Soil Application of Bacillus subtilis Regulates Flavonoid and Alkaloids Biosynthesis in Mulberry Leaves.

Flavonoids and alkaloids are the major active ingredients in mulberry leaves that have outstanding medicinal value. Bacillus subtilis can effectively activate the plants defense response and regulate the plant secondary metabolism. In this study, we explored the effects of soil application of B. subtilis on the content of flavonoids and the most important alkaloids (1-deoxynojirimycin, DNJ) in mulberry leaves. Significant decreases in flavonoid content were observed in tender leaves and mature leaves after treatment with B. subtilis; at the same time, significant increases in DNJ content were observed in tender leaves. Based on widely targeted LC-MS/MS and high-throughput approaches, we screened out 904 differentially synthesized metabolites (DSMs) and 9715 differentially expressed genes (DEGs). KEGG analyses showed that these DSMs and DEGs were both significantly enriched in the biosynthesis of secondary metabolites, flavonoid synthesis and plant hormone signal transduction. Further correlation analysis of DEMs and DEGs showed that 40 key genes were involved in flavonoid biosynthesis, with 6 key genes involved in DNJ biosynthesis. The expression of CHS, CHI, F3H, F3'H, FLS, UGT and AOC significantly responded to B. subtilis soil application. This study broadens our understanding of the molecular mechanisms underlying the accumulation of flavonoids and alkaloids in mulberry leaves.

[Research on Locating Device for the Entry Point of Intramedullary Nail Based on Inertial Navigation].

Objective: To introduce a locating device for the entry point of intramedullary nail based on the inertial navigation technology, which utilizes multi-dimensional angle information to assist in rapid and accurate positioning of the ideal direction of femoral anterograde intramedullary nails' entry point, and to verify its clinical value through clinical tests. Methods: After matching the locating module with the developing board, which are the two components of the locating device, they were placed on the skin surface of the proximal femur of the affected side. Anteroposterior fluoroscopy was performed. The developing angle corresponding to the ideal direction of entry point was selected based on the X-ray image, and then the yaw angle of the locating module was reset to zero. After resetting, the locating module was combined with the surgical instrument to guide the insertion angle of the guide wire. The ideal direction of entry point was accurately located based on the angle guidance. By setting up an experimental group and a control group for clinical surgical operations, the number of guide wire insertion times, surgical time, fluoroscopy frequency, and intraoperative blood loss with or without the locating device was recorded. Results: Compared to the control group, the experimental group showed significant improvement in the number of guide wire insertion times, surgical time, fluoroscopy frequency, and intraoperative blood loss, with a statistically significant difference (P<0.01). Conclusion: The locating device can assist doctors in quickly locating the entry point of intramedullary nail, effectively reducing the fluoroscopy frequency and surgical time by improving the success rate of the guide wire insertion with one shot, improving surgical efficiency, and possessing certain clinical value.

Datasets-Based IMPDH1 Revisited: Heterozygous Missense Variants for Dominant Retinitis Pigmentosa While Truncation Variants Are Likely Non-Pathogenic.

PURPOSE: Heterozygous variants of IMPDH1 are associated with autosomal dominant retinitis pigmentosa (adRP). The current study aims to investigate the characteristics of the adRP-associated variants. METHODS: IMPDH1 variants from our exome sequencing dataset were retrieved and systemically evaluated through multiple online prediction tools, comparative genomics (in-house dataset, HGMD, and gnomAD), and phenotypic association. Potential pathogenic variants (PPVs) were further confirmed by Sanger sequencing and segregation analysis. RESULTS: In total, seven heterozygous PPVs (six missenses and one inframe) were identified in 10 families with RP, in which six of the seven might be classified as pathogenic or likely pathogenic while one others as variants of uncertain significance. IMPDH1 variants contributed to 0.7% (10/1519) of RP families in our cohort, ranking the top four genes implicated in adRP. These adRP-associated variants were located in exons 8-10, a region within or downstream of the CBS domain. All these variants were predicted to be damaged by at least three of the six online prediction tools. Two truncation variants were considered non-pathogenic. Hitherto, 41 heterozygous variants of IMPDH1 were detected in 110 families in published literature, including 33 missenses, two inframes, and six truncations (including a synonymous variant affecting splicing). Of the 35 missense and inframe variants, most were clustered in exons 8-10 (77.1%, 27/35), including 18 (51.4%, 18/35) in exon 10 accounting for 70.9% (78/110) of the families. However, truncation variants were enriched in the general population with a pLI value of 0 (tolerated), and the reported variants in patients with RP did not cluster in specific region. CONCLUSIONS: Our data together with comprehensive analysis of existing datasets suggest that causative variants of IMPDH1 are usually missense and mostly clustered in exons 8-10. Conversely, most missense variants outside this region and truncation variants should be interpreted with great care in clinical gene test.

Optimization of ultrasound-assisted extraction of Imperata cylindrica polysaccharides and evaluation of its anti-oxidant and amelioration of uric acid stimulated cell apoptosis.

An efficient, cost-effective and environmentally friendly ultrasound-assisted hot water method for Imperata cylindrica polysaccharide (ICPs) extraction was developed. According to the response surface results, the optimal ultrasonic time was 85 min, ultrasonic power was 192.75 W, temperature was 90.74 °C, liquid-solid ratio was 26.1, and polysaccharide yield was 28.50 %. The polysaccharide mainly consisted of arabinose (Ara), galactose (Gal), and glucose (Glc), with a molecular weight of 62.3 kDa. Ultrasound-assisted extraction of Imperata cylindrica polysaccharide (UICP) exhibited stronger anti-oxidant activity and ability to ameliorate cellular damage due to uric acid stimulation compared with traditional hot water extraction of Imperata cylindrica polysaccharide (ICPC-b). It also exhibited higher thermal stability, indicating its potential value for applications in the food industry.

Genome-wide identification of cuticle protein superfamily in Frankliniella occidentalis provide insight into the control of both insect vectors and plant virus.

The structural cuticle proteins (CPs) play important roles in the development and fitness of insects. However, knowledge about CP gene superfamily is limited in virus-transmitting insect vectors, although its importance on transmission of plant virus has been gradually emphasized. In this study, the genome-wide identification of CP superfamily was conducted in western flower thrips Frankliniella occidentalis that is the globally invasive pest and plant virus vector pest. The pest transmits notorious tomato spotted wilt virus (TSWV) around the world, causing large damage to a wide array of plants. One hundred and twenty-eight F. occidentalis CP genes (FoCPs) were annotated in this study and they were classified into 10 distinct families, including 68 CPRs, 16 CPAP1s, 6 CPAP3s, 2 CPCFCs, 10 Tweedles, 4 CPFs, 16 CPLCPs, and 6 CPGs. The comprehensive analysis was performed including phylogenetic relationship, gene location and gene expression profiles during different development stages of F. occidentalis. Transcriptome analysis revealed more than 30% FoCPs were upregulated at least 1.5-fold when F. occidentalis was infected by TSWV, indicating their potential involvement in TSWV interactions. Our study provided an overview of F. occidentalis CP superfamily. The study gave a better understand of CP's role in development and virus transmission, which provided clues for reducing viral damages through silencing CP genes in insect vectors.

Overexpression of EphB2 in the basolateral amygdala is crucial for inducing visceral pain sensitization in rats subjected to water avoidance stress.

AIMS: Basolateral amygdala (BLA), as a center for stress responses and emotional regulation, is involved in visceral hypersensitivity of irritable bowel syndrome (IBS) induced by stress. In the present study, we aimed to investigate the role of EphB2 receptor (EphB2) in BLA and explore the underlying mechanisms in this process. METHODS: Visceral hypersensitivity was induced by water avoidance stress (WAS). Elevated plus maze test, forced swimming test, and sucrose preference test were applied to assess anxiety- and depression-like behaviors. Ibotenic acid or lentivirus was used to inactivate BLA in either the induction or maintenance stage of visceral hypersensitivity. The expression of protein was determined by quantitative PCR, immunofluorescence, and western blot. RESULTS: EphB2 expression was increased in BLA in WAS rats. Inactivation of BLA or downregulation of EphB2 in BLA failed to induce visceral hypersensitivity as well as anxiety-like behaviors. However, during the maintenance stage of visceral pain, visceral hypersensitivity was only partially relieved but anxiety-like behaviors were abolished by inactivation of BLA or downregulation of EphB2 in BLA. Chronic WAS increased the expression of EphB2, N-methyl-D-aspartate receptors (NMDARs), and postsynaptic density protein (PSD95) in BLA. Downregulation of EphB2 in BLA reduced NMDARs and PSD95 expression in WAS rats. However, activation of NMDARs after the knockdown of EphB2 expression still triggered visceral hypersensitivity and anxiety-like behaviors. CONCLUSIONS: Taken together, the results suggest that EphB2 in BLA plays an essential role in inducing visceral hypersensitivity. In the maintenance stage, the involvement of EphB2 is crucial but not sufficient. The increase in EphB2 induced by WAS may enhance synaptic plasticity in BLA through upregulating NMDARs, which results in IBS-like symptoms. These findings may give insight into the treatment of IBS and related psychological distress.

Variant and clinical landscape of Leber hereditary optic neuropathy based on 1516 families with mtDNA variants in a tertiary centre.

AIMS: To investigate the clinical characteristics of Leber hereditary optic neuropathy (LHON) with mtDNA primary mutations to better understand features associated with prognosis. METHODS: This study enrolled 1540 LHON patients from 1516 unrelated families genetically confirmed by Sanger or whole-mitochondrial sequencing between 1997 and 2022. The spectrum of variants was summarised and compared in different ethnic groups. Clinical data from outpatients were collected, including onset age, disease course, optic disc categories and the corresponding visual acuity. RESULTS: Of the 1516 LHON families, 13 pathogenic mtDNA variants were detected, in which the proportion of m.11778G>A, m.3460G>A and m.3635G>A was significantly different from non-East Asians (p<0.0001). About 95% (1075/1131) of patients were between 8 and 40 years old at onset, with a median onset age of 16. The eyes of m.14484T>C patients presented with better visual acuity and slower progression across patients with different onset ages and initial severity. Eyes (N=439) with available fundus images were divided into four categories (C1-C4). The progression grades were derived from the category and the corresponding time course, where a higher grade (C3-C4 within 1 year) was associated with greater visual impairment than a lower grade (C1-C2 over 1 year) (p=4.60E-05) . A prognostic matrix showed that later onset and a higher progression grade are associated with higher risk of blindness. CONCLUSION: Compared with non-East Asians, Chinese LHON patients had higher proportions of m.11778G>A and m.3635G>A and lower m.3460G>A mutations. A novel progression grade derived from optic disc category was proposed. The prognostic matrix indicated that lower grade and younger-onset age are the most favourable prognostic factors.

Clinical and Genetic Landscape of Ectopia Lentis Based on a Cohort of Patients From 156 Families.

Purpose: To extend the mutation spectrum and explore the characteristics of genotypes and ocular phenotypes in ectopia lentis (EL). Methods: Variants in all 14 reported EL-associated genes were selected from in-house data sets as well as literature review, and available clinical data were analyzed. Results: Likely pathogenic variants in three genes were identified in 156 unrelated families with EL from the in-house cohort, of which 97.4% resulted from variants in FBN1, whereas the remaining were caused by variants in ADAMTSL4 (1.3%) and LTBP2 (1.3%). A comparative analysis of the in-house data and literature review suggested several characteristics: (1) a higher proportion of cysteine involvement variants in FBN1, either variants introducing or eliminating cysteine, and an earlier diagnosis age were presented in our cohort than in published literature; (2) the axial length (AL) and refractive error increased more rapidly with age in preschool EL children than normal children, and the increased rate of AL was slower in patients with surgery than those without surgery; (3) aberrant astigmatism was common in EL; and (4) worse vision and earlier onset age were observed in patients with non-FBN1 variants (all P < 0.05). Conclusions: Variants in FBN1 are the predominant cause of EL, with the most common cysteine involvement variants. Early-stage EL manifests refractive error but gradually converts to axial myopia through defocus introduced by lens dislocation. Aberrant astigmatism is a suggestive sign of EL. Non-FBN1 variants cause early-onset and severe phenotypes. These results provide evidence for early diagnosis as well as timely treatment for EL.

Utilization of cannulated screw fixation of Jail and TiRobot-assisted percutaneous indirect reduction technique for AO/OTA type 41B2 tibial plateau fracture treatment.

PURPOSE: The present study was designed to investigate the precise procedure and effectiveness of percutaneous minimally invasive fixation assisted by TiRobot in managing AO/OTA type 41B2 tibial plateau fracture to provide an alternative solution for clinical application. METHODS: In total, 10 participants with AO/OTA type 41B2 tibial plateau fractures diagnosed by preoperative imaging examinations were enrolled in this study between May 2019 and May 2022. They were 5 males and 5 females, with an average age of 45.6 ± 11.3 years old (range 27-62 years old). All of them had closed fractures, including 6 cases with anterior cruciate ligament (ACL) tibial insertion avulsion fractures, 1 case with medial collateral ligament (MCL) tear, and 4 cases with a lateral meniscus tear. From injury through surgery, the entire time frame was 4.0 ± 1.5 days (range, 2-7 days). Following indirect percutaneous reduction assisted by TiRobot, the Jail method was used to treat all patients with minimally invasive internal fixation. Patients with ligament or meniscus injurieswere treated with arthroscopic surgery in one stage. The standardized functional exercise was performed postoperatively. The knee function was measured using the Hospital for Special Surgery (HSS) score, and the fracture reduction was assessed through the Rasmussen radiology score. RESULTS: All patients were followed up for 12.7 ± 6.8 months (6-24 months).The fracture healing time was 11.8 ± 0.8 weeks (10-13 weeks), and the X-rays revealed satisfactory fracture reduction.The knee joint's Rasmussen score was 17.8 ± 0.4 (in the range of 17-18) a year after the procedure, with 8 patients receiving outstanding ratings and 2 cases receiving satisfactory scores. The HSS score was 93.8 ± 2.3 (range, 89 to 96), of which 10 cases were excellent. The motion range of the kneewas 138.7°±2.7° (range, -5° to 0° to 135°). No adverse effects or serious complications, such as internal fixation failure, postoperative infection, popliteal vascular injury, and common peroneal nerve injury, were observed during the last follow-up visit. CONCLUSIONS: The intelligent assistance and accurate guidance of TiRobot can simplify and standardize procedures of percutaneous minimally invasive fixation in theSchatzker type Ⅲ tibial plateau fracture treatment. This technique increases the precision of indirect percutaneous reduction and screw fixation while minimizing bone grafting.

Trends and hotspots in research of traumatic brain injury from 2000 to 2022: A bibliometric study.

Traumatic brain injury (TBI) is a major health concern globally, which is characterized by high morbidity and mortality rates. Since the 21st century, TBI has received increasing attention and the number of publications is growing rapidly. This study aimed to characterize the volume and quality of scholarly output on TBI and identify the most impactful literature, research trends, and hotspots from the year 2000-2022. We searched publications on TBI through the Web of Science Core Collection-Science Citation Index Expanded database which were published from 2000 to 2022. Basic information of each paper, including publication year, countries, authors, affiliations, journal, fundings, subject areas, and keywords were collected for further analysis by using Microsoft Excel, VOSviewer, and CiteSpace software. A total of 47231 TBI-related publications were identified through database retrieval. The annual number of publications on TBI has increased steadily over the past twenty years and the number in the year 2022 is sevenfold higher than that in 2000. The United States of America (USA) was the leading country in both numbers of publications and citations, which is consistent with the finding that it had the most funding agencies. Menon DK was the author with the highest influence and the University of California System was the most productive affiliation. Moreover, keywords analysis suggested that the research topics can be mainly divided into six categories: management, rehabilitation, mechanisms, concussion, neuroimaging, and neuroendocrine. This study visualized the trends and focuses of scientific research related to TBI, both quantitatively and qualitatively. The USA had a relatively high academic impact owing to its productive experts and institutions in this field. Neuroinflammation, machine learning, tranexamic acid, and extracellular vesicles are currently hot topics in the field of TBI.

Mechanism of cryptotanshinone to improve endocrine and metabolic functions in the endometrium of PCOS rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Cryptotanshinone is the main bioactive component of Salvia miltiorrhiza, with various mechanisms of action, including antioxidant, anti-inflammatory, cardiovascular protection, neuroprotection, and hepatoprotection. Salvia miltiorrhiza is used clinically by gynecologists in China. AIM OF THE STUDY: Polycystic ovary syndrome (PCOS) has a significant impact on women's quality of life, leading to infertility and reproductive disorders. Hence, this study aims to assess the pharmacological activity of cryptotanshinone in the treatment of PCOS and investigate its therapeutic mechanism. MATERIALS AND METHODS: Human chorionic gonadotropin (HCG) combined with insulin is used to simulate a PCOS-like rat model and attempt to discover the abnormal changes that occur and the means by which the pathway acts in this model. RESULTS: The transcriptome sequencing method is used to identify 292 differential genes that undergo significant changes, of which 219 were upregulated and 73 were downregulated. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the signaling pathways reveals that differential expressed genes are significantly enriched in 23 typical pathways. Estrogen signaling pathways are screened in the cryptotanshinone and model groups, and significant differential changes in Fos, ALOX12, and AQP8 are found. This suggests that these signaling pathways and molecules may be the main signaling targets for regulating the differences in endometrial tissue. CONCLUSION: These results indicate that cryptotanshinone has targets for regulating the proliferation of endometrial tissue via estrogen signaling pathways in PCOS-like rats, providing an experimental basis for the clinical application of cryptotanshinone in the treatment of PCOS.

Sex modifies effects of imaging and CSF biomarkers on cognitive and functional outcomes: a study of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory and functional impairments. Two of 3 patients with AD are biologically female; therefore, the biological underpinnings of this diagnosis disparity may inform interventions slowing the AD progression. To bridge this gap, we conducted analyses of 1078 male and female participants from the Alzheimer's Disease Neuroimaging Initiative to examine associations between levels of cerebral spinal fluid (CSF)/neuroimaging biomarkers and cognitive/functional outcomes. The Chow test was used to quantify sex differences by determining if biological sex affects relationships between the studied biomarkers and outcomes. Multiple magnetic resonance imaging (whole brain, entorhinal cortex, middle temporal gyrus, fusiform gyrus, hippocampus), position emission tomography (AV45), and CSF (P-TAU, TAU) biomarkers were differentially associated with cognitive and functional outcomes. Post-hoc bootstrapped and association analyses confirmed these differential effects and emphasized the necessity of using separate, sex-stratified models. The studied imaging/CSF biomarkers may account for some of the sex-based variation in AD pathophysiology. The identified sex-varying relationships between CSF/imaging biomarkers and cognitive/functional outcomes warrant future biological investigation in independent cohorts.

Forgetfulness as the primary presenting symptom of type A acute aortic dissection.

Acute aortic dissection (AAD) is the most common lethal disease affecting the aorta. Neurological symptoms have been linked to AAD in some patients. Although aortic dissection patients have previously been shown to present with neurological symptoms, AAD with forgetfulness as the first manifestation is extremely rare. To increase the awareness of AAD among clinicians, we report the first case of a male Chinese patient with AD presenting with forgetfulness as the initial symptom. A 53-year-old man presented to the emergency department with forgetfulness. Based on the concept that "time is brain," stroke was initially considered in the differential diagnosis. The patient underwent emergency coronary angiography and was diagnosed with acute myocardial infarction. After contrast-enhanced computed tomography angiography, the patient was finally diagnosed with ADD. Because valuable time was lost in diagnosis rather than treatment, optimal timing for surgery missed. The patient died following an aortic dissection rupture while waiting for emergency surgery. When forgetfulness cannot be completely accounted for in patients presenting with acute myocardial infarction, ADD should be considered. We believe that this case report contains a worthwhile clinical lesson for clinicians.

Hypoxia induced Galectin-8 maintains stemness in glioma stem cells via autophagy regulation.

BACKGROUND: Glioma stem cells (GSCs) are the root cause of relapse and treatment resistance in glioblastoma (GBM). In GSCs, hypoxia in the microenvironment is known to facilitate the maintenance of stem cells, and evolutionally conserved autophagy regulates cell homeostasis to control cell population. The precise involvement of autophagy regulation in hypoxic conditions in maintaining the stemness of GSCs remains unclear. METHODS: The association of autophagy regulation and hypoxia was first assessed by in silico analysis and validation in vitro. Glioma databases and clinical specimens were used to determine galectin-8 (Gal-8) expression in GSCs and human GBMs, and the regulation and function of Gal-8 in stemness maintenance were evaluated by genetic manipulation in vitro and in vivo. How autophagy was stimulated by Gal-8 under hypoxia was systematically investigated. RESULTS: Hypoxia enhances autophagy in GSCs to facilitate self-renewal, and Gal-8 in the galectin family is specifically involved and expressed in GSCs within the hypoxic niche. Gal-8 is highly expressed in GBM and predicts poor survival in patients. Suppression of Gal-8 prevents tumor growth and prolongs survival in mouse models of GBM. Gal-8 binds to the Ragulator-Rag complex at the lysosome membrane and inactivates mTORC1, leading to the nuclear translocation of downstream TFEB and initiation of autophagic lysosomal biogenesis. Consequently, the survival and proliferative activity of GSCs are maintained. CONCLUSIONS: Our findings reveal a novel Gal-8-mTOR-TFEB axis induced by hypoxia in the maintenance of GSC stemness via autophagy reinforcement, highlighting Gal-8 as a candidate for GSCs-targeted GBM therapy.

Icariin improves cardiac function and remodeling via the TGF-ß1/Smad signaling pathway in rats following myocardial infarction.

BACKGROUND: Postinfarction cardiac remodeling presents a compensatory mechanism aimed at mitigating congestive heart failure. It is distinguished by progressive dilatation and hypertrophy of the ventricular chambers, fibrotic alterations, and prolonged apoptosis of cardiomyocytes. The primary objective of this study was to assess the effects of icariin on myocardial fibrosis and ventricular remodeling in rats subjected to myocardial infarction (MI). METHODS: Male Sprague‒Dawley (SD) rats were subjected to randomization and subsequently divided into distinct groups: the control group, the sham group (undergoing sham operation), the MI group (experiencing ligation of the left anterior descending artery), and the icariin group. Within the icariin group, rats were further categorized into three different dose groups based on the administered icariin dosage: the MI30 group (30 mg/kg/day), the MI60 group (60 mg/kg/day), and the MI120 group (120 mg/kg/day). Cardiac function evaluation was carried out using echocardiography. Histological examinations, including hematoxylin and eosin (HE) staining, Masson staining, and immunohistochemistry studies, were conducted 90 days after the occurrence of MI. Additionally, Western blotting was employed to assess TGF-ß1, p-Smad2, and p-Smad3 levels. RESULTS: The administration of icariin revealed a noteworthy enhancement in cardiac function among rats afflicted with left anterior descending coronary artery (LAD) ligation. In comparison to the icariin groups, the MI group exhibited reduced EF and FS, along with elevated LVEDD and LVESD. Furthermore, the cardiac fibrosis levels in the MI group rats exhibited a considerable increase compared to those in the icariin group. Notably, the levels of Collagen I, Collagen III, MMP2, and MMP9 were significantly higher in the MI group than in the icariin group, with evident distinctions. Moreover, the expression levels of TGF-ß, IL-13, p-Smad2, and p-Smad3 were notably upregulated in the MI group compared to the icariin group. CONCLUSIONS: In an experimental rat model of MI, the administration of icariin resulted in the amelioration of both cardiac function and remodeling processes, operating through the intricate TGF-ß1/Smad signaling pathway.

Double Hyperautofluorescence Rings as a Sign of CFAP410-related Retinopathy.

Purpose: Variants in CFAP410 have been reported to cause retinal dystrophy with or without systemic symptoms. This study was designed to characterize the fundus changes of patients with biallelic variants in CFAP410. Methods: Variants in CFAP410 were identified through whole exome sequencing and targeted exome sequencing of 10,530 probands. Biallelic variants in CFAP410 were evaluated by comprehensive in silico analysis and confirmed by Sanger sequencing and segregation analysis. Ocular phenotypes including fundus photographs, scanning laser ophthalmoscopy, autofluorescence images, ERG, and optical coherence tomography were characterized. Results: Nine patients from eight families were homozygotes or compound heterozygotes for a total of four variants in CFAP410, including c.144-6_159del (novel), c.340_351dup, c.347C>T, and c.545+1G>A. Three patients were diagnosed with cone-rod dystrophy, and the remaining six patients with RP. Among eight patients performed with ultra-wide scanning laser ophthalmoscopy, double hyperautofluorescence rings inside and outside of the macular vascular arcades were observed in six patients, and the remaining two older patients demonstrated single hyperautofluorescence ring surrounded by pigmentation. CFAP410-associated retinopathy in early stage was generally tapetoretinal degeneration without noticeable bone spicule pigmentation, with more severe degeneration in the inferior nasal retina. ERG recordings delineated a severely reduced cone response and mildly to severely reduced rod response. Posterior staphyloma was seen in seven patients who underwent optical coherence tomography examinations. Conclusions: The present study demonstrates the fundus characteristics of patients with biallelic variants in CFAP410 and expands the genotype-phenotype spectrum of CFAP410-related retinal degeneration, in which posterior staphyloma together with double hyperautofluorescence rings might be common peculiar signs.

Role of MRPs transporters in pharmacokinetics and intestinal toxicity of irinotecan.

To identify additional genetic markers contributing to variability in CPT-11 disposition and toxicity, we assessed impact of the multiple drug-resistant transporters 1, 2, and 3 (MRP1, MRP2, and MRP3) on the intestinal toxicity, pharmacokinetics, tissue distribution and biliary excretion of CPT-11 using a knockout mouse model. Mrp1/3 knockout had minor impact on intestinal toxicity of CPT-11, tissue distribution, biliary excretion, and PK parameter of its active metabolites SN38. Conversely, Mrp2-/- mice, with low carboxylesterase activity, displayed insensitivity to CPT-11 toxicity due to reduced intestinal exposure to SN38. In PK studies, Mrp1/2 knockout significantly increased the AUC of CPT-11 compared to their AUC in FVB mice. However, the AUC of SN38 in Mrp2 -/- mice was decreased by 3.25-fold. Mrp3 knockout only slightly increased SN38 plasma exposure. Lastly, Mrp2/3 knockout increased biliary excretion amount of CPT-11 by 67.2% and 48.5% compared to wild-type mice, respectively. Consequently, Mrp1/3 deficiency didn't change SN38 tissue distribution. Finally, correlation analysis demonstrated that tissue exposure to SN38 was better correlated with toxicity than plasma AUC of SN38. Mrp1/2/3 deficiency showed a minor impact on PK, biliary excretion, distribution and intestinal exposure of SN38, and as a result, did not affect the intestinal toxicity of CPT-11.

Effects of single and combined contamination of total petroleum hydrocarbons and heavy metals on soil microecosystems: Insights into bacterial diversity, assembly, and ecological function.

Deciphering the impact of single and combined contamination of total petroleum hydrocarbons (TPH) and heavy metals on soil microecosystems is essential for the remediation of contaminated habitats, yet it remains incompletely understood. In this study, we employed high-throughput sequencing to investigate the impact of single TPH contamination, single metal contamination, and their co-contamination on soil microbial diversity, assembly mechanisms, composition, ecological function, and resistome. Our results revealed that contamination led to a reduction in alpha diversity, with single contamination displaying lower diversity compared to co-contamination, depending on the concentration of pollutants. Community beta diversity was primarily driven by turnover rather than nestedness, and narrower ecological niches were detected under pollution conditions. The neutral community model suggested that homogenizing dispersal played a significant role in the community assembly process under single TPH or co-contamination, while homogeneous selection dominated under heavy metals pollution. Procrustes analysis demonstrated a correlation between community composition and functional divergence, while Mantel tests linked this divergence to concentrations of Cr, Cr6+, Pb, and TPH. Interestingly, soils co-polluted with TPH and heavy metals exhibited similar genera, community functions, and resistomes as soils contaminated with only metals, highlighting the significant impact of heavy metals. Ecological functions related to carbon (C), nitrogen (N), and sulfur (S) cycles were enhanced under TPH pollution but impaired under heavy metals stress. These findings enhance our understanding of soil microecosystems subjected to TPH, heavy metals, and their co-contamination, and carry significant implications for environmental microecology and pollutant risk assessment.