Structural Basis of the Dehydratase Module (hDH) of Human Fatty Acid Synthase.

The human fatty acid synthase (hFASN) produces fatty acids for cellar membrane construction, energy storage, biomolecule modifications and signal transduction. Abnormal expression and functions of hFASN highly associate with numerous human diseases such as obesity, diabetes, and cancers, and thereby it has been considered as a valuable potential drug target. So far, the structural and catalytic mechanisms of most of the hFASN enzymatic modules have been extensively studied, except the key dehydratase module (hDH). Here we presented the enzymatic characterization and the high-resolution crystal structure of hDH. We demonstrated that the hDH preferentially catalyzes the acyl substrates with short lengths between 4 to 8-carbons, and exhibits much lower enzymatic activity on longer substrates. Subsequent structural study showed that hDH displays a pseudo-dimeric organization with a single L-shaped composite hydrophobic catalytic tunnel as well as an atypical ACP binding site nearby, indicating that hDH achieves distinct substrate recognition and dehydration mechanisms compared to the conventional bacterial fatty acid dehydratases identified. Our findings laid the foundation for understanding the biological and pathogenic functions of hFASN, and may facilitate therapeutical drug development against diseases with abnormal functionality of hFASN.

A radiomics model for predicting perineural invasion in stage II-III colon cancer based on computer tomography.

BACKGROUND: Colon cancer, a frequently encountered malignancy, exhibits a comparatively poor survival prognosis. Perineural invasion (PNI), highly correlated with tumor progression and metastasis, is a substantial effective predictor of stage II-III colon cancer. Nonetheless, the lack of effective and facile predictive methodologies for detecting PNI prior operation in colon cancer remains a persistent challenge. METHOD: Pre-operative computer tomography (CT) images and clinical data of patients diagnosed with stage II-III colon cancer between January 2015 and December 2023 were obtained from two sub-districts of Sun Yat-sen Memorial Hospital (SYSUMH). The LASSO/RF/PCA filters were used to screen radiomics features and LR/SVM models were utilized to construct radiomics model. A comprehensive model, shown as nomogram finally, combining with radiomics score and significant clinical features were developed and validated by area under the curve (AUC) and decision curve analysis (DCA). RESULT: The total cohort, comprising 426 individuals, was randomly divided into a development cohort and a validation cohort as a 7:3 ratio. Radiomics scores were extracted from LASSO-SVM models with AUC of 0.898/0.726 in the development and validation cohorts, respectively. Significant clinical features (CA199, CA125, T-stage, and N-stage) were used to establish combining model with radiomics scores. The combined model exhibited superior reliability compared to single radiomics model in AUC value (0.792 vs. 0.726, p = 0.003) in validation cohorts. The radiomics-clinical model demonstrated an AUC of 0.918/0.792, a sensitivity of 0.907/0.813 and a specificity of 0.804/0.716 in the development and validation cohorts, respectively. CONCLUSION: The study developed and validated a predictive nomogram model combining radiomics scores and clinical features, and showed good performance in predicting PNI pre-operation in stage II-III colon cancer patients.

Pancancer analysis uncovers an immunological role and prognostic value of the m6A reader IGF2BP2 in pancreatic cancer.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant gastrointestinal tumors worldwide with a dismal prognosis and high relapse rate. PDAC is considered a "cold cancer" for which immunotherapy is not effective. Therefore, to improve the prognosis for PDAC patients, it is urgent to explore the mechanism driving its insensitivity to immunotherapy. MATERIALS AND METHODS: We conducted pancancer analyses to test IGF2BP family expression and survival in patients with different cancers via TCGA and GETx databases. Then, we determined the immunological role and prognostic value of IGF2BP2 in vitro, in vivo and in clinical specimens. RESULTS: In the present study, we found that the m6A reader IGF2BP2 was the most clinically relevant member of the IGF2BP family for pancreatic cancer. High expression of IGF2BP2 was most associated with poor prognosis and an immunosuppressive microenvironment in PDAC. By IGF2BP2 knockdown, we found that tumor cell proliferation and invasive ability were significantly diminished. Importantly, we found that IGF2BP2 expression was closely associated with high expression of immunosuppressive molecules such as PD-L1. IGF2BP2 modulated downstream PD-L1 expression by regulating its mRNA stability via m6A methylation control, and we obtained the same verification in animal experiments and human tissue specimens. CONCLUSION: Our study contributes to existing knowledge regarding the IGF2BP2-regulated PD-L1 signaling pathway as a potential prognostic and immune biomarker in pancreatic cancer.

The ß-Ketoacyl-ACP Synthase FabF Catalyzes Carbon-Carbon Bond Formation in a Bimodal Pattern for Fatty Acid Biosynthesis.

Fatty acids produced by the type-II fatty acid biosynthetic pathway (FAS-II) are essential biomaterials for bacterial membrane construction and numerous metabolic routes. The ß-ketoacyl-ACP synthase FabF catalyzes the key C-C bond formation step for fatty acid elongation in FAS-II. Here, we revealed the substrate recognition and catalytic mechanisms of FabF by determining FabF-ACP complexes. FabF displays a distinctive bimodal catalytic pattern specifically on C6 and C10 acyl-ACP substrates. It utilizes positively charged residues located on the η3-helix and loop1 regions near the catalytic tunnel entrance to bind ACP, and two hydrophobic cavities as well as "front", "middle", and "back" door residues to specifically stabilize C6 and C10 acyl substrates for preferential catalysis. Further quantum chemistry calculations suggest that the FabF catalytic residues Lys336 and His304 facilitate proton transfer during condensation catalysis and C-C bond formation. Our results provide key mechanistic insights into the biosynthesis of molecular carbon skeletons based on ketosynthases that are highly conserved through the FAS and polyketide synthase (PKS) analogous biosynthetic routes, broaden the understanding of the tricarboxylic acid cycle that utilizes lipoic acid derived from C8-ACP accumulated due to the FabF distinctive catalytic pattern for oxidative decarboxylations, and may facilitate the development of narrow-spectrum antibacterial drugs.

CCL3 secreted by hepatocytes promotes the metastasis of intrahepatic cholangiocarcinoma by VIRMA-mediated N6-methyladenosine (m6A) modification.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a malignant disease characterized by onset occult, rapid progression, high relapse rate, and high mortality. However, data on how the tumor microenvironment (TME) regulates ICC metastasis at the transcriptomic level remains unclear. This study aimed to explore the mechanisms and interactions between hepatocytes and ICC cells. METHODS: We analyzed the interplay between ICC and liver microenvironment through cytokine antibody array analysis. Then we investigated the role of N6-methyladenosine (m6A) modification and the downstream target in vitro, in vivo experiments, and in clinical specimens. RESULTS: Our study demonstrated that cytokine CCL3, which is secreted by hepatocytes, promotes tumor metastasis by regulating m6A modification via vir-like m6A methyltransferase associated (VIRMA) in ICC cells. Moreover, immunohistochemical analyses showed that VIRMA correlated with poor outcomes in ICC patients. Finally, we confirmed both in vitro and in vivo that CCL3 could activate VIRMA and its critical downstream target SIRT1, which fuels tumor metastasis in ICC. CONCLUSIONS: In conclusion, our results enhanced our understanding of the interaction between hepatocytes and ICC cells, and revealed the molecular mechanism of the CCL3/VIRMA/SIRT1 pathway via m6A-mediated regulation in ICC metastasis. These studies highlight potential targets for the diagnosis, treatment, and prognosis of ICC.

Arsenic exposure and pruritus: Evidence from observational, interventional, and mendelian randomization studies.

BACKGROUND: Pruritus is identified as an adverse drug reaction to arsenic trioxide, but the association of arsenic exposure with pruritus has not been investigated. METHODS: A cross-sectional study was conducted in Shimen, China. A Mendelian randomization analysis was conducted to confirm the causal relationship between genetically predicted percentages of monomethylated arsenic (MMA%) and dimethylated arsenic (DMA%) in urine with chronic pruritus in UK Biobank. A case-control study was then conducted to determine the biomarker for pruritus. Arsenite-treated mice were used to confirm the biomarker, and von Frey test was used to induce scratching bouts. Last, a randomized, double-blind, placebo-controlled trial was conducted to test the efficacy of naloxone in arsenic-exposed patients with pruritus in Shimen. RESULTS: Hair arsenic (µg/g) showed a dose-response relationship with the intensity of itch in 1079 participants, with odds ratios (OR) of 1.11 for moderate-to-severe itch (p = 0.012). The Mendelian randomization analysis confirmed the causal relationship, with ORs of 1.043 for MMA% (p = 0.029) and 0.904 for DMA% (p = 0.077) above versus under median. Serum ß-endorphin was identified as a significant biomarker for the intensity of itch (p < 0.001). Consistently, treatment with arsenite upregulated the level of ß-endorphin (p = 0.002) and induced scratching bouts (p < 0.001) in mice. The randomized controlled trial in 126 participants showed that treatment with sublingual naloxone significantly relieved the intensity of itch in arsenic-exposed participants in 2 weeks (ß = -0.98, p = 0.04). CONCLUSION: Arsenic exposure is associated with pruritus, and ß-endorphin serves as a biomarker of pruritus. Naloxone relieves pruritus in patients with arseniasis.

The Molecular Basis of Catalysis by SDR Family Members Ketoacyl-ACP Reductase FabG and Enoyl-ACP Reductase FabI in Type-II Fatty Acid Biosynthesis.

The short-chain dehydrogenase/reductase (SDR) superfamily members acyl-ACP reductases FabG and FabI are indispensable core enzymatic modules and catalytic orientation controllers in type-II fatty acid biosynthesis. Herein, we report their distinct substrate allosteric recognition and enantioselective reduction mechanisms. FabG achieves allosteric regulation of ACP and NADPH through ACP binding across two adjacent FabG monomers, while FabI follows an irreversible compulsory order of substrate binding in that NADH binding must precede that of ACP on a discrete FabI monomer. Moreover, FabG and FabI utilize a backdoor residue Phe187 or a "rheostat" α8 helix for acyl chain length selection, and their corresponding triad residues Ser142 or Tyr145 recognize the keto- or enoyl-acyl substrates, respectively, facilitating initiation of nucleophilic attack by NAD(P)H. The other two triad residues (Tyr and Lys) mediate subsequent proton transfer and (R)-3-hydroxyacyl- or saturated acyl-ACP production.

New Insights into the Microplastic Enrichment in the Blue Carbon Ecosystem: Evidence from Seagrass Meadows and Mangrove Forests in Coastal South China Sea.

Microplastics were recently found to aggregate in the blue carbon ecosystems (BCEs), which are known for their ability to store carbon by slowing down the water flow. However, evidence is largely lacking on how the accumulation of microplastics is related to carbon sequestration in BCEs and if this trap effect is driven by its biological characteristics. In this study, the trap effect of microplastics by BCEs was evaluated for various seagrasses (Zostera japonica, Halophila ovalis, and Halophila beccarii) and mangroves (Aegiceras corniculatum and Avicennia marina). Significant accumulation was found in the seagrass meadow dominated by H. beccarii and the mangrove forest dominated by A. marina, with microplastics enriched by 1.3 to 17.6 times compared to their corresponding unvegetated sites. The abundance of microplastics varied greatly from 17.68 ± 8.10 to 611.75 ± 81.52 particles per kg of dry sediment, with the highest abundance in A. marina mangrove sediments. A strong positive correlation was found between the abundance of microplastics and the particulate organic carbon content at all study sites (Pearson, R = 0.86, p < 0.01). Higher diversity of microplastic colors and size was found in the H. beccarii meadow, and higher diversity of shapes was found in the A. marina forest. Our results added new insights to the understanding of the mechanism of microplastic trapping by BCEs and coupled the behavior of microplastics with the organic carbon in the sediment.

Hereditary intrinsic factor deficiency in China caused by a novel mutation in the intrinsic factor gene-a case report.

BACKGROUND: Hereditary intrinsic factor deficiency is a rare disease characterized by cobalamin deficiency with the lack of gastric intrinsic factor because of gastric intrinsic factor (GIF) mutations. Patients usually present with cobalamin deficiency without gastroscopy abnormality and intrinsic factor antibodies. CASE PRESENTATION: A Chinese patient presented with recurrent severe anemia since age 2 with low cobalamin level and a mild elevation of indirect bilirubin. The hemoglobin level normalized each time after intramuscular vitamin B12 injection. Gene test verified a c.776delA frame shift mutation in exon 6 combined with c.585C > A nonsense early termination mutation in exon 5 of GIF which result in the dysfunction of gastric intrinsic factor protein. The hereditary intrinsic factor deficiency in literature was further reviewed and the ancestry of different mutation sites were discussed. CONCLUSIONS: A novel compound heterozygous mutation of GIF in a Chinese patient of hereditary intrinsic factor deficiency was reported. It was the first identified mutation of GIF in East-Asia and may indicate a new ancestry.

Daily Intake of Soft Drinks and Moderate-to-Severe Acne Vulgaris in Chinese Adolescents.

OBJECTIVES: To investigate the association of soft drink consumption and the intake of sugar from soft drinks with the prevalence of acne in adolescents. STUDY DESIGN: This was a university-based epidemiologic investigation that included 8226 students who underwent health examinations and a questionnaire survey inquiring about the intake of soft drinks. Skin diseases were diagnosed by certificated dermatologists during the health examination. Two-level logistic and generalized additive models were used to estimate the associations, and aORs were presented as the effect size. RESULTS: A total of 8197 student survey responses were analyzed. Frequent intake (≥7 times per week) of carbonated sodas (aOR 1.61, 95% CI 0.96-2.72), sweetened tea drinks (aOR 2.52, 95% CI 1.43-4.43), and fruit-flavored drinks (aOR 1.90, 95% CI 1.18-3.07) was associated with moderate-to-severe acne after adjustments for confounders. The occasional intake of fruit-flavored drinks (1-2 times per week) had a weak protective effect on acne (aOR 0.86, 95% CI 0.74-0.99). The intake of sugar from any soft drinks showed a nonlinear association with acne (P < .01), and sugar intake ≥100 g/d was significantly associated with moderate-to-severe acne (aOR 3.12, 95% CI 1.80-5.41). CONCLUSIONS: Daily soft drink consumption significantly increases the risk of moderate-to-severe acne in adolescents, especially when the sugar intake from any type of soft drink exceeds 100 g per day.

Prediction of thrombosis risk in patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic disease with thrombosis as a major complication. The mechanism of thrombosis and related risk factors in PNH patients are still not well characterized. We retrospectively enrolled 99 patients with newly diagnosed PNH at our institute from 2011 to 2016. According to binary logistic regression model analysis, we first identified four baseline clinical risk factors which may be associated with incidence of thrombosis in the PNH cohort, including PNH clone sizes (fluorescent aerolysin of neutrophil) ≤ 80 (OR 1.056, 95%CI 1.016-1.097, P = 0.005), hemoglobin ≤ 75 g/L (OR 4.202, 95%CI 0.984-17.954, P = 0.053), platelet > 100 × 109/L (OR 6.547, 95%CI 1.490-28.767, P = 0.013) and rs495828 = G (OR 5.243, 95%CI 1.314-20.916, P = 0.019). These independent risk factors were combined together to develop a risk model to evaluate thrombosis risk (AUC = 0.756, 95%CI 0.607-0.905, P < 0.001). Our risk model revealed a higher cumulative incidence of thrombosis and an earlier thrombosis events in PNH patients with high risk (risk score ≥ 23) compared with those with low risk (risk score < 23, P < 0.001 and P = 0.043, respectively). Although with some limitations, we set up a prediction model for thrombosis risk in patients with PNH for the first time, but it needed to be verified in a prospective study with larger patients and longer follow-up time in the future.

Correction to: prediction of thrombosis risk in patients with paroxysmal nocturnal hemoglobinuria.

The authors determined an error in the affiliation section; it was captured as Department of Hematology, Peking Union Hospital, CAMS & PUMC, Beijing 100,730, China. The correct affiliation should be Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.

The Prevalence of Atopic Dermatitis and Chronic Spontaneous Urticaria are Associated with Parental Socioeconomic Status in Adolescents in China.

The association of atopic dermatitis and chronic spontaneous urticaria with socioeconomic status has been little studied. The aim of this study was to investigate the prevalence of skin diseases and their association with socioeconomic status in adolescents in China. A cross-sectional study was conducted at Central South University, Changsha, China. All newly enrolled students underwent dermatological examination and completed a survey. Socioeconomic status was measured in terms of parental education level and income. Two-level logistic regression models were used. A total of 8,226 students consented to participate. On dermatological examination, moderate to severe acne (10.2%) had the highest prevalence, followed by chronic spontaneous urticaria (2.7%), atopic dermatitis (2.5%), and tinea (1.7%). Socioeconomic status was positively associated with the prevalence of chronic spontaneous urticaria (ptrend = 0.001) and atopic dermatitis (ptrend = 0.0094). Tinea was inversely associated with socioeconomic status (ptrend = 0.025). Higher parental socioeconomic status was associated with higher risk of atopic dermatitis and chronic spontaneous urticaria, but lower risk of tinea.

Daily intake of soft drinks is associated with symptoms of anxiety and depression in Chinese adolescents.

OBJECTIVE: The association of soft drink consumption with mental problems in Asian adolescents has not been reported. The present study aimed to investigate the association of soft drink consumption and symptoms of anxiety and depression in adolescents in China. DESIGN: A cross-sectional study to investigate the association of intake of soft drinks and sugars from soft drinks with symptoms of anxiety and depression measured by the two-item Generalized Anxiety Disorder (GAD-2) and the Patient Health Questionnaire (PHQ-2), respectively. SETTING: A comprehensive university in Changsha, China. PARTICIPANTS: Newly enrolled college students in 2017. RESULT: In total, 8226 students completed the investigation and 8085 students with no systemic disorders were finally analysed. Students consuming soft drinks ≥7 times/week had significantly higher (mean difference; 95 % CI) GAD-2 (0·15; 0·07, 0·23) and PHQ-2 (0·27; 0·19, 0·35) scores compared with those barely consuming soft drinks, adjusted for demographic and behavioural factors. Those consuming >25 g sugar/d from soft drinks had significantly higher GAD-2 (0·11; 0·04, 0·18) and PHQ-2 (0·22; 0·15, 0·29) scores compared with non-consumers. The mediation effect of obesity in the associations was not clinically significant. CONCLUSIONS: Adolescents consuming soft drinks ≥7 times/week, or >25 g sugar/d from soft drinks, had significantly higher levels of anxiety and depression. Dietary suggestion is needed to prevent anxiety and depression in adolescents.

Assessment of the Dermatology Life Quality Index (DLQI) in a homogeneous population under lifetime arsenic exposure.

PURPOSE: The psychometric property of the Dermatology Life Quality Index (DLQI) is underappreciated in public health settings. Our study aimed to assess the reliability, validity, and measurement invariance of DLQI in a homogeneous population with arsenic-related skin lesions and symptoms. METHODS: A cross-sectional study was conducted in communities under lifetime arsenic exposure. The DLQI was measured through a face-to-face interview. Skin examinations were performed by certificated dermatologists. The intensity of itching was measured by a numerical rating scale. Reliability, structural validity, and measurement invariance were determined using classical and modern test theories, including confirmatory factor analysis and item response models. RESULTS: 465 participants with arsenic-related skin lesions and symptoms completed the DLQI assessment. The Cronbach's alpha was 0.79, and the split-half reliability was 0.77. A two-factor model exhibited the best model fit among models evaluated, but local dependencies among items were identified. The model showed good root mean square error of approximation (0.031) and acceptable Tucker-Lewis index (0.92). Multi-group confirmatory factor analysis showed no measurement invariance across subgroups of age, gender, ethnicity, and intensity of itching. CONCLUSIONS: The DLQI had acceptable psychometric properties, but measurement invariance was not observed across different groups of participants.

The dependence in microcystin removal with powdered activated carbon on variant properties, carbon properties, and dissolved organic matter.

Powdered activated carbon (PAC) is commonly used by water treatment plants to remove harmful cyanotoxins such as microcystins (MCs) produced during seasonal harmful algal blooms. MC removal by PAC depends upon the properties of the PAC, the properties of the MC variant, and the presence and properties of dissolved organic matter (DOM). To identify which of these factors has the greatest impact on the removal of MC by PAC, we evaluated the removal of four different MC variants (MC-LR, MC-LA, MC-RR and desmethylated MC-RR) by three different PAC types (wood-based, coal-blend and coal-based). The role of DOM properties was evaluated using DOM isolated from two different sources, a terrestrial source (Suwannee River Fulvic Acid, SRFA) and a microbial source (Grand Lake St Marys DOM, GLSM). The results of adsorption experiments conducted over a period of 72 h demonstrated the wood-based PAC, which had the highest surface area and mesopore volume of the PAC tested, had the highest adsorption rate and capacity for all four MC variants. Of the variants studied, neutrally charged MC-RR was adsorbed more rapidly and to a greater extent on all of the PAC types than were the other variants. Although MC-LA and MC-LR had the greatest hydrophobicity, their negative charges resulted in their being adsorbed the least. As expected, DOM inhibited microcystin adsorption to PAC. The degree of inhibition, however, did not significantly vary for the two DOM types evaluated, indicating the properties of the DOM on MC adsorption to PAC was less important than the PAC properties or MC variant properties. Overall, PAC properties were a more important factor in MC removal than were the MC properties or DOM conditions.

Tumor-associated macrophages drive glycolysis through the IL-8/STAT3/GLUT3 signaling pathway in pancreatic cancer progression.

Glycolytic metabolism is a hallmark of pancreatic ductal adenocarcinoma (PDAC), and tumor-associated stromal cells play important roles in tumor metabolism. We previously reported that tumor-associated macrophages (TAMs) facilitate PDAC progression. However, little is known about whether TAMs are involved in regulating glycolysis in PDAC. Here, we found a positive correlation between CD68+ TAM infiltration and FDG maximal standardized uptake (FDG SUVmax) on PET-CT images of PDAC. We discovered that the glycolytic gene set was prominently enriched in the high TAM infiltration group through Gene Set Enrichment Analysis using The Cancer Genome Atlas database. Mechanistically, TAMs secreted IL-8 to promote GLUT3 expression in PDAC cells, enhancing tumor glycolysis both in vitro and in vivo, whereas this effect could be blocked by the IL-8 receptor inhibitor reparixin. Furthermore, IL-8 promoted the translocation of phosphorylated STAT3 into the nucleus to activate the GLUT3 promoter. Overall, we demonstrated that TAMs boosted PDAC cell glycolysis through the IL-8/STAT3/GLUT3 signaling pathway. Our cumulative findings suggest that the abrogation of TAM-induced tumor glycolysis by reparixin might exhibit an antitumor impact and offer a potential therapeutic target for PDAC.

FANCI Inhibition Induces PARP1 Redistribution to Enhance the Efficacy of PARP Inhibitors in Breast Cancer.

Breast cancer is a global public health concern with high mortality rates, necessitating the development of innovative treatment strategies. PARP inhibitors have shown efficacy in certain patient populations, but their application is largely limited to cancers with homologous recombination deficiency. Here, we identified the suppression of FANCI as a therapeutic strategy to enhance the efficacy of PARP inhibitors in breast cancer. Elevated FANCI expression in breast cancer was associated with poor prognosis and increased cell proliferation and migration. FANCI interacted with PARP1, and suppressing FANCI limited the nuclear localization and functionality of PARP1. Importantly, FANCI inhibition sensitized breast cancer cells to the PARP inhibitor talazoparib in the absence of BRCA mutations. Additionally, the CDK4/6 inhibitor palbociclib enhanced the sensitivity of breast cancer cells to talazoparib through FANCI inhibition. These findings highlight the potential of targeting FANCI to enhance the efficacy of PARP inhibitors in treating breast cancer. Significance: Targeting FANCI is a promising therapeutic strategy for enhancing PARP inhibitor sensitivity in breast cancer that holds potential for broader therapeutic applications beyond cancers harboring BRCA mutations.

[Comparison of Cyclosporine A and Cyclosporine A Combined with Corticosteroid in the Treatment of Acquired Pure Red Cell Aplasia].

OBJECTIVE: To evaluate the efficacy, safety and relapse of cyclosporine A (CsA) and CsA combined with corticosteroid (CS) as the frontline therapy for patients with newly diagnosed acquired pure red cell aplasia (aPRCA). METHODS: The clinical features, treatment responses, relapses and clinical outcomes of patients with newly diagnosed aPRCA in Peking Union Medical College Hospital (PUMCH) from January 2015 to May 2020 were analyzed retrospectively. All the enrolled patients had been treated with either CsA or CsA+CS for at least 6 months and had been followed up for at least 12 months, with complete clinical data and consent forms. RESULTS: 96 patients including 72 treated with CsA and 24 treated with CsA+CS were enrolled. With comparable baseline characteristics and follow-up periods, patients treated with CsA or with CsA+CS had similar overall response rates (ORRs) and complete response rates (CRRs) at the 3rd, 6th and 12th month and at the end of follow-up (P>0.05). Meanwhile, no significant difference was found between the two groups in the optimal ORR, optimal CRR, time to response or time to complete response. CsA+CS and CsA groups had similar adverse event (AE) rates, but CsA+CS group had higher CS-related infection rate (P <0.05). One patient in CsA+CS group died of multiple infections. As for the relapse, the two groups had compatible relapse rates at different time points, time to relapse, overall relapse rate and relapse-free survival (P>0.05). CsA exposure time, rather than different therapy regimens, was the only influence factor for either ORR or relapse rate (P <0.05). CONCLUSION: CsA monotherapy has similar efficacy, AE rate and relapse rate as compared with CsA+CS for patients with newly diagnosed aPRCA, and shows less CS-related AEs such as infection.

Algal community structure prediction by machine learning.

The algal community structure is vital for aquatic management. However, the complicated environmental and biological processes make modeling challenging. To cope with this difficulty, we investigated using random forests (RF) to predict phytoplankton community shifting based on multi-source environmental factors (including physicochemical, hydrological, and meteorological variables). The RF models robustly predicted the algal communities composed by 13 major classes (Bray-Curtis dissimilarity = 9.2 ± 7.0%, validation NRMSE mostly <10%), with accurate simulations to the total biomass (validation R2 > 0.74) in Norway's largest lake, Lake Mjosa. The importance analysis showed that the hydro-meteorological variables (Standardized MSE and Node Purity mostly >0.5) were the most influential factors in regulating the phytoplankton. Furthermore, an in-depth ecological interpretation uncovered the interactive stress-response effect on the algal community learned by the RF models. The interpretation results disclosed that the environmental drivers (i.e., temperature, lake inflow, and nutrients) can jointly pose strong influence on the algal community shifts. This study highlighted the power of machine learning in predicting complex algal community structures and provided insights into the model interpretability.