the criteria for other histomolecular subtypes. Whether these tumors represent a continuum of 1 TS C/ MTOR -mutation-associated disease is unknown. DESIGN: We evaluated the clinicopathologic and IHC profiles of 39 eosinophilic renal tumors with targeted DNA sequencing-confirmed TSC/MTOR mutations. Twenty-eight of these, plus 6 ChRCC, 5 RO, 5 ccRCC, 7 MiT RCC and 6 normal renal tissues, were profiled transcriptionally by RNA-seq. RESULTS: The 39 cases were reclassified based on morphological and IHC features as ESC RCC (12), EVT (9), LOT, (8) and TSC -mt RCC-NOS (10). The mutation profiles demonstrated consistency; ESC RCCs (12/12) had TSC mutations, and most LOTs (7/8) had MTOR mutations. Ten TSC -mt RCC-NOSs exhibited heterogeneous morphology, arising a differential diagnosis with other renal tumors, including MiT RCC, PRCC and epithelioid PEComa. RNA sequencing-based clustering segregated ESC RCC, EVT and LOT from each other and other renal tumors, indicating expression profile-level differences. Most TSC- mt RCC-NOSs (6/7) formed a mixed cluster with ESC RCC, indicating similar expression signatures; one TSC- mt RCC-NOS with unusual biphasic morphology clustered with EVT. CONCLUSIONS: We expanded the TSC/MTOR -associated eosinophilic renal tumor morphologic spectrum, identified gene mutation characteristics, and highlighted differential diagnosis challenges, especially with MiT RCC. ESC RCC, EVT, and LOT having distinct expression profiles. TSC -mt RCC-NOS may cluster with recognized TSC/MTOR -associated entities.

Physicochemical properties, molecular structure, antioxidant activity, and biological function of extracellular melanin from Ascosphaera apis.

Ascosphaera apis spores containing a dark-colored pigment infect honeybee larvae, resulting in a large-scale collapse of the bee colony due to chalkbrood disease. However, little is known about the pigment or whether it plays a role in bee infection caused by A. apis. In this study, the pigment was isolated by alkali extraction, acid hydrolysis, and repeated precipitation. Ultraviolet (UV) analysis revealed that the pigment had a color value of 273, a maximum absorption peak at 195 nm, and a high alkaline solubility (7.67%) and acid precipitability. Further chemical structure analysis of the pigment, including elemental composition, Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy, mass spectrometry, and nuclear magnetic resonance (NMR), proved that it was a eumelanin with a typical indole structure. The molecular formula of melanin is C10H6O4N2, and its molecular weight is 409 Da. Melanin has hydroxyl, carboxyl, amino, and phenolic groups that can potentially chelate to metal ions. Antioxidant function analyses showed that A. apis melanin had a high scavenging activity against superoxide, hydroxyl, and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals, and a high reducing ability to Fe3+. Indirect immunofluorescence assay (IFA), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) analyses showed that A. apis melanin was located on the spore wall. The spore wall localization, antioxidant activity, and metal ion chelating properties of fungal melanin have been suggested to contribute to spore pathogenicity. However, further infection experiments showed that melanin-deficient spores did not reduce the mortality of bee larvae, indicating that melanin does not increase the virulence of A. apis spores. This study is the first report on melanin produced by A. apis, providing an important background reference for further study on its role in A. apis.

Direct arylation of N-heterocycles enabled by photoredox catalysis.

N-Heterobiaryls are common skeletons found in biological molecules, pharmaceuticals and ligands. Herein, we document an efficient and redox-neutral photocatalytic system to obtain functionalized N-heterobiaryls under mild conditions. Substrates bearing variegated functional groups are compatible with the developed photocatalytic conditions. This method is translatable to gram-scale synthesis, with a photocatalyst loading as low as 0.1 mol% and minimal variation of the yield. The starting materials are commercially available, demonstrating the practicality and accessibility of this methodology. Interestingly, phenols can serve both as coupling partners and proton donors. Arenes without a phenolic hydroxyl group also underwent efficient coupling with HFIP as a solvent.

Rare-Earth hydroxide nanosheets based ratio fluorescence nanoprobe for dipicolinic acid detection.

We demonstrate a novel ratio fluorescence nanoprobe for dipicolinic acid (DPA) as an anthrax biomarker based on layered rare-earth hydroxide (LRH). 3-Amino-benzenesulfonic acid (AS) was intercalated into layered terbium hydroxide to form composite and then delaminated into nanosheets in formamide. The monolayer nanosheets were beneficial to expose the Ln3+ luminescence centers to the environment more completely, contributing a high sensitive detection to the environment. With the increase of DPA concentration, the emission intensity of AS kept constant which worked as a stable internal reference, while the fluorescence of Tb3+ was enhanced obviously due to the antenna effect. In the 0.05-5.0 µM concentration range, the I544/I360 fluorescence ratio changed with the DPA concentration, which exhibited a good linear relationship (R2 = 0.999) and an ultralow detection limit of 3.8 nM. In addition, the probe showed high selectivity and sensitivity to the DPA detection as an anthrax biomarker, which can be applied in real tap water with good performances. This work could extend the applications of LRH nanosheets in detection and offer an extremely effective and easy technique for detecting DPA.

Deciphering Genetic Alterations of Taiwanese Patients with Pancreatic Adenocarcinoma through Targeted Sequencing.

Pancreatic adenocarcinoma (PAC) is the 8th leading cause of cancer-related deaths in Taiwan, and its incidence is increasing. The development of PAC involves successive accumulation of multiple genetic alterations. Understanding the molecular pathogenesis and heterogeneity of PAC may facilitate personalized treatment for PAC and identify therapeutic agents. We performed tumor-only next-generation sequencing (NGS) with targeted panels to explore the molecular changes underlying PAC patients in Taiwan. The Ion Torrent Oncomine Comprehensive Panel (OCP) was used for PAC metastatic lesions, and more PAC samples were sequenced with the Ion AmpliSeq Cancer Hot Spot (CHP) v2 panel. Five formalin-fixed paraffin-embedded (FFPE) metastatic PAC specimens were successfully assayed with OCP, and KRAS was the most prevalent alteration, which might contraindicate the use of anti-EGFR therapy. One PAC patient harbored a FGFR2 p. C382R mutation, which might benefit from FGFR tyrosine kinase inhibitors. An additional 38 samples assayed with CHP v2 showed 100 hotspot variants, collapsing to 54 COSMID IDs. The most frequently mutated genes were TP53, KRAS, and PDGFRA (29, 23, 10 hotspot variants), impacting 11, 23, and 10 PAC patients. Highly pathogenic variants, including COSM22413 (PDGFRA, FATHMM predicted score: 0.88), COSM520, COSM521, and COSM518 (KRAS, FATHMM predicted score: 0.98), were reported. By using NGS with targeted panels, somatic mutations with therapeutic potential were identified. The combination of clinical and genetic information is useful for decision making and precise selection of targeted medicine.