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In the context of global climate change, one central interest is an improved understanding of the global carbon cycle. A large number of studies have investigated carbon cycling and associated elements, mainly nitrogen and phosphorus. However, as an essential element for diatom growth, Si has been largely ignored. Si is the second most abundant element and is widely distributed on Earth. The chemical weathering of silicates on land and photosynthesis of diatoms in the ocean play an important role in atmospheric CO2 levels at various timescales. Diatoms are the primary producers in the ocean and account for as much as 40% of the annual ocean carbon fixation, which have an absolute requirement for Si to form siliceous cells. The main mechanism underlying ocean carbon sinks is a "biological pump." The biological pump is driven by the biological Si pump to a large extent. Therefore, the biogeochemical process of Si has become one of the key research issues for global environmental change.Based on previous studies, the regulation and influence of the Si biogeochemical cycle on the carbon cycle are discussed in this review. The coupling effect and mechanism of the Si and carbon cycles in shellfish culture ecosystems were analyzed and the key research questions were explored. Chemical weathering of silicates and the cycling of their products form the basis of Si biogeochemistry. CO2 is consumed during weathering reactions. Therefore, silicate weathering on land represents an important sink for atmospheric CO2. Furthermore, at the geological timescale, primary silicate mineral weathering is the source of secondary silicate. Terrestrial plants absorb soluble silica through their root system during growth. Amorphous silica deposited in plant tissue after maturity is called phytolith. Phytoliths have excellent geochemical stability and occlude a certain amount of organic carbon during the formation process. The organic carbon occluded within phytolith is called phytolith-occluded carbon (PhytOC) and is buried in the soil. PhytOC is released into the soil with phytolith and may be preserved in soils for several thousands of years. As a consequence, PhytOC in terrestrial ecosystems could be significant potential carbon sinks globally due to the refractory phytolith. Primarily through river input, the dissolved silicate (DSi) is transported into the coastal ocean (approximately 84% of DSi input to the oceans). As the major primary producer, diatoms absorb DSi during growth and account for a large fraction of the total carbon fixation in the modern oceans. DSi is converted into biogenic silica via biological processes, is transported to the deep ocean, and is finally buried into sediments with organic carbon in the marine ecosystem. Thus, by controlling the contribution of diatoms to the total primary production, DSi can affect the carbon cycle in oceans. The carbon pump is driven by the Si pump.Mariculture has developed quickly in recent decades. Shellfish, which are dominated by filter-feeding species, are the main mariculture species. The filter-feeding shellfish consume particulate organic carbon as phytoplankton and use dissolved inorganic carbon to build their shell during growth. Filter-feeding shellfish are an import fishery carbon sink. As one of the important feed sources of filter-feeding shellfish, diatoms form fishery carbon sinks in coastal shellfish culture areas. Silicate is an essential salt for diatom growth. Consequently, the carbon sink of filter-feeding shellfish culture is connected with DSi through diatoms. Si could play an important role in driving the formation of carbon sinks in filter-feeding shellfish culture. Hence, it is necessary to consider all processes and coupling effects in the study of the Si biogeochemical cycle. It is important to understand its role in the carbon sinks of shellfish culture.Nowadays, in many systems, human perturbation has resulted in a decline in the ratio of Si: N to 1:1 or less, with severe impacts on the quality and structure of aquatic ecosystems. DSi limitation has been reported in many studies, in both coastal and marine waters. DSi limitation causes shifts from diatoms to non-siliceous algae and is supposedly related to the decreasing export of carbon. A shift from diatoms to other species would enhance the recycling of organic matter in the upper water column because diatoms are very effective in carbon sequestration. DSi limitation has also appeared in some aquaculture bays in China, such as Jiaozhou Bay and Laizhou Bay, in spring. Regarding future directions, it is suggested that more research be conducted on Si biogeochemistry in shellfish culture systems and coupling with the carbon cycle. The subsequent results could evaluate the role of Si in the carbon sink of filter-feeding shellfish culture. Future studies are expected to provide ideas for alleviating Si deficiency in the aquaculture bay and exploring the expansion path in shellfish farming.

Abstract Optical chemical structure recognition (OCSR) is a fundamental and crucial task in the field of chemistry, which aims at transforming intricate chemical structure images into machine-readable formats. Current deep learning-based OCSR methods typically use image feature extractors to extract visual features and employ encoder-decoder architectures for chemical structure recognition. However, the performance of these methods is limited by their image feature extractors and the class imbalance of elements in chemical structure representation. This paper proposes MPOCSR (multi-path optical chemical structure recognition), which introduces the multi-path Vision Transformer (MPViT) and the class-balanced (CB) loss function to address these two challenges. MPOCSR uses MPViT as an image feature extractor, combining the advantages of convolutional neural networks and Vision Transformers. This strategy enables the provision of richer visual information for subsequent decoding processes. Furthermore, MPOCSR incorporates CB loss function to rebalance the loss weights among different categories. For training and validation of our method, we constructed a dataset that includes both Markush and non-Markush structures. Experimental results show that MPOCSR achieves an accuracy of 90.95% on the test set, surpassing other existing methods.

Purpose Develop an albumin nanoparticle-based nanoprobe for targeted glioblastoma (GBM) diagnosis and treatment, utilizing Angopep-2 for low-density lipoprotein receptor-related protein (LRP) targeting. Methods Combined albumin-coated superparamagnetic iron oxide (SPIO), Carmustine (BCNU), and indocyanine green (ICG). Assessed morphology, size, Zeta potential, fluorescence, and drug encapsulation. Conducted in vitro fluorescence/MRI imaging and cell viability assays, and in vivo nanoprobe accumulation evaluation in brain tumors. Results ANG-BSA/BCNU/ICG MNPs exhibited superior targeting and cytotoxicity against GBM cells in vitro. In vivo, enhanced brain tumor accumulation during imaging was observed. Conclusion This targeted imaging and drug delivery system holds promise for efficient GBM therapy and intraoperative localization, addressing Blood-brain barrier (BBB) limitations with precise drug delivery and imaging capabilities.

Farmed aquaculture species play an important role in regulating nutrient cycles in farming systems. Compared with nitrogen and phosphorus, the role of farmed species in the silicon (Si) cycle remains poorly understood. To help reduce this uncertainty, we clarified the sources and sinks of silicate and quantified the Si pools in an aquaculture system in Sanggou Bay (SGB). The results showed that dissolved inorganic nutrient levels were significantly lower during the dry season than during the wet. Dissolved silicate (DSi) is a potential limiting factor for phytoplankton growth during spring, and phosphorus limitation occurs during summer. The budget results indicated that large amounts of nitrogen, phosphate (DIP), and DSi were buried in the sediment or transformed into other forms during both the wet and dry seasons. The nitrogen and DIP cycles were strongly influenced by bivalve excretion and farmed species harvesting; however, these processes had little impact on the Si cycle. Si availability depends on both external inputs and internal recycling. DSi was primarily supplied from the Yellow Sea, with a minor contribution from the river due to river discharge during spring. However, during summer, riverine inflow (accounting for 83% of the total influx) was the major DSi source followed by benthic flux (12%). Biogenic silica (BSi) burial efficiency in the sediment was estimated to be 78% during spring and 23% during summer. The BSi preservation efficiency in bivalves during spring was high (53%), leading to a higher Si retention than in river discharge. Bivalves biodeposition plays an important role in the Si burial process. We suggest that this high retention is essentially controlled by the biodeposition mechanism, which is directly controlled by the exotic suspension feeders. Bivalves have the potential to alter Si retention in the bay by producing large amounts of biodeposits and accelerating the silica cycle, which may lead to more carbon dioxide being absorbed by diatoms.

Summary: Background: The accurate evaluation of axillary lymph node (ALN) response to neoadjuvant chemotherapy (NAC) in breast cancer holds great value. This study aimed to develop an artificial intelligence system utilising multiregional dynamic contrast-enhanced MRI (DCE-MRI) and clinicopathological characteristics to predict axillary pathological complete response (pCR) after NAC in breast cancer. Methods: This study included retrospective and prospective datasets from six medical centres in China between May 2018 and December 2023. A fully automated integrated system based on deep learning (FAIS-DL) was built to perform tumour and ALN segmentation and axillary pCR prediction sequentially. The predictive performance of FAIS-DL was assessed using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. RNA sequencing analysis were conducted on 45 patients to explore the biological basis of FAIS-DL. Findings: 1145 patients (mean age, 50 years ±10 [SD]) were evaluated. Among these patients, 506 were in the training and validation sets (axillary pCR rate of 40.3%), 127 in the internal test set (axillary pCR rate of 37.8%), 414 in the pooled external test set (axillary pCR rate of 48.8%), and 98 in the prospective test set (axillary pCR rate of 43.9%). For predicting axillary pCR, FAIS-DL achieved AUCs of 0.95, 0.93, and 0.94 in the internal test set, pooled external test set, and prospective test set, respectively, which were also significantly higher than those of the clinical model and deep learning models based on single-regional DCE-MRI (all P

Abstract We show that the recent construction of N f = 1 baryons on the η′ domain wall can be understood as vortexes of the principal effective theory — the Chern-Simons-Higgs theory — on a 2+1-dimensional sheet. This theory has a series of vortex solutions, and the vortex with unit topological charge naturally spins N c /2, which coincides with the spin of the one-flavor baryon in QCD. Since the N c scaling of the vortexes is the same as that of baryons, the latter can be regarded as the former. By virtue of the particle-vortex symmetry, the dual Zhang-Hansson-Kivelson theory indicates that the quark carries topological charge 1/N c and obeys fractional statistics. The generalization to arbitrary N f is also discussed.

Abstract Background Aberrant fucosylation observed in cancer cells contributes to an augmented release of fucosylated exosomes into the bloodstream, where miRNAs including miR-4732-3p hold promise as potential tumor biomarkers in our pilot study. However, the mechanisms underlying the sorting of miR-4732-3p into fucosylated exosomes during lung cancer progression remain poorly understood. Methods A fucose-captured strategy based on lentil lectin-magnetic beads was utilized to isolate fucosylated exosomes and evaluate the efficiency for capturing tumor-derived exosomes using nanoparticle tracking analysis (NTA). Fluorescence in situ hybridization (FISH) and qRT-PCR were performed to determine the levels of miR-4732-3p in non-small cell lung cancer (NSCLC) tissue samples. A co-culture system was established to assess the release of miRNA via exosomes from NSCLC cells. RNA immunoprecipitation (RIP) and miRNA pull-down were applied to validate the interaction between miR-4732-3p and heterogeneous nuclear ribonucleoprotein K (hnRNPK) protein. Cell functional assays, cell derived xenograft, dual-luciferase reporter experiments, and western blot were applied to examine the effects of miR-4732-3p on MFSD12 and its downstream signaling pathways, and the impact of hnRNPK in NSCLC. Results We enriched exosomes derived from NSCLC cells using the fucose-captured strategy and detected a significant upregulation of miR-4732-3p in fucosylated exosomes present in the serum, while its expression declined in NSCLC tissues. miR-4732-3p functioned as a tumor suppressor in NSCLC by targeting 3'UTR of MFSD12, thereby inhibiting AKT/p21 signaling pathway to induce cell cycle arrest in G2/M phase. NSCLC cells preferentially released miR-4732-3p via exosomes instead of retaining them intracellularly, which was facilitated by the interaction of miR-4732-3p with hnRNPK protein for selective sorting into fucosylated exosomes. Moreover, knockdown of hnRNPK suppressed NSCLC cell proliferation, with the elevated levels of miR-4732-3p in NSCLC tissues but the decreased expression in serum fucosylated exosomes. Conclusions NSCLC cells escape suppressive effects of miR-4732-3p through hnRNPK-mediated sorting of them into fucosylated exosomes, thus supporting cell malignant properties and promoting NSCLC progression. Our study provides a promising biomarker for NSCLC and opens a novel avenue for NSCLC therapy by targeting hnRNPK to prevent the "exosome escape" of tumor-suppressive miR-4732-3p from NSCLC cells.

Abstract Hypomyelinating leukodystrophy (HLD) is a rare genetic heterogeneous disease that can affect myelin development in the central nervous system. This study aims to analyze the clinical phenotype and genetic function of a family with HLD-7 caused by POLR3A mutation. The proband (IV6) in this family mainly showed progressive cognitive decline, dentin dysplasia, and hypogonadotropic hypogonadism. Her three old brothers (IV1, IV2, and IV4) also had different degrees of ataxia, dystonia, or dysarthria besides the aforementioned manifestations. Their brain magnetic resonance imaging showed bilateral periventricular white matter atrophy, brain atrophy, and corpus callosum atrophy and thinning. The proband and her two living brothers (IV2 and IV4) were detected to carry a homozygous mutation of the POLR3A (NM_007055.4) gene c. 2300G > T (p.Cys767Phe), and her consanguineous married parents (III1 and III2) were p.Cys767Phe heterozygous carriers. In the constructed POLR3A wild-type and p.Cys767Phe mutant cells, it was seen that overexpression of wild-type POLR3A protein significantly enhanced Pol III transcription of 5S rRNA and tRNA Leu-CAA. However, although the mutant POLR3A protein overexpression was increased compared to the wild-type protein overexpression, it did not show the expected further enhancement of Pol III function. On the contrary, Pol III transcription function was frustrated (POLR3A, BC200, and tRNA Leu-CAA expression decreased), and MBP and 18S rRNA expressions were decreased. This study indicates that the POLR3A p.Cys767Phe variant caused increased expression of mutated POLR3A protein and abnormal expression of Pol III transcripts, and the mutant POLR3A protein function was abnormal.

[ Objective ] From the aspect of species representativeness and diversity , the article aims to pro- vide evidence for plant diversity conservation and plant resource utilization in Qinghai area of the Kunlun Mountain National Park. [ Methods ] Based on field surveys , historical data , and literatures , we sorted out a list of seed plants in the assessment area and analyzed the composition , dominant taxa , geographic com- ponent , and endangered species of seed flora. [ Results ] ( 1 ) There was a total of 46 families , 146 genera , and 384 species of seed plants in Qinghai area of the Kunlun Mountain National Park , including 3 families , 3 genera , and 5 species of gymnosperms as well as 43 families , 143 genera , and 379 species of angio- sperms. The 4 families included Amaranthaceae , Asteraceae , Fabaceae and Poaceae occupy an important position in the seed flora of the assessed area , where monospecie and oligospecie constitute the main part of the family. ( 2 ) The dominant phenomenon of the seed plant family and genus was obvious in this area with 8 dominant families and 36 dominant genera , where 6 large genera had more than 10 species including Astragalus , Oxytropis , Artemisia , Saussurea , Poa , and Carex . ( 3 ) The areal-type of the families in this seed flora was mainly cosmopolitan , which was showing a temperate nature. The areal-type of genera was mainly temperate distribution with a close connection to the Laurasia. ( 4 ) There were 4 species of na- tional Grade Ⅱ protected wild plants , 8 species of Qinghai Province protected plants , and 6 species listed in “ China􀆴s Red List of Biodiversity ” . [ Conclusion ] The Qinghai area of the Kunlun National Park has di- verse geographical composition , but the endemic phenomenon is not obvious. The biodiversity is low. The floral composition shows the characteristics of arid to semi-arid transition and temperate to tropical transi- tion in the horizontal gradient.

Abstract Objective ω-3 polyunsaturated fatty acids (PUFA) are a key modifiable factor in the intervention of type 2 diabetes, yet recommendations for dietary consumption of ω-3 PUFA in type 2 diabetes remain ambiguous and controversial. Here, we revisit the subject in the light of population pharmacokinetic-pharmacodynamic (PPK-PD) modeling and propose a threshold for intake. Research design and methods Plasma levels of ω-3 PUFA and glycosylated hemoglobin (HbA1c) were measured as pharmacokinetic and pharmacodynamic indicator, respectively. The nonlinear mixed effect analysis was used to construct a PPK-PD model for ω-3 PUFA and to quantify the effects of FADS gene polymorphism, age, liver and kidney function, and other covariables. Results Data from 161 patients with type 2 diabetes in the community were modeled in a two-compartment model with primary elimination, and HDL was a statistically significant covariate. The simulation results showed that HbA1c showed a dose-dependent decrease of ω-3 PUFA plasma level. A daily intake of ω-3 PUFA at 0.4 g was sufficient to achieve an HbA1c level of 7% in more than 95% of patients. Conclusions PPK/PD modeling was proposed as a multilevel analytical framework to quantitatively investigate finer aspects of the complex relationship between ω-3 PUFA and type 2 diabetes on genetic and non-genetic influence factors. The results support a beneficial role for ω-3 PUFA in type 2 diabetes and suggested the intake threshold. This new approach may provide insights into the interaction of the two and an understanding of the context in which changes occur.

IntroductionWe previously reported that ATP1A3 c.823G>C (p.Ala275Pro) mutant causes varying phenotypes of alternative hemiplegia of childhood and rapid-onset dystonia-parkinsonism in the same family. This study aims to investigate the function of ATP1A3 c.823G>C (p.Ala275Pro) mutant at the cellular and zebrafish models.MethodsATP1A3 wild-type and mutant Hela cell lines were constructed, and ATP1A3 mRNA expression, ATP1A3 protein expression and localization, and Na+-K+-ATPase activity in each group of cells were detected. Additionally, we also constructed zebrafish models with ATP1A3 wild-type overexpression (WT) and p.Ala275Pro mutant overexpression (MUT). Subsequently, we detected the mRNA expression of dopamine signaling pathway-associated genes, Parkinson’s disease-associated genes, and apoptosisassociated genes in each group of zebrafish, and observed the growth, development, and movement behavior of zebrafish.ResultsCells carrying the p.Ala275Pro mutation exhibited lower levels of ATP1A3 mRNA, reduced ATP1A3 protein expression, and decreased Na+-K+-ATPase activity compared to wild-type cells. Immunofluorescence analysis revealed that ATP1A3 was primarily localized in the cytoplasm, but there was no significant difference in ATP1A3 protein localization before and after the mutation. In the zebrafish model, both WT and MUT groups showed lower brain and body length, dopamine neuron fluorescence intensity, escape ability, swimming distance, and average swimming speed compared to the control group. Moreover, overexpression of both wild-type and mutant ATP1A3 led to abnormal mRNA expression of genes associated with the dopamine signaling pathway and Parkinson’s disease in zebrafish, and significantly upregulated transcription levels of bad and caspase-3 in the apoptosis signaling pathway, while reducing the transcriptional level of bcl-2 and the bcl-2/bax ratio.ConclusionThis study reveals that the p.Ala275Pro mutant decreases ATP1A3 protein expression and Na+/K+-ATPase activity. Abnormal expression of either wild-type or mutant ATP1A3 genes impairs growth, development, and movement behavior in zebrafish.

Chemical Exchange Saturation Transfer (CEST) is a technique that uses specific off-resonance saturation pulses to pre-saturate targeted substances. This process influences the signal intensity of free water, thereby indirectly providing information about the pre-saturated substance. Among the clinical applications of CEST, Amide Proton Transfer (APT) is currently the most well-established. APT can be utilized for the preoperative grading of gliomas. Tumors with higher APTw signals generally indicate a higher likelihood of malignancy. In predicting preoperative molecular typing, APTw values are typically lower in tumors with favorable molecular phenotypes, such as isocitrate dehydrogenase (IDH) mutations, compared to IDH wild-type tumors. For differential diagnosis, the average APTw values of meningiomas are significantly lower than those of high-grade gliomas. Various APTw measurement indices assist in distinguishing central nervous system lesions with similar imaging features, such as progressive multifocal leukoencephalopathy, central nervous system lymphoma, solitary brain metastases, and glioblastoma. Regarding prognosis, APT effectively differentiates between tumor recurrence and treatment effects, and also possesses predictive capabilities for overall survival (OS) and progression-free survival (PFS).

Wasp venom injections from wasp stings can damage several organs, most commonly the kidneys. Despite literature evidence, wasp sting-induced acute kidney injury (AKI) is rare and involves complex pathophysiological processes. While acute tubular necrosis (ATN) is the most prevalent histological result of wasp sting-induced AKI, uncommon combinations of chronic renal lesions have been described, alerting us to the patient's underlying illness. We report a 55-year-old hypertensive patient with unknown renal function who got AKI following multiple wasp stings. His renal function had not improved after continuous hemodialysis and plasma exchange; therefore, a kidney biopsy was performed. The pathology revealed that in addition to ATN, his kidney's distinguishing feature was a mix of chronic interstitial renal disease and chronic glomerulosclerosis. We think that his current renal pathological results were caused by hypertension in addition to wasp venom.

Ethylene glycol (EG, 1,2-ethanediol) is a two-carbon dihydroxy alcohol that can be derived from fermentation of plant-derived xylose and arabinose and which can be formed during food fermentations. Here we show that Propionibacterium freudenreichii DSM 20271 is able to convert EG in anaerobic conditions to ethanol and acetate in almost equimolar amounts. The metabolism of EG led to a moderate increase of biomass, indicating its metabolism is energetically favourable. A proteomic analysis revealed EG induced expression of the pdu-cluster, which encodes a functional bacterial microcompartment (BMC) involved in the degradation of 1,2-propanediol, with the presence of BMCs confirmed using transmission electron microscopy. Cross-examination of the proteomes of 1,2-propanediol and EG grown cells revealed PDU BMC-expressing cells have elevated levels of DNA repair proteins and cysteine biosynthesis proteins. Cells grown in 1,2-propanediol and EG also showed enhanced resistance against acid and bile salt-induced stresses compared to lactate-grown cells. Our analysis of whole genome sequences of selected genomes of BMC-encoding microorganisms able to metabolize EG with acetaldehyde as intermediate indicate a potentially broad-distributed role of the pdu operon in metabolism of EG. Based on our results we conclude EG is metabolized to acetate and ethanol with acetaldehyde as intermediate within BMCs in P. freudenreichii.

Starch is the main carbohydrate used in fish feed, but excess dietary starch may lead to excess fat deposition in tissues, especially liver, which can lead to health problems in farmed fish. Aaldopentose monosaccharides, such as xylose and arabinose, appear to have the potential to inhibit the glucose-based lipid synthesis pathway, although the mechanism is unclear. In the present study, rabbitfish (Siganus canaliculatus) were fed two diets with basal (BSD, 15%) and high (HSD, 25%) starch levels, and six other diets in which 1.25% 2.5% and 5% D-xylose (Diets X1, X2 and X3) or L-arabinose (Diets A1, A2 and A3) were added to the HSD by replacing corresponding starch component, respectively. After 8-week feeding experiment, the results showed the HSD reduced growth performance and increased tissue lipid deposition in rabbitfish and these negative effects were generally reversed by the addition of xylose and arabinose to HSD. Specifically, the inclusion of xylose and arabinose reduced the HSD-induced activities of enzymes related to carbohydrate metabolism, including digestion (maltase and sucrase), glycolysis (HK, PFK, PK) and the production of acetyl-CoA from pyruvate (PDH). Addition of xylose or arabinose also decreased the liver expression of genes related to lipid biosynthesis (srebp1, fas and acc), and increased liver gene expression (cpt-1, hsl and lpl) and protein levels of enzymes related to lipid catabolism. Therefore, both xylose and arabinose mitigated the negative effects of HSD on growth performance, and liver and muscle lipid contents by reducing the rate of carbohydrate digestion and metabolism, and inhibiting lipid accumulation by reducing lipid biosynthesis and increasing lipid catabolism in liver. The metabolic impacts of xylose and arabinose revealed in the present study provide further insights into the molecular mechanisms underpinning the actions of the dietary aldopentose monosaccharides in reducing excess fat deposition in tissues of fish fed HSD.

Objective To compare the ability of gadolinium ethoxybenzyl dimeglumine (Gd-EOB-DTPA) and gadobenate dimeglumine (Gd-BOPTA) to display the 3 major features recommended by the Liver Imaging Reporting and Data System (LI-RADS 2018v) for diagnosing hepatocellular carcinoma (HCC). Materials and Methods In this retrospective study, we included 98 HCC lesions that were scanned with either Gd-EOB-DTPA-MR or Gd-BOPTA-M.For each lesion, we collected multiple variables, including size and enhancement pattern in the arterial phase (AP), portal venous phase (PVP), transitional phase (TP), delayed phase (DP), and hepatobiliary phase (HBP). The lesion-to-liver contrast (LLC) was measured and calculated for each phase and then compared between the 2 contrast agents. A P value 0.750). When conducting a total evaluation of the combined data across the 5 phases, the display efficiency was excellent (AUC > 0.950). Conclusion Gd-BOPTA and Gd-EOB-DTPA are liver-specific contrast agents widely used in clinical practice. They have their own characteristics in displaying the 3 main signs of HCC. For accurate noninvasive diagnosis, the choice of agent should be made according to the specific situation.

Abstract Background This study aimed to investigate the clinicopathological characteristics, diagnostic indicators, and critical factors for the differential diagnosis of rosette-forming glioneuronal tumor (RGNT). Patients and methods This retrospective study included six surgically treated RGNT cases. We analyzed and summarized their clinical manifestations, radiological features, histological morphology, immunophenotype, and molecular genetic changes, supplemented with a literature review. Results The patients comprised four males and two females with a mean age of 35 years. The tumors were located in the cerebellum (two cases); the fourth ventricle, quadrigeminal cistern, and third ventricle (one case each); and the fourth ventricle and brainstem (one case). Clinical manifestations included headaches in four cases, left eyelid ptosis in one case, and one asymptomatic case only identified during physical examination. Microscopically, the tumor cells were uniform in size and were marked by rosette-like or pseudorosette-like structures around the neuropil and blood vessels. Immunohistochemistry revealed biphasic patterns. The central neuropil components of the rosette-like structures around the neuropil and the pseudorosette structures of the perivascular regions expressed Syn, while the cells surrounding the rosettes expressed Olig2 and not GFAP. GFAP and S-100 were expressed in the glial components but not in the rosette or pseudorosette regions. The Ki-67 proliferation index was typically low. Molecular genetic analysis showed that the main molecular changes involved FGFR1 mutation accompanied by PIK3R1 mutation. None of the patients received chemoradiotherapy postoperatively. Follow-up durations varied between 4 and 23 months with no recorded recurrence or metastasis. Conclusion RGNT is a comparatively rare mixed glioneuronal tumor that occurs in the midline structures. Its morphology shows certain overlaps with other low-grade neuroepithelial tumors. Identifying the rosettes around the neuropil is critical for morphological diagnosis, and the molecular identification of FGFR1 mutations accompanied by PIK3R1 mutations can facilitate diagnosis.

ObjectivesIn this study, we compared the dynamic changes in body composition during XELOX/SOX chemotherapy in patients with gastric cancer. Furthermore, we investigated the potential impact of these changes on the occurrence of toxic side effects.MethodsPatients with gastric cancer who received adjuvant or first-line XELOX/SOX chemotherapy between January 2020 and June 2023 were enrolled. The Brief Conghua Scale was used to assess energy intake, and nutritional management was carried out with reference to the Chinese Guidelines for Nutritional Therapy of Cancer 2020. The NRS 2002 Nutritional Risk Screening Scale, PG-SGA scale, bioelectrical impedance analysis, and dynamic changes in lumbar 3 vertebral skeletal muscle index were compared between baseline and post-chemotherapy in the study. The neutropenia was evaluated using the Common Terminology Criteria for Adverse Events V.5.0, developed by the National Institutes of Health.ResultsDynamic follow-up was completed in 39 cases, with a mean follow-up time of 117.62 ± 43.38 days. The incidence of sarcopenia increased significantly after chemotherapy, escalating from 46.2% to 51.3%. After chemotherapy, the mean L3SMI decreased from 36.00 cm2/m2 to 34.99 cm2/m2. Furthermore, when compared to pre-chemotherapy values, the body composition indexes body mass index (BMI), SL3, fat mass free index (FFMI), lean body mass (LBM), and body surface area (BSA) were significantly reduced after chemotherapy. Regardless of baseline or post-chemotherapy status, the incidence of grade ≥ 3 neutropenia was significantly higher in the sarcopenia group than in the non-sarcopenia group. Furthermore, when the skeletal muscle index decreased during chemotherapy, the incidence of grade ≥ 3 neutropenia was significantly higher in both the sarcopenia and non-sarcopenia groups compared to baseline. When the incidence of grade ≥ 3 neutropenia in the post-chemotherapy sarcopenia group was compared to baseline status, the increase was significantly higher in the sarcopenia group than in the maintenance/increase group.ConclusionsSkeletal muscle mass decreased progressively during XELOX/SOX chemotherapy in gastric cancer patients, followed by a higher incidence of grade ≥ 3 neutropenia.

Abstract Motor proteins, encoded by Kinesin superfamily (KIF) genes, are critical for brain development and plasticity. Increasing studies reported KIF’s roles in neurodevelopmental disorders. Here, a 6 years and 3 months‐old Chinese boy with markedly symptomatic epilepsy, intellectual disability, brain atrophy, and psychomotor retardation was investigated. His parents and younger sister were phenotypically normal and had no disease‐related family history. Whole exome sequencing identified a novel heterozygous in‐frame deletion (c.265_267delTCA) in exon 3 of the KIF5C in the proband, resulting in the removal of evolutionarily highly conserved p.Ser90, located in its ATP‐binding domain. Sanger sequencing excluded the proband's parents and family members from harboring this variant. The activity of ATP hydrolysis in vitro was significantly reduced as predicted. Immunofluorescence studies showed wild‐type KIF5C was widely distributed throughout the cytoplasm, while mutant KIF5C was colocalized with microtubules. The live‐cell imaging of the cargo‐trafficking assay revealed that mutant KIF5C lost the peroxisome‐transporting ability. Drosophila models also confirmed p.Ser90del's essential role in nervous system development. This study emphasized the importance of the KIF5C gene in intracellular cargo‐transport as well as germline variants that lead to neurodevelopmental disorders and might enable clinicians for timely and accurate diagnosis and disease management in the future.

Background: Chronic kidney disease (CKD) is a major public health concern. However, validated and broadly applicable biomarkers for early CKD diagnosis are currently not available. We aimed to identify serum metabolic signatures at an early stage of CKD to provide a reference for future investigations into the early diagnostic biomarkers. Methods: Serum metabolites were extracted from 65 renal dysfunction (RD) patients and 121 healthy controls (discovery cohort: 12 RD patients and 55 health participants; validation cohort: 53 RD patients and 66 health participants). Metabolite extracts were analyzed by ultraperformance liquid chromatography coupled with quadrupole-electrostatic field orbital trap mass spectrometry (UPLC-QE-Orbitrap MS) for untargeted metabolomics. Orthogonal partial least squares-discriminant analysis (OPLS-DA) was performed to detect different compounds between groups. Receiver operating characteristic (ROC) curve analysis was carried out to determine the diagnostic value of the validated differential metabolites between groups. We referred to the Kyoto Encyclopedia of Gene and Genomes (KEGG) to elucidate the metabolic pathways of the validated differential metabolites. Results: A total of 22 and 23 metabolites had significantly different abundances in the discovery and validation cohort, respectively. Six of them (creatinine, L-proline, citrulline, butyrylcarnitine, 1-methylhistidine, and valerylcarnitine) in the RD group was more abundant than that of the health group in both cohorts. The combination of the six validated differential metabolites were able to accurately detect RD (AUC 0.86). Three of the six metabolites are involved in the metabolism of arginine and proline. Conclusions: The present study highlights that creatinine, L-proline, citrulline, butyrylcarnitine, 1-methylhistidine, and valerylcarnitine are metabolite indicators with potential predictive value for CKD.

Abstract Epidermal growth factor receptor‐targeted (EGFR‐targeted) therapies show promise for non‐small cell lung cancer (NSCLC), but they are ineffective in a third of patients who lack EGFR mutations. This underlines the need for personalized treatments for patients with EGFR wild‐type NSCLC. A genome‐wide CRISPR/Cas9 screen has identified the enzyme phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), which is vital in de novo purine biosynthesis and tumor development, as a potential drug target for EGFR wild‐type NSCLC. We have further confirmed that PAICS expression is significantly increased in NSCLC tissues and correlates with poor patient prognosis. Knockdown of PAICS resulted in a marked reduction in both in vitro and in vivo proliferation of EGFR wild‐type NSCLC cells. Additionally, PAICS silencing led to cell‐cycle arrest in these cells, with genes involved in the cell cycle pathway being differentially expressed. Consistently, an increase in cell proliferation ability and colony number was observed in cells with upregulated PAICS in EGFR wild‐type NSCLC. PAICS silencing also caused DNA damage and cell‐cycle arrest by interacting with DNA repair genes. Moreover, decreased IMPDH2 activity and activated PI3K–AKT signaling were observed in NSCLC cells with EGFR mutations, which may compromise the effectiveness of PAICS knockdown. Therefore, PAICS plays an oncogenic role in EGFR wild‐type NSCLC and represents a potential therapeutic target for this disease.

Abstract Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10−9) and 10p11.21 (P = 3.6 × 10−8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10−3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10−3) and increased seizure-like events (P = 6.8 × 10−7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10−3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

Abstract Temozolomide (TMZ) is a standard treatment for glioblastoma (GBM) patients. However, TMZ has moderate therapeutic effects due to chemoresistance of GBM cells through less clarified mechanisms. Here, we demonstrate that TMZ-derived 5-aminoimidazole-4-carboxamide (AICA) is converted to AICA ribosyl-5-phosphate (AICAR) in GBM cells. This conversion is catalyzed by hypoxanthine phosphoribosyl transferase 1 (HPRT1), which is highly expressed in human GBMs. As the bona fide activator of AMP-activated protein kinase (AMPK), TMZ-derived AICAR activates AMPK to phosphorylate threonine 52 (T52) of RRM1, the catalytic subunit of ribonucleotide reductase (RNR), leading to RNR activation and increased production of dNTPs to fuel the repairment of TMZ-induced-DNA damage. RRM1 T52A expression, genetic interruption of HPRT1-mediated AICAR production, or administration of 6-mercaptopurine (6-MP), a clinically approved inhibitor of HPRT1, blocks TMZ-induced AMPK activation and sensitizes brain tumor cells to TMZ treatment in mice. In addition, HPRT1 expression levels are positively correlated with poor prognosis in GBM patients who received TMZ treatment. These results uncover a critical bifunctional role of TMZ in GBM treatment that leads to chemoresistance. Our findings underscore the potential of combined administration of clinically available 6-MP to overcome TMZ chemoresistance and improve GBM treatment.

Abstract Background Several studies have explored the connection between follicle-stimulating hormone (FSH) and nonalcoholic fatty liver disease (NAFLD). However, the impact of FSH elevation on NAFLD remains a topic of debate. Hence, this investigation aimed to evaluate the potential correlation between FSH levels and NAFLD in the aging population. Methods This was a retrospective observational cross-sectional study between July 2017 and August 2018 in our hospital. We used data obtained from 455 patients over 60 years old. Anthropometrics and laboratory tests were performed for each patient. NAFLD was diagnosed by sonographic features and the fatty liver index (LFI). Results Of the 455 patients, 200 (43.96%) had NAFLD on their ultrasound and 169 (37.14%) had NAFLD according to the LFI. An intraclass correlation coefficient of the two methods was 80.4% (P

Background: Differentiating adrenal adenomas from metastases poses a significant challenge, particularly in patients with a history of extra-adrenal malignancy. This study investigates the performance of three-phase computed tomography (CT) based robust federal learning algorithm and traditional deep learning for distinguishing metastases from benign adrenal lesions. Material and methods: This retrospective analysis includes 1187 instances who underwent three-phase CT scans between January 2008 and March 2021, comprising 720 benign lesions and 467 metastases. Utilizing the three-phase CT images, both a Robust Federal Learning Signature (RFLS) and a traditional Deep Learning Signature (DLS) were constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression. Their diagnostic capabilities were subsequently validated and compared using metrics such as the Areas Under the Receiver Operating Curve (AUCs), Net Reclassification Improvement (NRI), and Decision Curve Analysis (DCA). Results: Compared with DLS, the RFLS showed better capability in distinguishing metastases from benign adrenal lesions (average AUC: 0.816 vs.0.798, NRI = 0.126, P

Porphyra polysaccharide (PPS), derived from marine red seaweeds of the Porphyra genus, has been reported to improve growth performance, lipid metabolism, and antioxidant capability in animals. The present study investigated the effects of PPS supplementation to a high-carbohydrate diet on growth performance, lipid metabolism, immunity, antioxidant capacity, intestinal morphology, and microbial composition in rabbitfish (Siganus canaliculatus). Rabbitfish were fed a basal starch diet (BSD, 15% starch) and high-starch diets (HSD, 25% starch) supplemented with varying levels of PPS (0%, 1.25%, 2.5%, and 5%) for 8 weeks. The results showed that HSD intake significantly decreased body weight and increased hepatosomatic index compared to rabbitfish fed BSD. But all dietary levels of PPS reversed these two indicators of fish fed HSD. In addition, the supplementation of 2.5% and 5% PPS significantly reduced the higher lipid contents in whole fish and abdominal muscle of fish fed HSD. Notably, 2.5% PPS reduced lipid droplets in the liver, possibly through the downregulation of genes associated with lipid synthesis and the upregulation of genes associated with lipid catabolism. Moreover, all levels of PPS supplementation decreased the higher serum alanine aminotransferase activity in fish fed HSD, indicating the alleviation of HSD-induced liver impairment. Additionally, PPS inclusion significantly increased the activity of serum lysozyme, superoxide dismutase, and catalase while decreasing serum malondialdehyde in fish fed HSD, suggesting improvements in immunity and antioxidant capacity. Furthermore, PPS inclusion mitigated damage to intestinal villi induced by HSD. Interestingly, 2.5% PPS increased the abundance of Bacteroidetes and Tenericutes while reducing the abundance of Proteobacteria and Spirochetes, indicating the reshaping of gut microbiota. In summary, dietary PPS alleviated the negative effects of HSD on growth performance, lipid metabolism, immunity, antioxidant capacity, and intestinal morphology and altered microbial composition in rabbitfish. This highlighted the beneficial effects of dietary PPS in fish and suggested it could contribute to the new strategies for treating metabolic syndrome and health impacts in aquatic animals.

The widespread use of commercial feeds with high-fat content in aquaculture may lead to oxidative stress and inflammation in fish during culture, which may cause changes in fish muscle texture. Therefore, mitigating oxidative stress and inflammation during fish farming holds paramount importance in improving fish muscle quality. In this study, we investigated the effect of different dietary levels of chlorogenic acid (CGA; 0, 100, 200, 400, 800, 1600 mg/kg diet, P1–P6) in commercial diets on the muscle of blackspotted croaker (Protonibea diacanthus) through an 8-week feeding trial in open sea cages. The results showed that high dietary CGA levels (P5–P6) could significantly reduce muscle oxidative stress and inflammation (P

The escalating prevalence of hyperlipidemia has a profound impact on individuals' daily physiological well-being. The traditional Chinese medicine (TCM) prescription Danggui Shaoyao San (DSS) has demonstrated significant clinical efficacy and promising prospects for clinical application. Leveraging network pharmacology and bioinformatics, we hypothesize that DSS can ameliorate lipid metabolic disorders in hyperlipidemia by modulating the PPAR signaling pathway. In this study, we employed a zebrafish model to investigate the impact of DSS on lipid metabolism in hyperlipidemia. Body weight alterations were monitored by pre- and postmodeling weight measurements. Behavioral assessments and quantification of liver biochemical markers were conducted using relevant assay kits. Pathways associated with lipid metabolism were identified through network pharmacology and GEO analysis, while PCR was utilized to assess genes linked to lipid metabolism. Western blotting was employed to analyze protein expression levels, and liver tissue underwent Oil Red O and immunofluorescence staining to evaluate liver lipid deposition. Our findings demonstrate that DSS effectively impedes weight gain and reduces liver lipid accumulation in zebrafish models with elevated lipid levels. The therapeutic effects of DSS on lipid metabolism are mediated through its modulation of the PPAR signaling pathway, resulting in a significant reduction in lipid accumulation within the body and alleviation of certain hyperlipidemia-associated symptoms.

Abstract Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is currently the standard first-line therapy for EGFR-mutated advanced non-small cell lung cancer (NSCLC). The life quality and survival of this subgroup of patients were constantly improving owing to the continuous iteration and optimization of EGFR-TKI. Osimertinib, an oral, third-generation, irreversible EGFR-TKI, was initially approved for the treatment of NSCLC patients carrying EGFR T790M mutations, and has currently become the dominant first-line targeted therapy for most EGFR mutant lung cancer. Unfortunately, resistance to osimertinib inevitably develops during the treatment and therefore limits its long-term effectiveness. For both fundamental and clinical researchers, it stands for a major challenge to reveal the mechanism, and a dire need to develop novel therapeutics to overcome the resistance. In this article, we focus on the acquired resistance to osimertinib caused by EGFR mutations which account for approximately 1/3 of all reported resistance mechanisms. We also review the proposed therapeutic strategies for each type of mutation conferring resistance to osimertinib and give an outlook to the development of the next generation EGFR inhibitors. Video Abstract

This study pioneered a non-destructive testing approach to evaluating the physicochemical properties of golden passion fruit by developing a platform to analyze the fruit’s electrical characteristics. By using dielectric properties, the method accurately predicted the soluble solids content (SSC), Acidity and pulp percentage (PP) in passion fruit. The investigation entailed measuring the relative dielectric constant (ε′) and dielectric loss factor (ε″) for 192 samples across a spectrum of 34 frequencies from 0.05 to 100 kHz. The analysis revealed that with increasing frequency and fruit maturity, both ε′ and ε″ showed a declining trend. Moreover, there was a discernible correlation between the fruit’s physicochemical indicators and dielectric properties. In refining the dataset, 12 outliers were removed using the Local Outlier Factor (LOF) algorithm. The study employed various advanced feature extraction techniques, including Recursive Feature Elimination with Cross-Validation (RFECV), Permutation Importance based on Random Forest Regression (PI-RF), Permutation Importance based on Linear Regression (PI-LR) and Genetic Algorithm (GA). All the variables and the selected variables after screening were used as inputs to build Extreme Gradient Boosting (XGBoost) and Categorical Boosting (Cat-Boost) models to predict the SSC, Acidity and PP in passion fruit. The results indicate that the PI-RF-XGBoost model demonstrated superior performance in predicting both the SSC (R2 = 0.9240, RMSE = 0.2595) and the PP (R2 = 0.9092, RMSE = 0.0014) of passion fruit. Meanwhile, the GA-CatBoost model exhibited the best performance in predicting Acidity (R2 = 0.9471, RMSE = 0.1237). In addition, for the well-performing algorithms, the selected features are mainly concentrated within the frequency range of 0.05–6 kHz, which is consistent with the frequency range highly correlated with the dielectric properties and quality indicators. It is feasible to predict the quality indicators of fruit by detecting their low-frequency dielectric properties. This research offers significant insights and a valuable reference for non-destructive testing methods in assessing the quality of golden passion fruit.

Reynoutria japonica Houtt. is an important medical plant with a long history of thousands of years in China, however, its mitochondrial genome (mitogenome) has not been reported yet. In this work, we reported and analyzed the R. japonica mitogenome. The main results include: The R. japonica mitogenome was 302,229 bp in length and encoded 48 genes, including 27 protein-coding genes (PCGs), 3 rRNA genes, and 18 tRNA genes. Repeat sequence analysis revealed that there were 54 repeat sequences ranging from 193 bp to 1,983 bp in the R. japonica mitogenome. Relative synonymous codon usage (RSCU) analysis showed that leucine (900, 11.01%) and serine (732, 8.96%) were the two most abundant amino acids, and the codons with RSCU values showed the preference of A or T ending when greater than 1. The RNA editing sites of PCGs in the R. japonica mitogenome were characterized, and 299 RNA editing sites were found. Extensive sequences transfer between mitochondrion and chloroplast were found in R. japonica, where 11 complete plastid-derived tRNA genes stayed intact in the R. japonica mitogenome. Three genes (ccmFC, cox1, and nad1) were seen to play essential roles in the evolution through selection pressure analysis. The phylogenetic analysis showed that Fallopia multiflora was the closest species with R. japonica, in consistency with the results of chloroplast genome. Overall, the current work presents the first mitogenome of R. japonica and could contribute to the phylogenetic analysis of the family Polygonaceae.

BackgroundPatients with atrial septal defect (ASD) exhibit distinctive electrocardiogram (ECG) patterns. However, ASD cannot be diagnosed solely based on these differences. Artificial intelligence (AI) has been widely used for specifically diagnosing cardiovascular diseases other than arrhythmia. Our study aimed to develop an artificial intelligence-enabled 8-lead ECG to detect ASD among adults.MethodIn this study, our AI model was trained and validated using 526 ECGs from patients with ASD and 2,124 ECGs from a control group with a normal cardiac structure in our hospital. External testing was conducted at Wuhan Central Hospital, involving 50 ECGs from the ASD group and 46 ECGs from the normal group. The model was based on a convolutional neural network (CNN) with a residual network to classify 8-lead ECG data into either the ASD or normal group. We employed a 10-fold cross-validation approach.ResultsStatistically significant differences (p

While existing research has illuminated the environmental dangers and neurotoxic effects of MC-LR exposure, the molecular underpinnings of brain damage from environmentally-relevant MC-LR exposure remain elusive. Employing a comprehensive approach involving RNA sequencing, histopathological examination, and biochemical analyses, we discovered genes differentially expressed and enriched in the ferroptosis pathway. This finding was associated with mitochondrial structural impairment and downregulation of Gpx4 and Slc7a11 in mice brains subjected to low-dose MC-LR over 180 days. Mirroring these findings, we noted reduced cell viability and GSH/GSSH ratio, along with an increased ROS level, in HT-22, BV-2, and bEnd.3 cells following MC-LR exposure. Intriguingly, MC-LR also amplified phospho-Erk levels in both in vivo and in vitro settings, and the effects were mitigated by treatment with PD98059, an Erk inhibitor. Taken together, our findings implicate the activation of the Erk/MAPK signaling pathway in MC-LR-induced ferroptosis, shedding valuable light on the neurotoxic mechanisms of MC-LR. These insights could guide future strategies to prevent MC-induced neurodegenerative diseases.

Abstract Background Mean platelet volume (MPV) is a marker of platelet activation, which is usually negatively correlated with platelet count (PC). The ratio of MPV to PC (MPV/PC) has an essential role in the diagnosis of multiple malignancies. However, only a few studies investigated the value of MPV/PC in colorectal cancer (CRC) and the combination of MPV/PC with tumor markers in CRC. This retrospective clinical study aimed to evaluate the diagnostic value of MPV/PC and tumor markers (CA72-4, CA125, CA199) used alone or in combination in CRC. Methods 200 patients with CRC and 317 patients with colorectal benign polypus pathologically diagnosed during 2019/01/04 to 2022/06/30 were included. Hematological and pathological parameters of the above patients were collected, data were analyzed with Student’s t-test, one-way ANOVA or Kruskal-Wallis H test and receiver operating characteristic (ROC) curve, and ROC curve was used to evaluate the diagnostic value of tumor markers and MPV/PC used alone or in combination in CRC. Results The MPV/PC in CRC group was significantly lower than the control group (P

Abstract Background Anticancer peptide (ACP) inhibits and kills tumor cells. Research on ACP is of great significance for the development of new drugs, and the prediction of ACPs and non-ACPs is the new hotspot. Results We propose a new machine learning-based method named GCNCPR-ACPs (a Graph Convolutional Neural Network Method based on collapse pooling and residual network to predict the ACPs), which automatically and accurately predicts ACPs using residual graph convolution networks, differentiable graph pooling, and features extracted using peptide sequence information extraction. The GCNCPR-ACPs method can effectively capture different levels of node attributes for amino acid node representation learning, GCNCPR-ACPs uses node2vec and one-hot embedding methods to extract initial amino acid features for ACP prediction. Conclusions Experimental results of ten-fold cross-validation and independent validation based on different metrics showed that GCNCPR-ACPs significantly outperformed state-of-the-art methods. Specifically, the evaluation indicators of Matthews Correlation Coefficient (MCC) and AUC of our predicator were 69.5% and 90%, respectively, which were 4.3% and 2% higher than those of the other predictors, respectively, in ten-fold cross-validation. And in the independent test, the scores of MCC and SP were 69.6% and 93.9%, respectively, which were 37.6% and 5.5% higher than those of the other predictors, respectively. The overall results showed that the GCNCPR-ACPs method proposed in the current paper can effectively predict ACPs.

Abstract. Background:. To date, there is no effective medicine to treat coronavirus disease 2019 (COVID-19), and the antiviral efficacy of arbidol in the treatment for COVID-19 remained equivocal and controversial. The purpose of this study was to evaluate the efficacy and safety of arbidol tablets in the treatment of COVID-19. Methods:. This was a prospective, open-label, controlled and multicenter investigator-initiated trial involving adult patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients were stratified 1:2 to either standard-of-care (SOC) or SOC plus arbidol tablets (oral administration of 200 mg per time, three times a day for 14 days). The primary endpoint was negative conversion of SARS-CoV-2 within the first week. The rates and 95% confidential intervals were calculated for each variable. Results:. A total of 99 patients with laboratory-confirmed SARS-CoV-2 infection were enrolled; 66 were assigned to the SOC plus arbidol tablets group, and 33 to the SOC group. The negative conversion rate of SARS-CoV-2 within the first week in patients receiving arbidol tablets was significantly higher than that of the SOC group (70.3% [45/64] vs. 42.4% [14/33]; difference of conversion rate 27.9%; 95% confidence interval [CI], 7.7%–48.1%; P = 0.008). Compared to those in the SOC group, patients receiving arbidol tablets had a shorter duration of clinical recovery (median 7.0 days vs. 12.0 days; hazard ratio [HR]: 1.877, 95% CI: 1.151–3.060, P = 0.006), symptom of fever (median 3.0 days vs. 12.0 days; HR: 18.990, 95% CI: 5.350–67.410, P 0.05). The most common adverse event in the arbidol tablets group was the elevation of transaminase (5/200, 2.5%), and no one withdrew from the study due to adverse events or disease progression. Conclusions:. SOC plus arbidol tablets significantly increase the negative conversion rate of SARS-CoV-2 within the first week and accelerate the recovery of COVID-19 patients. During the treatment with arbidol tablets, we find no significant serious adverse events. Trial registration:. Chinese Clinical Trial Registry, NCT04260594, www.clinicaltrials.gov/ct2/show/NCT04260594?term=NCT04260594&draw=2&rank=1

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT), as one of the life-saving treatments for severe aplastic anemia (SAA), is widely used because of its great donor availability. Over decades, granulocyte colony-stimulating factor (G-CSF)/antithymocyte globulin (ATG)-based protocol (the so-called Beijing Protocol) has achieved favorable engraftment and survival outcomes. In this study, we modified the conventional Beijing Protocol: the full-dose Cyclophosphamide (Cy) (200 mg/kg in total) was divided into 42.75 mg/kg Cy on day -5 to day -2 and Low dose post-transplant Cy (PTCy) (14.5 mg/kg on days +3 and +4), hoping to reduce the incidence of severe acute graft-versus-host disease (aGVHD) and to guarantee successful and stable engraftment. Here we retrospectively reported and analyzed the data of first 17 patients with SAA who had received haplo-HSCT using this novel regimen between August 2020 and August 2022. The median follow-up was 522 days (range, 138-859 days). No patient developed primary graft failure. Four (23.5%) patients developed grade II bladder toxicity, two (11.8%) patients developed grade II cardiotoxicity. All patients achieved neutrophil and platelet engraftment at median times of 12 days (range, 11–20 days) and14 days (range, 8-36 days). During our follow-up, no patients developed grade III-IV aGVHD. The cumulative incidence of grade II and grade I aGVHD at 100 days was 23.5% (95% CI, 6.8%-49.9%) and 47.1% (95% CI, 23.0%-72.2%). Three patients (17.6%) developed chronic GVHD of skin, mouth, and eyes and all of which were mild. All patients are alive by the end of the follow-up, with a failure-free survival of 100%, which was defined as survival without treatment failures, such as death, graft failure, or relapse rate. The rate of cytomegalovirus (CMV) reactivation was 82.4% (95% CI, 64.3%-100%). The rate of Epstein-Barr virus (EBV) reactivation was 17.6% (95% CI, 3.8%-43.4%). No CMV disease and post-transplantation lymphoproliferative disorder (PTLD) occurred among these patients. In conclusion, the encouraging results of prolonged survival outcomes and reduced incidence of GVHD suggest promising effect of this novel regimen in haplo-HSCT for patients with SAA. Larger-sample prospective clinical trials are needed to confirm the effectiveness of this regimen.

Summary: Background: Breast cancer is the leading cause of cancer-related deaths in women. However, accurate diagnosis of breast cancer using medical images heavily relies on the experience of radiologists. This study aimed to develop an artificial intelligence model that diagnosed single-mass breast lesions on contrast-enhanced mammography (CEM) for assisting the diagnostic workflow. Methods: A total of 1912 women with single-mass breast lesions on CEM images before biopsy or surgery were included from June 2017 to October 2022 at three centres in China. Samples were divided into training and validation sets, internal testing set, pooled external testing set, and prospective testing set. A fully automated pipeline system (FAPS) using RefineNet and the Xception + Pyramid pooling module (PPM) was developed to perform the segmentation and classification of breast lesions. The performances of six radiologists and adjustments in Breast Imaging Reporting and Data System (BI-RADS) category 4 under the FAPS-assisted strategy were explored in pooled external and prospective testing sets. The segmentation performance was assessed using the Dice similarity coefficient (DSC), and the classification was assessed using heatmaps, area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. The radiologists’ reading time was recorded for comparison with the FAPS. This trial is registered with China Clinical Trial Registration Centre (ChiCTR2200063444). Findings: The FAPS-based segmentation task achieved DSCs of 0.888 ± 0.101, 0.820 ± 0.148 and 0.837 ± 0.132 in the internal, pooled external and prospective testing sets, respectively. For the classification task, the FAPS achieved AUCs of 0.947 (95% confidence interval [CI]: 0.916–0.978), 0.940 (95% [CI]: 0.894–0.987) and 0.891 (95% [CI]: 0.816–0.945). It outperformed radiologists in terms of classification efficiency based on single lesions (6 s vs 3 min). Moreover, the FAPS-assisted strategy improved the performance of radiologists. BI-RADS category 4 in 12.4% and 13.3% of patients was adjusted in two testing sets with the assistance of FAPS, which may play an important guiding role in the selection of clinical management strategies. Interpretation: The FAPS based on CEM demonstrated the potential for the segmentation and classification of breast lesions, and had good generalisation ability and clinical applicability. Funding: This study was supported by the Taishan Scholar Foundation of Shandong Province of China (tsqn202211378), National Natural Science Foundation of China (82001775), Natural Science Foundation of Shandong Province of China (ZR2021MH120), and Special Fund for Breast Disease Research of Shandong Medical Association (YXH2021ZX055).

Abstract The increased transmissibility of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Delta and Omicron variants due to their complex mutations has been confirmed by many studies, but the disease severity caused by these two variants and vaccine efficacy have not been clearly concluded. This meta‐analysis evaluated and compared disease severity and vaccine efficacy for infection with these two variants. Databases were searched on July 29, 2022, for original studies. Data extracted included participants, hospitalization rate, intensive care unit (ICU) admission rate, mortality rate, and vaccination status. Total 15 studies (570,713 subjects) were included. The risk of hospitalization, ICU admission and death in patients with Delta were increased compared with patients with Omicron, especially hospitalization (Log risk ratio [RR]: 1.09, 95% confidence interval [CI]: 0.65–1.53). The Delta was associated with a higher risk of death in the unvaccinated population (Log RR: 0.48, 95% CI: 0.04–0.93). No significant differences in the risk of severe illness between BA.1 and BA.2 were observed. All three risks were reduced in fully vaccinated populations infected with Delta and Omicron. The existing evidence shows that the inherent virulence and disease severity of Omicron are reduced compared with Delta, and fully vaccination is effective in preventing severe infection of both variants.

Stimulator of interferon genes (STING) is a cytosolic DNA sensor which is regarded as a potential target for antitumor immunotherapy. However, clinical trials of STING agonists display limited anti-tumor effects and dose-dependent side-effects like inflammatory damage and cell toxicity. Here, we showed that tetrahedral DNA nanostructures (TDNs) actively enter macrophages to promote STING activation and M1 polarization in a size-dependent manner, and synergized with Mn2+ to enhance the expressions of IFN-β and iNOS, as well as the co-stimulatory molecules for antigen presentation. Moreover, to reduce the cytotoxicity of Mn2+, we constructed a TDN–MnO2 complex and found that it displayed a much higher efficacy than TDN plus Mn2+ to initiate macrophage activation and anti-tumor response both in vitro and in vivo. Together, our studies explored a novel immune activation effect of TDN in cancer therapy and its synergistic therapeutic outcomes with MnO2. These findings provide new therapeutic opportunities for cancer therapy.

Abstract Over 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF. We investigate the relationship between rs7512462, a marker of SLC26A9 activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD). Rs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p = 0.008); and for gating (p = 0.033) and p.Phe508del/ p.Phe508del (p = 0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p = 0.0022). Beyond CF, rs7512462 is associated with peak expiratory flow in a meta-analysis of the UK Biobank and Spirometa Consortium (p = 2.74 × 10−44) and provides p = 0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry. These findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.

Equilibrium geometries and properties of self-assembled (InN)12n (n = 1–9) nanoclusters (nanowires and nanosheets) are studied using the GGA-PBE (general gradient approximation with Perdew–Burke–Ernzerh) method. The relative stabilities and growth patterns of semiconductor (InN)12n nanoclusters are investigated. The odd-numbered nano-size (InN)12n (n is odd) have weaker stabilities compared with the neighboring even-numbered (InN)12n (n is even) ones. The most stable (InN)48 nanosheet is selected as a building unit for self-assembled nano-size film materials. In particular, the energy gaps of InN nanoclusters show an even–odd oscillation and reflect that (InN)12n (n = 1–9) nanoclusters are good optoelectronic materials and nanodevices due to their energy gaps in the visible region. Interestingly, the calculated energy gaps for (InN)12n nanowires varies slightly compared with that of individual (InN)12 units. Additionally, the predicted natural atomic populations of In atoms in (InN)12n nanoclusters show that the stabilities of (InN)12n nanoclusters is enhanced through the ionic bonding and covalent bonding of (InN)12n (n = 1–9) nanoclusters.

BackgroundWe developed a novel system for quantifying DNA damage response (DDR) to help diagnose and predict the risk of Alzheimer’s disease (AD).MethodsWe thoroughly estimated the DDR patterns in AD patients Using 179 DDR regulators. Single-cell techniques were conducted to validate the DDR levels and intercellular communications in cognitively impaired patients. The consensus clustering algorithm was utilized to group 167 AD patients into diverse subgroups after a WGCNA approach was employed to discover DDR-related lncRNAs. The distinctions between the categories in terms of clinical characteristics, DDR levels, biological behaviors, and immunological characteristics were evaluated. For the purpose of choosing distinctive lncRNAs associated with DDR, four machine learning algorithms, including LASSO, SVM-RFE, RF, and XGBoost, were utilized. A risk model was established based on the characteristic lncRNAs.ResultsThe progression of AD was highly correlated with DDR levels. Single-cell studies confirmed that DDR activity was lower in cognitively impaired patients and was mainly enriched in T cells and B cells. DDR-related lncRNAs were discovered based on gene expression, and two different heterogeneous subtypes (C1 and C2) were identified. DDR C1 belonged to the non-immune phenotype, while DDR C2 was regarded as the immune phenotype. Based on various machine learning techniques, four distinctive lncRNAs associated with DDR, including FBXO30-DT, TBX2-AS1, ADAMTS9-AS2, and MEG3 were discovered. The 4-lncRNA based riskScore demonstrated acceptable efficacy in the diagnosis of AD and offered significant clinical advantages to AD patients. The riskScore ultimately divided AD patients into low- and high-risk categories. In comparison to the low-risk group, high-risk patients showed lower DDR activity, accompanied by higher levels of immune infiltration and immunological score. The prospective medications for the treatment of AD patients with low and high risk also included arachidonyltrifluoromethane and TTNPB, respectively,ConclusionsIn conclusion, immunological microenvironment and disease progression in AD patients were significantly predicted by DDR-associated genes and lncRNAs. A theoretical underpinning for the individualized treatment of AD patients was provided by the suggested genetic subtypes and risk model based on DDR.

ObjectiveThe preoperative MRI scans of meningiomas were analyzed based on the 2021 World Health Organization (WHO) Central Nervous System (CNS) Guidelines, and the efficacy of MRI features in diagnosing WHO grades and brain invasion was analyzed.Materials and methodsThe data of 675 patients with meningioma who underwent MRI in our hospital from 2006 to 2022, including 108 with brain invasion, were retrospectively analyzed. Referring to the WHO Guidelines for the Classification of Central Nervous System Tumors (Fifth Edition 2021), 17 features were analyzed, with age, sex and meningioma MRI features as risk factors for evaluating WHO grade and brain invasion. The risk factors were identified through multivariable logistic regression analysis, and their receiver operating characteristic (ROC) curves for predicting WHO grades and brain invasion were generated, and the area under the curve (AUC), sensitivity and specificity were calculated.ResultsUnivariate analysis showed that sex, tumor size, lobulated sign, peritumoral edema, vascular flow void, bone invasion, tumor-brain interface, finger-like protrusion and mushroom sign were significant for diagnosing meningioma WHO grades, while these features and ADC value were significant for predicting brain invasion (P < 0.05). Multivariable logistic regression analysis showed that the lobulated sign, tumor-brain interface, finger-like protrusion, mushroom sign and bone invasion were independent risk factors for diagnosing meningioma WHO grades, while the above features, tumor size and ADC value were independent risk factors for diagnosing brain invasion (P < 0.05). The tumor-brain interface had the highest efficacy in evaluating WHO grade and brain invasion, with AUCs of 0.779 and 0.860, respectively. Combined, the variables had AUCs of 0.834 and 0.935 for determining WHO grade and brain invasion, respectively.ConclusionPreoperative MRI has excellent performance in diagnosing meningioma WHO grade and brain invasion, while the tumor-brain interface serves as a key factor. The preoperative MRI characteristics of meningioma can help predict WHO grade and brain invasion, thus facilitating complete lesion resection and improving patient prognosis.

Background and objectivesPheochromocytoma and adrenal adenoma are common space-occupying lesions of the adrenal gland, and incorrect surgery may lead to adrenal crisis. We used a new method, dual-energy spectral detector computed tomography (SDCT), to differentiate between the two.Materials and methodsWe analysed the imaging images of patients with SDCT scans and pathologically confirmed adrenal adenomas (n=70) and pheochromocytomas (n=15). The 40, 70, and 100 KeV virtual monoenergetic images (VMIs) were reconstructed based on the SCDT arterial phase, and the correlation between the arterial/venous phase iodine concentration (AP-IC/VP-IC), the effective atomic number (Z-effect), the slope of the Hounsfield unit attenuation plot (VMI slope) and the pathological results was tested. The Shapiro−Wilk test was used to determine whether the above data conformed to a normal distribution. For parameters with P greater than 0.05, Student’s t test was used, and the Mann−Whitney test was used for the remaining parameters. A ROC curve was drawn based on the results.ResultsStudent’s t test showed that the 40 KeV VMI and the VMI slope were both statistically significant (P

Summary: Phasing of heterozygous alleles is critical for interpretation of cis-effects of disease-relevant variation. We sequenced 477 individuals with cystic fibrosis (CF) using linked-read sequencing, which display an average phase block N50 of 4.39 Mb. We use these samples to construct a graph representation of CFTR haplotypes, demonstrating its utility for understanding complex CF alleles. These are visualized in a Web app, CFTbaRcodes, that enables interactive exploration of CFTR haplotypes present in this cohort. We perform fine-mapping and phasing of the chr7q35 trypsinogen locus associated with CF meconium ileus, an intestinal obstruction at birth associated with more severe CF outcomes and pancreatic disease. A 20-kb deletion polymorphism and a PRSS2 missense variant p.Thr8Ile (rs62473563) are shown to independently contribute to meconium ileus risk (p = 0.0028, p = 0.011, respectively) and are PRSS2 pancreas eQTLs (p = 9.5 × 10−7 and p = 1.4 × 10−4, respectively), suggesting the mechanism by which these polymorphisms contribute to CF. The phase information from linked reads provides a putative causal explanation for variation at a CF-relevant locus, which also has implications for the genetic basis of non-CF pancreatitis, to which this locus has been reported to contribute.