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Abstract Purpose The purpose of this study was to investigate the correlation between podocyte related biomarker cofilin-1 and renal function, and explore the value of cofilin-1 in predicting the risk of renal adverse prognosis in IgA nephropathy (IgAN). Methods Patients with primary IgAN diagnosed by initial renal biopsy performed in our hospital from January 2019 to February 2022 were included. This study was a prospective cohort study. All IgAN patients were detected the expression of cofilin-1 and other related biomarkers (RhoA, NGAL) in urine by enzyme-linked immunosorbent assay (ELISA) and follow-up at least 6 months. We also collected baseline clinicopathologial data of IgAN. The decreased renal function group was defined as baseline eGFR

Abstract Background Facing the significant challenge of overcoming drug resistance in cancer treatment, particularly resistance caused by mutations in epidermal growth factor receptor (EGFR), the aim of our study was to identify potent EGFR inhibitors effective against the T790M/C797S/L858R mutant, a key player in resistance mechanisms. Methods Our integrated in silico approach harnessed machine learning, virtual screening, and activity evaluation techniques to screen 5105 compounds from three libraries, aiming to find candidates capable of overcoming the resistance conferred by the T790M and C797S mutations within EGFR. This methodical process narrowed the search down to six promising compounds for further examination. Results Kinase assays identified three compounds to which the T790M/C797S/L858R mutant exhibited increased sensitivity compared to the T790M/L858R mutant, highlighting the potential efficacy of these compounds against resistance mechanisms. Among them, T001-10027877 exhibited dual inhibitory effects, with IC50 values of 4.34 µM against EGFRT790M/C797S/L858R and 1.27 µM against EGFRT790M/L858R. Further investigations into the antiproliferative effects in H1975, A549, H460 and Ba/F3-EGFRL858/T790M/C797S cancer cells revealed that T001-10027877 was the most potent anticancer agent among the tested compounds. Additionally, the induction of H1975 cell apoptosis and cell cycle arrest by T001-10027877 were confirmed, elucidating its mechanism of action. Conclusions This study highlights the efficacy of combining computational techniques with bioactivity assessments in the quest for novel antiproliferative agents targeting complex EGFR mutations. In particular, T001-10027877 has great potential for overcoming EGFR-mediated resistance and merits further in vivo exploration. Our findings contribute valuable insights into the development of next-generation anticancer therapies, demonstrating the power of an integrated drug discovery approach.

Abstract Forest soils store substantial amounts of carbon in various soil organic matter (SOM) components due to high plant litter inputs and active microbial turnover. However, the variations in plant- and microbial-derived SOM components in surface and subsurface forest soils across a wide geographic scale remain poorly understood. This study investigated the SOM components from aboveground and belowground plant inputs and fungal and bacterial necromass in surface (soil0–5 cm) and subsurface (soil5–10 cm) soils across 32 forest sites in China and analyzed their relationships with climate and edaphic factors. Compared to soil0–5 cm, soil5–10 cm exhibited lower soil organic carbon content and cutin biomarker concentration but higher concentrations of fungal necromass carbon and lignin phenols. Higher mean annual precipitation led to higher concentrations of cutin and suberin biomarkers in soil0–5 cm and soil5–10 cm, respectively. Higher soil organic carbon content was associated with lower plant-derived lignin biomarkers, higher lignin oxidation degrees, and increased microbial necromass-derived amino sugars across sites, highlighting the pivotal role of microbial necromass in SOM stabilization. Additionally, both fungal and bacterial necromass decreased with increasing mineral weathering across sites. These insights improve the understanding of environmental drivers of source-specific carbon storage in forest soils. Graphical Abstract

Abstract Background The association of BCAAs (isoleucine, leucine, and valine) with cardiovascular and cerebrovascular diseases has been widely recognized by researchers, but there is limited evidence to support the relationship between BCAAs and multiple chronic conditions (MCCs) in older adults. This study aimed to explore the correlation between BCAA levels in the diets of older adults and MCCs. Methods Based on a health management cohort project in Nanshan District of Shenzhen, 4278 individuals over 65 years old were selected as participants via multi-stage stratified sampling from May 2018 to December 2019. Data were collected using a validated semi-quantitative food frequency questionnaire, as well as anthropometric and chronic disease reports. MCC was defined as the coexistence of two or more chronic diseases, namely, hypertension, dyslipidemia, diabetes, CAD, stroke, CKD, and CLD. Multivariate unconditional logistic regression analysis was used to analyze the relationship between dietary BCAAs and MCCs in older adults, and then, gender stratification analysis was performed. A restricted cubic spline model (a fitted smooth curve) was used to determine the dose–response relationship of isoleucine with MCCs. Results A total of 4278 older adults aged 65 and above were included in this study, with an average age of 72.73 ± 5.49 years. The cohort included 1861 males (43.50%). Regardless of whether confounding factors were corrected, isoleucine was a risk factor for MCCs (OR = 3.388, 95%CI:1.415,8.109). After gender stratification, the relationships between dietary isoleucine and MCCs (OR = 6.902, 95%CI:1.875,25.402) and between leucine (OR = 0.506,95%CI:0.309,0.830) and MCCs were significant in women, but not in men. No significant association between valine and MCCs was observed. In addition, isoleucine was a risk factor for MCCs when its intake was greater than 4.297 g/d. Conclusion Isoleucine may play an important role in regulating age-related diseases. BCAAs such as isoleucine can be used as risk markers for MCCs in older adults.

Abstract Background Sitosterolemia, an autosomal recessive condition, is characterized by impaired metabolism of plant sterols. Clinical symptoms include skin xanthoma, premature atherosclerotic disease, arthritis, and unexplained hematological abnormalities. However, there is a dearth of studies on sitosterolemia-related brain damage. Methods This study focused on the family of two sitosterolemia patients who presented with severe hypercholesterolemia and xanthoma. Radiological examinations, biopsies, whole-exome sequencing (WES), and plant sterol tests were conducted. Results The index patient, a 66-year-old female, initially exhibited weakness in both lower limbs and later developed urinary and fecal incontinence. Neuroimaging showed that the falx of the brain had irregular fusiform thickening. Significant tissue edema was observed around the lesions in the bilateral frontal-parietal lobes. Pathological analysis of the biopsied brain lesion revealed extensive cholesterol crystal deposition and lymphocyte infiltration in the matrix. The index patient who experienced cerebral impairment and her sister both carried two compound heterozygous variants in ATP binding cassette transporter G5 (ABCG5). These included the nonsense variants NM_022436: c.751 C > T (p.Q251X) in exon 6 and NM_022436: c.1336 C > T (p.R446X) in exon 10. A notable increase in plant sterol levels was observed in the younger sister of the index patient. Conclusion This study highlights a previously unreported neurological aspect of sitosterolemia. Imaging and pathology findings suggest that cholesterol crystals may be deposited in connective tissues such as the cerebral falx and pia mater through blood circulation.

Abstract The hepatocytes within the liver present an immense capacity to adapt to changes in nutrient availability. Here, by using high resolution volume electron microscopy, we map how hepatic subcellular spatial organization is regulated during nutritional fluctuations and as a function of liver zonation. We identify that fasting leads to remodeling of endoplasmic reticulum (ER) architecture in hepatocytes, characterized by the induction of single rough ER sheet around the mitochondria, which becomes larger and flatter. These alterations are enriched in periportal and mid-lobular hepatocytes but not in pericentral hepatocytes. Gain- and loss-of-function in vivo models demonstrate that the Ribosome receptor binding protein1 (RRBP1) is required to enable fasting-induced ER sheet-mitochondria interactions and to regulate hepatic fatty acid oxidation. Endogenous RRBP1 is enriched around periportal and mid-lobular regions of the liver. In obesity, ER-mitochondria interactions are distinct and fasting fails to induce rough ER sheet-mitochondrion interactions. These findings illustrate the importance of a regulated molecular architecture for hepatocyte metabolic flexibility.

To investigate the corrosion damage and degradation mechanism of NiCoCrAlY/AlSiY composite coatings in alternating high and low temperature marine environments, the corrosion damage behavior of NiCoCrAlY/AlSiY composite coatings was studied by designing the alternating high and low temperature oxidation and high temperature oxidation-acidic salt spray alternating tests. Results showed that after 50 cycles of alternating high and low temperature oxidation at 750 ℃, the coating underwent oxidative erosion in the oxidation test, but the integrity of the surface structure was not damaged. After the experiment, the weight of the alloy increased by only 3.87 mg/cm2, indicating that the coating effectively inhibited the diffusion of oxygen into the interior and prevented the substrate from oxidative attack. During the 50 cycles of alternating high temperature oxidation and acidic salt spray tests, the NiCoCrAlY/AlSiY composite coating experienced severe corrosion degradation, and the alloy weight increased to as high as 13.52 mg/cm2 by the end of the test. Due to long-term salt spray erosion, the oxide layer structure weakened, leading to surface loosening, the formation of corrosion pits, and even peeling. As the number of alternating cycles of high temperature oxidation-acidic salt spray increased, the critical reaction causing coating damage shifted from oxidative erosion to thermal corrosion. The chlorine, generated from the eutectic reaction of the mixed salt, acted as a catalytic carrier and accelerated the growth of oxidation products, demonstrating that the NiCoCrAlY/AlSiY composite coatings had weak corrosion resistance under alternating high temperature oxidation-acidic salt spray environments.

Abstract The colloidal borescope, using colloidal particle motion, is used to monitor the flow velocities and directions of groundwater. It integrates advanced techniques such as microscopy, high-speed photography, and big data computing and enjoys high sensitivity at the micron level. However, In the same well, the groundwater flow velocity monitored by colloidal hole mirror is varies greatly from that obtained by conventional hydrogeological monitoring, such as pumping test. In order to solve this problem, the stability catcher and stratified packer are designed to control the interference of the vertical flow in drilling, and to monitor the flow velocity and direction of groundwater velocity at the target aquifer and target fracture. Five wells with different aquifers and different groundwater types were selected for monitoring in south-central China. The instantaneous velocity and direction are converted into east–west component and north–south component, the average velocity and direction is calculated according to the time of 10 min, and the particle trajectory diagram is established. Based on these results, it proposed a concept of cumulative flow velocity. Using curve-fitting equations, the limits of cumulative flow velocities as the monitoring time tends to infinity were then calculated as the actual flow velocities of the groundwater. The permeability coefficient of aquifer is calculated by using the fissure ratio of aquifer, hydraulic slope and flow velocity, and compared with the permeability coefficient obtained by pumping test. The results are as follows: (1) The variation coefficient of the instantaneous flow velocity measured at the same depth in the same well at different times is greater than that of the time average flow velocity and greater than that of the cumulative flow velocity. The variation coefficient of the actual velocity is the smallest, indicating that the risk of using the actual flow velocity is lower. (2) The variation coefficient of the flow rate monitored at different depths in the same well is mainly controlled by the properties of the aquifer. The more uniform water storage space in the aquifer, the smaller the variation coefficient. (3) The comparison between the permeability coefficient obtained by monitoring and the permeability coefficient obtained by pumping test shows that the flow of structural fissure water controlled by planar fissure is more surface flow, and the results are consistent. When the groundwater flow is controlled by pores and solution gaps, the flow channel is complicated, which is easy to produce turbulent flow, and the result consistency is poor. (4) According to different research accuracy requirements, different monitoring and calculation methods can be selected for different aquifers and groundwater types. Researches show that, the permeability coefficient calculated for the actual flow velocity in well DR01 is the same as that calculated for the pumping test. The aquifer characteristics reflected by the coefficient of variation of the actual flow velocity in the same aquifer are more realistic. The pumping test method obtains the comprehensive parameters of a certain aquifer, and this method can be used to monitor a certain fissure. In this paper, the new technology developed for monitoring, and the new algorithm established for data processing, can accurately obtain the flow velocity and direction of groundwater, using capsule hole mirror monitoring method. The key parameters of hydrogeology can be obtained by using one well, which can reduce the time and cost input and improve the work efficiency.

IntroductionFreezing of gait (FOG) is a disabling and heterogeneous symptom in patients with Parkinson’s disease (PD). Among them, dopamine-induced FOG is rare and difficult to identify. The treatment of dopamine-induced FOG is complex.Case presentationWe herein presented a case of PD patient who complicated with refractory FOG. It was identified as dopamine-induced FOG during levodopa challenge test. Her symptoms were alleviated after we reduced the total equivalent dosage of levodopa.ConclusionOur report emphasizes the importance of levodopa challenge test in identifying different types of FOG, which is very important for further adjusting treatment.

Pituitary neuroendocrine tumors (PitNETs) are a special class of tumors of the central nervous system that are closely related to metabolism, endocrine functions, and immunity. In this study, network pharmacology was used to explore the metabolites and pharmacological mechanisms of PitNET regulation by gut microbiota. The metabolites of the gut microbiota were obtained from the gutMGene database, and the targets related to the metabolites and PitNETs were determined using public databases. A total of 208 metabolites were mined from the gutMGene database; 1,192 metabolite targets were screened from the similarity ensemble approach database; and 2,303 PitNET-related targets were screened from the GeneCards database. From these, 392 overlapping targets were screened between the metabolite and PitNET-related targets, and the intersection between these overlapping and gutMGene database targets (223 targets) were obtained as the core targets (43 targets). Using the protein–protein interaction (PPI) network analysis, Kyoto encyclopedia of genes and genomes (KEGG) signaling pathway and metabolic pathway analysis, CXCL8 was obtained as a hub target, tryptophan metabolism was found to be a key metabolic pathway, and IL-17 signaling was screened as the key KEGG signaling pathway. In addition, molecular docking analysis of the active metabolites and target were performed, and the results showed that baicalin, baicalein, and compound K had good binding activities with CXCL8. We also describe the potential mechanisms for treating PitNETs using the information on the microbiota (Bifidobacterium adolescentis), signaling pathway (IL-17), target (CXCL8), and metabolites (baicalin, baicalein, and compound K); we expect that these will provide a scientific basis for further study.

Under the background of rapid urbanization, a series of urgent problems have emerged in China, such as tightening resource constraints and intensifying land use conflicts (LUCs). Based on the perspective of agricultural production – residents’ life – ecological security, this study took China as the study area, applied the multi-criteria evaluation analysis method to diagnose the LUC type based on spatial statistics, coupling relationship matrix, comprehensive conflict index, and spatial autocorrelation model, then divided the LUC risk changes into seven patterns, and analyzed their spatial evolution characteristics. The results demonstrated that the scale of competition for scarce land between agriculture, construction, and ecology increased by 3.4 % over the last 20-year period. High conflict zone was mainly located in the eastern plains, which was also the main distribution zone of agriculture-construction conflict, while the agriculture-ecology conflict zone was mainly located in the west. Over time, LUC risk grade changed in 14.3 % of the study area, with the largest area of transitions from no conflict to moderate conflict (34.78 %). High intensification zone coincided almost entirely with ecologically fragile regions of the Midwest, underscoring the critical importance of LUC perspectives in ecological conservation. We provided a new perspective for the study of LUC changes and a scientific reference for realizing sustainable land use management in China and other regions.

ABSTRACT Background Helicobacter pylori (H. pylori) infection is currently widespread throughout the world. Bismuth‐containing quadruple therapy is widely used, but it has rarely been associated with interstitial lung disease. Case Presentation We described six cases with similar clinical symptoms and typical pulmonary interstitial imaging changes during anti‐H. pylori therapy, usually on Days 7–12 following treatment. Anti‐H. pylori infection treatment was discontinued when it was suspected to be the cause of the clinical symptoms, and all of the patients accepted observation therapy. All of them had a favorable outcome, the clinical symptoms returned to normal almost 1 week later, and the chest computed tomography (CT) scan images showed remarkable absorption 4 weeks later. Conclusions Drug interactions could be the cause, and the most likely drug was furazolidone. All of the patients recovered quickly after drug discontinuation, and low‐dose steroid may help shorten the recovery time.

BackgroundMultiple sclerosis (MS) is the most common non-traumatic disabling disease affecting young adults. A definitive curative treatment is currently unavailable. Many randomized controlled trials (RCTs) have reported the efficacy of Chinese herbal medicine (CHM) on MS. Because of the uncertain quality of these RCTs, the recommendations for routine use of CHM for MS remain inconclusive. The comprehensive evaluation of the quality of RCTs of CHM for MS is urgent.MethodsNine databases, namely, PubMed, Embase, Web of Science, Cochrane Library, EBSCO, Sinomed, Wanfang Database, China National Knowledge Infrastructure, and VIP Database, were searched from inception to September 2023. RCTs comparing CHM with placebo or pharmacological interventions for MS were considered eligible. The Consolidated Standards of Reporting Trials (CONSORT) and its extension for CHM formulas (CONSORT-CHM Formulas) checklists were used to evaluate the reporting quality of RCTs. The risk of bias was assessed using the Cochrane Risk of Bias tool. The selection criteria of high-frequency herbs for MS were those with cumulative frequency over 50% among the top-ranked herbs.ResultsA total of 25 RCTs were included. In the included RCTs, 33% of the CONSORT items and 21% of the CONSORT-CHM Formulas items were reported. Eligibility title, sample size calculation, allocation concealment, randomized implementation, and blinded description in CONSORT core items were reported by less than 5% of trials. For the CONSORT-CHM Formulas, the source and authentication method of each CHM ingredient was particularly poorly reported. Most studies classified the risk of bias as “unclear” due to insufficient information. The top five most frequently used herbs were, in order, Radix Rehmanniae Preparata, Radix Rehmanniae Recens, Herba Epimedii, Scorpio, and Poria. No serious adverse effect had been reported.ConclusionsThe low reporting of CONSORT items and the unclear risk of bias indicate the inadequate quality of RCTs in terms of reporting completeness and result validity. The CONSORT-CHM Formulas appropriately consider the unique characteristics of CHM, including principles, formulas, and Chinese medicinal substances. To improve the quality of RCTs on CHM for MS, researchers should adhere more closely to CONSORT-CHM Formulas guidelines and ensure comprehensive disclosure of all study design elements.

Summary: Background: The E1A-associated protein p300 (p300) has emerged as a promising target for cancer therapy due to its crucial role in promoting oncogenic signaling pathways in various cancers, including prostate cancer. This need is particularly significant in prostate cancer. While androgen deprivation therapy (ADT) has demonstrated promising efficacy in prostate cancer, its long-term use can eventually lead to the development of castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). Notably, p300 has been identified as an important co-activator of the androgen receptor (AR), highlighting its significance in prostate cancer progression. Moreover, recent studies have revealed the involvement of p300 in AR-independent oncogenes associated with NEPC. Therefore, the blockade of p300 may emerge as an effective therapeutic strategy to address the challenges posed by both CRPC and NEPC. Methods: We employed AI-assisted design to develop a peptide-based PROTAC (proteolysis-targeting chimera) drug that targets p300, effectively degrading p300 in vitro and in vivo utilizing nano-selenium as a peptide drug delivery system. Findings: Our p300-targeting peptide PROTAC drug demonstrated effective p300 degradation and cancer cell-killing capabilities in both CRPC, AR-negative, and NEPC cells. This study demonstrated the efficacy of a p300-targeting drug in NEPC cells. In both AR-positive and AR-negative mouse models, the p300 PROTAC drug showed potent p300 degradation and tumor suppression. Interpretation: The design of peptide PROTAC drug targeting p300 is feasible and represents an efficient therapeutic strategy for CRPC, AR-negative prostate cancer, and NEPC. Funding: The funding details can be found in the Acknowledgements section.

Abstract Objective Transbronchial biopsy is a safe manner with fewer complications than percutaneous transthoracic needle biopsy; however, the current diagnostic yield is still necessitating further improvement. We aimed to evaluate the diagnostic yield of using virtual bronchoscopic navigation (VBN) and cone-beam CT (CBCT) for transbronchial biopsy and to investigate the factors that affected the diagnostic sensitivity. Methods We retrospectively investigated 255 patients who underwent VBN-CBCT-guided transbronchial biopsy at our two centers from May 2021 to April 2022. A total of 228 patients with final diagnoses were studied. Patient characteristics including lesion size, lesion location, presence of bronchus sign, lesion type and imaging tool used were collected and analyzed. Diagnostic yield was reported overall and in groups using different imaging tools. Results The median size of lesion was 21 mm (range of 15.5–29 mm) with 46.1% less than 2 cm in diameter. Bronchus sign was present in 87.7% of the patients. The overall diagnostic yield was 82.1%, and sensitivity for malignancy was 66.3%. Patients with lesion > 2 cm or with bronchus sign were shown to have a significantly higher diagnostic yield. Four patients had bleeding and no pneumothorax occurred. Conclusion Guided bronchoscopy with VBN and CBCT was an effective diagnostic method and was associated with a high diagnostic yield in a safe manner. In addition, the multivariant analysis suggested that lesion size and presence of bronchus sign could be a predictive factor for successful bronchoscopic diagnosis.

Abstract CDK4/6 inhibitors (CDK4/6i) show anticancer activity in certain human malignancies, such as breast cancer. However, their application to other tumor types and intrinsic resistance mechanisms are still unclear. Here, we demonstrate that MYC amplification confers resistance to CDK4/6i in bladder, prostate and breast cancer cells. Mechanistically, MYC binds to the promoter of the E3 ubiquitin ligase KLHL42 and enhances its transcription, leading to RB1 deficiency by inducing both phosphorylated and total pRB1 ubiquitination and degradation. We identify a compound that degrades MYC, A80.2HCl, which induces MYC degradation at nanomolar concentrations, restores pRB1 protein levels and re-establish sensitivity of MYC high-expressing cancer cells to CDK4/6i. The combination of CDK4/6i and A80.2HCl result in marked regression in tumor growth in vivo. Altogether, these results reveal the molecular mechanisms underlying MYC-induced resistance to CDK4/6i and suggest the utilization of the MYC degrading molecule A80.2HCl to potentiate the therapeutic efficacy of CDK4/6i.

Abstract Objective Preimplantation genetic testing for monogenic disorders (PGT-M) has been used for over 20 years to detect many serious genetic conditions. However, there is still a lack of reference materials (RMs) to validate the test performance during the development and quality control of PGT-M. Method Sixteen thalassemia cell lines from four thalassemia families were selected to establish the RMs. Each family consisted of parents with heterozygous mutations for α- and/or β-thalassemia and two children, at least one of whom carried a homozygous thalassemia mutation (proband). The RM panel consisted of 12 DNA samples (parents and probands in 4 families) and 4 simulated embryos (cell lines constructed from blood samples from the four nonproband children). Four accredited genetics laboratories that offer verification of thalassemia samples were invited to evaluate the performance of the RM panel. Furthermore, the stability of the RMs was determined by testing after freeze‒thaw cycles and long-term storage. Results PGT-M reference materials containing 12 genome DNA (gDNA) reference materials and 4 simulated embryo reference materials for thalassemia testing were successfully established. Next-generation sequencing was performed on the samples. The genotypes and haplotypes of all 16 PGT-M reference materials were concordant across the four labs, which used various testing workflows. These well-characterized PGT-M reference materials retained their stability even after 3 years of storage. Conclusion The establishment of PGT-M reference materials for thalassemia will help with the standardization and accuracy of PGT-M in clinical use.

Objective To explore the correlation between serum level of immunoglobulin G4 （IgG4）, renal function and micro inflammatory status in patients with IgG4-related nephropathy. Methods From January 2018 to August 2022, 60 patients hsopiatlized with IgG4-related nephropathy were selected as study group while another 60 healthy volunteers chosen as control group in 1∶1 ratio based upon propensity matching. Serum level of IgG4, renal function parameters of serum creatinine （Scr）, blood urea nitrogen （BUN）, estimated glomerular filtration rate （eGFR） and 24 h urinary total protein quantification （24 hUTP） and micro inflammatory status [including interleukin-6 （IL-6）, high-sensitivity C-reactive protein （hs-CRP） and tumor necrosis factor-α （TNF-α）] were detected in both groups. Serum level of IgG4, renal function and micro inflammatory status were compared between two groups. Pearson’s method was employed for examining the correlation between serum level of IgG4, renal function and micro inflammatory status in study group. Logistic regression analysis was performed for determining the risk factors for renal insufficiency. Results Serum level of IgG4 [（67.75 ± 18.63） mg/L vs （6.54 ± 1.19） mg/L], Scr [（182.75 ± 32.69） μmol/L vs （75.40 ± 15.61） μmol/L], BUN [（10.15 ± 2.90） mmol/L vs （5.28 ± 1.04） mmol/L], IL-6 [（5.18 ± 1.04） ng/L vs （0.40 ± 0.05） ng/L], hs-CRP [（24.69 ± 5.06） mg/L vs （4.58 ± 0.92） mg/L], TNF-α [（6.85 ± 1.79） μg/L vs （1.18 ± 0.21） μg/L] and 24 hUTP [（182.75 ± 32.69） mg vs （89.75 ± 12.36） mg] were higher in study group than those in control group （P＜0.05）; eGFR was lower than that in control group [（90.10 ± 9.87） mL·min−1·（1.73 m2）−1 vs （104.36 ± 20.15） mL·min−1·（1.73 m2）−1] （P＜0.05）. Serum level of IgG4 was correlated positively with Scr, BUN, 24 hUTP, IL-6, hs-CRP and TNF-α （r = 0.586, 0.543, 0.575, 0.602, 0.596, 0.574, P＜0.05） and negatively with eGFR in study group （r = −0.602, P＜0.05）. The incidence of renal insufficiency was 78.33% in study group. Course of disease, hypertension and serum level of IgG4 were the influencing factors of renal insufficiency （OR = 3.190, 2.401, 3.466, P＜0.05）. Conclusions An elevated serum level of IgG4 in patients with IgG4-related nephropathy is correlated with renal function and micro inflammatory status. And course of disease, concurrent hypertension and serum IgG4 level are the influencing factors for renal insufficiency.

Tumor-derived exosomes have been shown to play a key role in organ-specific metastasis, and the androgen receptor regulates prostate cancer (PCa) progression. It is unclear whether the androgen receptor regulates the recruitment of prostate cancer cells to the bone microenvironment, even bone metastases, through exosomes. Here, we found that exosomes isolated from PCa cells after knocking down androgen receptor (AR) or enzalutamide treatment can facilitate the migration of prostate cancer cells to osteoblasts. In addition, AR silencing or treatment with the AR antagonist enzalutamide may increase the expression of circular RNA-deoxyhypusine synthase (circ-DHPS) in PCa cells, which can be transported to osteoblasts by exosomes. Circ-DHPS acts as a competitive endogenous RNA (ceRNA) against endogenous miR-214-3p to promote C-C chemokine ligand 5 (CCL5) levels in osteoblasts. Increasing the level of CCL5 in osteoblasts could recruit more PCa cells into the bone microenvironment. Thus, blocking the circ-DHPS/miR-214-3p/CCL5 signal may decrease exosome-mediated migration of prostate cancer cells to osteoblasts.

Abstract The last glacial inception (LGI) marks the transition from the interglacial warm climate to the glacial period with extensive Northern Hemisphere ice sheets and colder climate. This transition is initiated by decreasing boreal summer insolation but requires positive feedbacks to stimulate the appearance of perennial snow. We perform simulations of LGI with climate model AWI‐ESM‐2.1, forced by the astronomical and greenhouse gas forcing of 115,000 years before present. To compare with the preindustrial (PI) simulation, we use a consistent definition of the seasons during the LGI and the PI and evaluate model output on an angular astronomical calendar. Our study reveals a prominent role of the sea‐ice albedo feedback to amplify the delayed climate signal at polar latitudes. Through a radiative budget analysis, we examine that the ice‐albedo feedback exceeds the shortwave radiative forcing, contributing to the cooling and high latitude snow built‐up during LGI.

Summary: Background: Finding the oncogene, which was able to inhibit tumor cells intrinsically and improve the immune answers, will be the future direction for renal cancer combined treatment. Following patient sample analysis and signaling pathway examination, we propose p21-activated kinase 4 (PAK4) as a potential target drug for kidney cancer. PAK4 exhibits high expression levels in patient samples and plays a regulatory role in the immune microenvironment. Methods: Utilizing AI software for peptide drug design, we have engineered a specialized peptide proteolysis targeting chimera (PROTAC) drug with selectivity for PAK4. To address challenges related to drug delivery, we developed a nano-selenium delivery system for efficient transport of the peptide PROTAC drug, termed PpD (PAK4 peptide degrader). Findings: We successfully designed a peptide PROTAC drug targeting PAK4. PpD effectively degraded PAK4 with high selectivity, avoiding interference with other homologous proteins. PpD significantly attenuated renal carcinoma proliferation in vitro and in vivo. Notably, PpD demonstrated a significant inhibitory effect on tumor proliferation in a fully immunocompetent mouse model, concomitantly enhancing the immune cell response. Moreover, PpD demonstrated promising tumor growth inhibitory effects in mini-PDX and PDO models, further underscoring its potential for clinical application. Interpretation: This PAK4-targeting peptide PROTAC drug not only curtails renal cancer cell proliferation but also improves the immune microenvironment and enhances immune response. Our study paves the way for innovative targeted therapies in the management of renal cancer. Funding: This work is supported by Research grants from non-profit organizations, as stated in the Acknowledgments.

Drawing upon a genealogy density of chairpersons’ native places for Chinese family firms to measure the intensity of clan culture, this study uses regression analysis and chooses the fixed model with firm clusters to examine the impact of regional clan culture on firms’ corporate social responsibility (CSR). The findings suggest that family firms’ CSR performance increases with greater clan cultural intensity; specifically, firms characterized by a robust clan culture tend to engage more in socially responsible activities, prioritizing internal CSR over external initiatives. Drawing on imprinting theory, the results illustrate that clan culture shapes CSR activities by influencing chairpersons’ ethics and fostering a sense of mutual assistance. Further insights indicate that the influence of clan culture is particularly pronounced when entrepreneurs operate within their local environments or hail from large clans. However, factors such as population mobility, formal institution development, and the gender of the chairperson serve to weaken the impact of clan culture. In general, this study contributes evidence toward understanding the drivers behind family firms’ CSR behaviors from the vantage point of traditional culture.

Cardiovascular diseases (CVD) are the leading cause of death worldwide, despite advances in understanding cardiovascular health. Significant barriers still exist in effectively preventing and managing these diseases. Vascular smooth muscle cells (VSMCs) are crucial for maintaining vascular integrity and can switch between contractile and synthetic functions in response to stimuli such as hypoxia and inflammation. These transformations play a pivotal role in the progression of cardiovascular diseases, facilitating vascular modifications and disease advancement. This article synthesizes the current understanding of the mechanisms and signaling pathways regulating VSMC phenotypic transitions, highlighting their potential as therapeutic targets in cardiovascular disease interventions.

BackgroundWe sought to assess the risk of hypertension based on the trajectory of changes in serum albumin concentrations.MethodsA total of 11,946 nonhypertension adults aged 30–60 years who underwent at least 3 medical examinations between 2009 and 2016 were included in this study. Group-based trajectory models were obtained for 4 category groups, and logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for each category group of serum albumin concentration and the risk of hypertension.ResultsDuring a mean follow-up period of 4.30 years, 1,537 hypertension events occurred in 11,946 subjects without hypertension. A high stable trajectory of serum albumin concentrations (OR, 0.70, 95% CI, 0.51–0.96) was associated with a significantly lower risk of developing hypertension. The results of the sensitivity analysis of the high stable trajectory (OR, 0.64, 95% CI, 0.43–0.96) remained statistically significant. Subjects with normal weight and those ≥45 years of age had a significantly lower risk of hypertension at moderate increase (P = 0.053 or 0.026) and high stable trajectories (P = 0.011 or 0.016). In males and overweight subjects, the risk of hypertension was significantly lower in the high stable trajectory (P = 0.038 or 0.044).ConclusionIn this study, we found that moderate increase in serum albumin concentrations and a high stable trajectory were significantly associated with a reduced risk of hypertension in subjects aged ≥45 years and those with normal weight and that high stable serum albumin concentrations were significantly associated with a reduced risk of hypertension in males and overweight subjects.

BackgroundThe successful implementation of assisted ventilation depends on matching the patient’s effort with the ventilator support. Pressure muscle index (PMI), an airway pressure based measurement, has been used as noninvasive monitoring to assess the patient’s inspiratory effort. The authors aimed to evaluate the feasibility of pressure support adjustment according to the PMI target and the diagnostic performance of PMI to predict the contribution of the patient’s effort during ventilator support.MethodsIn this prospective physiological study, 22 adult patients undergoing pressure support ventilation were enrolled. After an end-inspiratory airway occlusion, airway pressure reached a plateau, and the magnitude of change in plateau from peak airway pressure was defined as PMI. Pressure support was adjusted to obtain the PMI which was closest to −1, 0, +1, +2, and + 3 cm H2O. Each pressure support level was maintained for 20 min. Esophageal pressure was monitored. Pressure–time products of respiratory muscle and ventilator insufflation were measured, and the fraction of pressure generated by the patient was calculated to represent the contribution of the patient’s inspiratory effort.ResultsA total of 105 datasets were collected at different PMI-targeted pressure support levels. The differences in PMI between the target and the obtained value were all within ±1 cm H2O. As targeted PMI increased, pressure support settings decreased significantly from a median (interquartile range) of 11 (10–12) to 5 (4–6) cm H2O (p

The present study aimed to investigate the impact of hydrogen (H2) on chronic intermittent hypoxia (CIH)-induced cardiac hypertrophy in mice by modulating iron metabolism. C57BL/6N mice were randomly allocated into four groups: control (Con), CIH, CIH + H2, and H2. The mice were exposed to CIH (21–5% FiO2, 3 min/cycle, 8 h/d), and received inhalation of a hydrogen–oxygen mixture (2 h/d) for 5 weeks. Cardiac and mitochondrial function, levels of reactive oxygen species (ROS), and iron levels were evaluated. The H9C2 cell line was subjected to intermittent hypoxia (IH) and treated with H2. Firstly, we found H2 had a notable impact on cardiac hypertrophy, ameliorated pathological alterations and mitochondrial morphology induced by CIH (p < 0.05). Secondly, H2 exhibited a suppressive effect on oxidative injury by decreasing levels of inducible nitric oxide synthase (i-NOS) (p < 0.05) and 4-hydroxynonenal (4-HNE) (p < 0.01). Thirdly, H2 demonstrated a significant reduction in iron levels within myocardial cells through the upregulation of ferroportin 1 (FPN1) proteins (p < 0.01) and the downregulation of transferrin receptor 1 (TfR1), divalent metal transporter 1 with iron-responsive element (DMT1(+ire)), and ferritin light chain (FTL) mRNA or proteins (p < 0.05). Simultaneously, H2 exhibited the ability to decrease the levels of Fe2+ and ROS in H9C2 cells exposed to IH (p < 0.05). Moreover, H2 mediated the expression of hepcidin, hypoxia-inducible factor-1α (HIF-1α) (p < 0.01), and iron regulatory proteins (IRPs), which might be involved in the regulation of iron-related transporter proteins. These results suggested that H2 may be beneficial in preventing cardiac hypertrophy, a condition associated with reduced iron toxicity.

Abstract Ample evidence has suggested the stress etiology of depression, but the underlying mechanism is not fully understood yet. Here, we report that chronic social defeat stress (CSDS) attenuates the excitatory output of the claustrum (CLA) to the prelimbic cortex (PL) through the dynorphin/κ-opioid receptor (KOR) signaling, being critical for depression-related behaviors in male mice. The CSDS preferentially impairs the excitatory output from the CLA onto the parvalbumin (PV) of the PL, leading to PL micronetwork dysfunction by disinhibiting pyramidal neurons (PNs). Optogenetic activation or inhibition of this circuit suppresses or promotes depressive-like behaviors, which is reversed by chemogenetic inhibition or activation of the PV neurons. Notably, manipulating the dynorphin/KOR signaling in the CLA-PL projecting terminals controls depressive-like behaviors that is suppressed or promoted by optogenetic activation or inhibition of CLA-PL circuit. Thus, this study reveals both mechanism of the stress etiology of depression and possibly therapeutic interventions by targeting CLA-PL circuit.

The non-stationary, complex, and non-linear characteristics of streamflow time series have a significant impact on the simulation results of the conventional hydrological forecasting models. To improve the performances, this paper develops an enhanced machine learning model for streamflow time series forecasting, where the twin support vector regression (TSVR) is combined with singular spectrum analysis (SSA) and grey wolf optimizer (GWO). Specially, the SSA method is set as the data preprocessing tool for pattern identification; the TSVR model is set as the basic forecasting module for each pattern and the GWO method is used as the optimizer to select feasible parameter combination. Multi-step-ahead streamflow forecasting tasks are used to examine the feasibility and predictability of the proposed model. The results indicate that the proposed model can yield superior results compared with the traditional forecasting models. Thus, a robust and reliable tool is provided for streamflow time series forecasting under uncertainty.

Abstract Background Pyroptosis is crucial for controlling various immune cells. However, the role of allergen-induced CD11c + dendritic cell (DC) pyroptosis in allergic rhinitis (AR) remains unclear. Methods Mice were grouped into the control group, AR group and necrosulfonamide-treated AR group (AR + NSA group). The allergic symptom scores, OVA-sIgE titres, serum IL-1β/IL-18 levels, histopathological characteristics and T-helper cell-related cytokines were evaluated. CD11c/GSDMD-N-positive cells were examined by immunofluorescence analysis. Murine CD11c + bone marrow-derived DCs (BMDCs) were induced in vitro, stimulated with OVA/HDM, treated with necrosulfonamide (NSA), and further cocultured with lymphocytes to assess BMDC function. An adoptive transfer murine model was used to study the role of BMDC pyroptosis in allergic rhinitis. Results Inhibiting GSDMD-N-mediated pyroptosis markedly protected against Th1/Th2/Th17 imbalance and alleviated inflammatory responses in the AR model. GSDMD-N was mainly coexpressed with CD11c (a DC marker) in AR mice. In vitro, OVA/HDM stimulation increased pyroptotic morphological abnormalities and increased the expression of pyroptosis-related proteins in a dose-dependent manner; moreover, inhibiting pyroptosis significantly decreased pyroptotic morphology and NLRP3, C-Caspase1 and GSDMD-N expression. In addition, OVA-induced BMDC pyroptosis affected CD4 + T-cell differentiation and related cytokine levels, leading to Th1/Th2/Th17 cell imbalance. However, the Th1/Th2/Th17 cell immune imbalance was significantly reversed by NSA. Adoptive transfer of OVA-loaded BMDCs promoted allergic inflammation, while the administration of NSA to OVA-loaded BMDCs significantly reduced AR inflammation. Conclusion Allergen-induced dendritic cell pyroptosis promotes the development of allergic rhinitis through GSDMD-N-mediated pyroptosis, which provides a clue to allergic disease interventions. Video Abstract

Abstract Direct seeding of rice (Oryza sativa L.) is a low-labor and sustainable cultivation method that is used worldwide. Seed vigor and early vigor are important traits associated with seedling stand density (SSD) and weed competitive ability (WCA), which are key factors in direct-seeded rice (DSR) cultivation systems. Here, we developed a set of chromosome segment substitution lines with Xiushui134 as receptor parent and Yangdao6 as donor parent and used these lines as a mapping population to identify quantitative trait loci (QTLs) for seed vigor, which we evaluated based on germinability–related indicators (germination percentage (GP), germination energy (GE), and germination index (GI)) and seedling vigor–related indicators (root number (RN), root length (RL), and shoot length (SL) at 14 days after imbibition) under controlled conditions in an incubator. Ten QTLs were detected across four chromosomes, of which a cluster of QTLs (qGP11, qGE11, qGI11, and qRL11) co-localized on Chr. 11 with high LOD values (12.03, 8.13, 7.14, and 8.75, respectively). Fine mapping narrowed down the QTL cluster to a 0.7-Mb interval between RM26797 and RM6680. Further analysis showed that the QTL cluster has a significant effect (p

The physical body of an organism serves as a vital interface for interactions with its environment. Here, we investigated the impact of human body size on the perception of action possibilities (affordances) offered by the environment. We found that the body size delineated a distinct boundary on affordances, dividing objects of continuous real-world sizes into two discrete categories with each affording distinct action sets. Additionally, the boundary shifted with imagined body sizes, suggesting a causal link between body size and affordance perception. Intriguingly, ChatGPT, a large language model lacking physical embodiment, exhibited a modest yet comparable affordance boundary at the scale of human body size, suggesting the boundary is not exclusively derived from organism-environment interactions. A subsequent fMRI experiment offered preliminary evidence of affordance processing exclusively for objects within the body size range, but not for those beyond. This suggests that only objects capable of being manipulated are the objects capable of offering affordance in the eyes of an organism. In summary, our study suggests a novel definition of object-ness in an affordance-based context, advocating the concept of embodied cognition in understanding the emergence of intelligence constrained by an organism’s physical attributes.

The ongoing pace of urbanization poses a substantial obstacle to the concurrent progress of both financial and ecological development. Recognizing this challenge, governments globally are formulating cutting-edge strategies for urban renewal to ensure the long-term sustainability of cities. In this context, we employ a difference-in-differences model to scrutinize the intricate relationship between smart cities and the growth of renewable energy, utilizing the Chinese smart city pilot program as a pertinent experiment. This analytical approach provides novel insights into the underlying reasons behind this correlation. The research yields three noteworthy findings. Firstly, it underscores the indispensable role of pilot initiatives in smart cities for advancing the cause of renewable energy. Secondly, the study reveals a positive and beneficial interplay between creativity, economic inclusion, and the utilization of technological innovation in experimental urban programs, suggesting a potential multiplier effect. Thirdly, the local context significantly influences the impact of smart city pilots, with the dissemination of renewable energy being particularly effective in resource-rich, metropolitan, and coastal cities. Observable impacts of current smart city experiment on energy security and sustainable development are already apparent. The research findings contribute fresh perspectives to the complex challenges of sustainable energy production and urban planning, especially in developing countries like China.

Background: Arterial pulsation has been suggested as a key driver of paravascular cerebrospinal fluid flow, which is the foundation of glymphatic clearance. However, whether intracranial arterial pulsatility is associated with glymphatic markers in humans has not yet been studied. Methods: Seventy-three community participants were enrolled in the study. 4D phase-contrast magnetic resonance imaging (MRI) was used to quantify the hemodynamic parameters including flow pulsatility index (PIflow) and area pulsatility index (PIarea) from 13 major intracerebral arterial segments. Three presumed neuroimaging markers of the glymphatic system were measured: including dilation of perivascular space (PVS), diffusivity along the perivascular space (ALPS), and volume fraction of free water (FW) in white matter. We explored the relationships between PIarea, PIflow, and the presumed glymphatic markers, controlling for related covariates. Results: PIflow in the internal carotid artery (ICA) C2 segment (OR, 1.05; 95 % CI, 1.01–1.10, per 0.01 increase in PI) and C4 segment (OR, 1.05; 95 % CI, 1.01–1.09) was positively associated with the dilation of basal ganglia PVS, and PIflow in the ICA C4 segment (OR, 1.06, 95 % CI, 1.02–1.10) was correlated with the dilation of PVS in the white matter. ALPS was associated with PIflow in the basilar artery (β, -0.273, p, 0.046) and PIarea in the ICA C2 (β, -0.239, p, 0.041) and C7 segments (β, -0.238, p, 0.037). Conclusions: : Intracranial arterial pulsatility was associated with presumed neuroimaging markers of the glymphatic system, but the results were not consistent across different markers. Further studies are warranted to confirm these findings.

ABSTRACT: Wenchang chicken, a prized local breed in Hainan Province of China renowned for its exceptional adaptability to tropical environments and good meat quality, is deeply favored by the public. However, an insufficient understanding of its population architecture and the unclear genetic basis that governs its typical attributes have posed challenges in the protection and breeding of this precious breed. To address these gaps, we conducted whole-genome resequencing on 200 Wenchang chicken samples derived from 10 distinct strains, and we gathered data on an array of 21 phenotype traits. Population genomics analysis unveiled distinctive population structures in Wenchang chickens, primarily attributed to strong artificial selection for different feather colors. Selection sweep analysis identified a group of candidate genes, including PCDH9, DPF3, CDIN1, and SUGCT, closely linked to adaptations that enhance resilience in tropical island habitats. Genome-wide association studies (GWAS) highlighted potential candidate genes associated with diverse feather color traits, encompassing TYR, RAB38, TRPM1, GABARAPL2, CDH1, ZMIZ1, LYST, MC1R, and SASH1. Through the comprehensive analysis of high-quality genomic and phenotypic data across diverse Wenchang chicken resource groups, this study unveils the intricate genetic backgrounds and population structures of Wenchang chickens. Additionally, it identifies multiple candidate genes linked to environmental adaptation, feather color variations, and production traits. These insights not only provide genetic reference for the purification and breeding of Wenchang chickens but also broaden our understanding of the genetic basis of phenotypic diversity in chickens.

Three-dimensional (3D) phenotyping is important for studying plant structure and function. Light detection and ranging (LiDAR) has gained prominence in 3D plant phenotyping due to its ability to collect 3D point clouds. However, organ-level branch detection remains challenging due to small targets, sparse points, and low signal-to-noise ratios. In addition, extracting biologically relevant angle traits is difficult. In this study, we developed a stratified, clustered, and growing-based algorithm (SCAG) for soybean branch detection and branch angle calculation from LiDAR data, which is heuristic, open-source, and expandable. SCAG achieved high branch detection accuracy (F-score = 0.77) and branch angle calculation accuracy (r = 0.84) when evaluated on 152 diverse soybean varieties. Meanwhile, the SCAG outperformed 2 other classic algorithms, the support vector machine (F-score = 0.53) and density-based methods (F-score = 0.55). Moreover, after applying the SCAG to 405 soybean varieties over 2 consecutive years, we quantified various 3D traits, including canopy width, height, stem length, and average angle. After data filtering, we identified novel heritable and repeatable traits for evaluating soybean density tolerance potential, such as the ratio of average angle to height and the ratio of average angle to stem length, which showed greater potential than the well-known ratio of canopy width to height trait. Our work demonstrates remarkable advances in 3D phenotyping and plant architecture screening. The algorithm can be applied to other crops, such as maize and tomato. Our dataset, scripts, and software are public, which can further benefit the plant science community by enhancing plant architecture characterization and ideal variety selection.

Early and precise detection and identification of various pathogens are essential for epidemiological monitoring, disease management, and reducing the prevalence of clinical infectious diseases. Traditional pathogen detection techniques, which include mass spectrometry, biochemical tests, molecular testing, and culture-based methods, are limited in application and are time-consuming. Next generation sequencing (NGS) has emerged as an essential technology for identifying pathogens. NGS is a cutting-edge sequencing method with high throughput that can create massive volumes of sequences with a broad application prospects in the field of pathogen identification and diagnosis. In this review, we introduce NGS technology in detail, summarizes the application of NGS in that identification of different pathogens, including bacteria, fungi, and viruses, and analyze the challenges and outlook for using NGS to identify clinical pathogens. Thus, this work provides a theoretical basis for NGS studies and provides evidence to support the application of NGS in distinguishing various clinical pathogens.

Freshwater lakes as an essential component of the ecosystem, provide ecological resources in addition to economic source for humans. Under recent climate change scenario, preserving the biodiversity of freshwater ecosystems is crucial. This study aimed to characterize the diversity of zooplankton communities in Dianchi Lake, located in Kunming Municipality, Yunnan Province, China, using Illumina high-throughput sequencing of the cytochrome oxidase subunit 1 (COI) gene marker. A total of 18 water samples were collected including 16 from the outer sea area of Dianchi Lake: 4 from the east (E1-4), 4 from the west (W1-4), 4 from the south (S1-4), and 4 from the north (N1-4), and: 2 from the Caohai area (C1-2) as research sites. All environmental parameters including pH, ammonium (NH4+), total nitrogen (TN), total phosphorus (TP), chlorophyll a content (CHLA) were found to be insignificant (p > 0.05), except for chemical oxygen demand (COD) and transparency (T), which were found to be significant (p < 0.05). Alpha diversity indices including ACE, Chao1, Shannon, and Simpson showed non-significant differences (p > 0.05), indicating no variation in the richness of zooplankton communities at different locations of Dianchi Lake. However, principal coordinate analysis (PCoA) showed that most of the samples from East, West, and South groups were close to each other, showing more similarities among them, while Caohai and North group samples were distant from each other, showing more differences with other groups. Rotifera, Arthropoda, and Chordata were the top three phyla, while Keratella, Macrothrix, and Brachionus were the dominant genera. Mantel test analysis showed that COD and transparency were important environmental factors that shaped the Rotifera community structure of Dianchi Lake. In conclusion, this study provides insights on conserving the diversity of zooplankton communities in Dianchi Lake, especially by controlling COD and maintaining water transparency, in order to preserve its ecological resources and economic significance.