Biogeographic patterns of meio- and micro-eukaryotic communities in dam-induced river-reservoir systems.

Although the Three Gorges Dam (TGD) is the world's largest hydroelectric dam, little is known about the spatial-temporal patterns and community assembly mechanisms of meio- and micro-eukaryotes and its two subtaxa (zooplankton and zoobenthos). This knowledge gap is particularly evident across various habitats and during different water-level periods, primarily arising from the annual regular dam regulation. To address this inquiry, we employed mitochondrial cytochrome c oxidase I (COI) gene-based environmental DNA (eDNA) metabarcoding technology to systematically analyze the biogeographic pattern of the three communities within the Three Gorges Reservoir (TGR). Our findings reveal distinct spatiotemporal characteristics and complementary patterns in the distribution of meio- and micro-eukaryotes. The three communities showed similar biogeographic patterns and assembly processes. Notably, the diversity of these three taxa gradually decreased along the river. Their communities were less shaped by stochastic processes, which gradually decreased along the longitudinal riverine-transition-lacustrine gradient. Hence, deterministic factors, such as seasonality, environmental, and spatial variables, along with species interactions, likely play a pivotal role in shaping these communities. Environmental factors primarily drive seasonal variations in these communities, while hydrological conditions, represented as spatial distance, predominantly influence spatial variations. These three communities followed the distance-decay pattern. In winter, compared to summer, both the decay and species interrelationships are more pronounced. Taken together, this study offers fresh insights into the composition and diversity patterns of meio- and micro-eukaryotes at the spatial-temporal level. It also uncovers the mechanisms behind community assembly in various environmental niches within the dam-induced river-reservoir systems. KEY POINTS: • Distribution and diversity of meio- and micro-eukaryotes exhibit distinct spatiotemporal patterns in the TGR. • Contribution of stochastic processes in community assembly gradually decreases along the river. • Deterministic factors and species interactions shape meio- and micro-eukaryotic community.

Bacteriophage-based techniques for elucidating the function of zebrafish gut microbiota.

Bacteriophages (or phages) are unique viruses that can specifically infect bacteria. Since their discovery by Twort and d'Herelle, phages with bacterial specificity have played important roles in microbial regulation. The intestinal microbiota and host health are intimately linked with nutrient, metabolism, development, and immunity aspects. However, the mechanism of interactions between the composition of the microbiota and their functions in maintaining host health still needs to be further explored. To address the lack of methodology and functions of intestinal microbiota in the host, we first proposed that, with the regulations of special intestinal microbiota and applications of germ-free (GF) zebrafish model, phages would be used to infect and reduce/eliminate the defined gut bacteria in the conventionally raised (CR) zebrafish and compared with the GF zebrafish colonized with defined bacterial strains. Thus, this review highlighted the background and roles of phages and their functional characteristics, and we also summarized the phage-specific infection of target microorganisms, methods to improve the phage specificity, and their regulation within the zebrafish model and gut microbial functional study. Moreover, the primary protocol of phage therapy to control the intestinal microbiota in zebrafish models from larvae to adults was recommended including phage screening from natural sources, identification of host ranges, and experimental design in the animal. A well understanding of the interaction and mechanism between phages and gut bacteria in the host can potentially provide powerful strategies or techniques for preventing bacteria-related human diseases by precisely regulating in vitro and in vivo, which will provide novel insights for phages' application and combined research in the future. KEY POINTS: • Zebrafish models for clarifying the microbial and phages' functions were discussed • Phages infect host bacteria with exquisite specificity and efficacy • Phages can reduce/eliminate the defined gut bacteria to clarify their function.

The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition.

BACKGROUND: The activation of the unfolded protein response (UPR) is closely linked to the pathogenesis of renal injuries. However, the role of XBP1, a crucial regulator of adaptive UPR, remains unclear during the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). METHODS: We characterized XBP1 expressions in different mouse models of kidney injuries, including unilateral ischemia-reperfusion injury (UIRI), unilateral ureteral obstruction, and adenine-induced CKD, followed by generating proximal tubular XBP1 conditional knockout (XBP1cKO) mice for examining the influences of XBP1. Human proximal tubular epithelial cells (HK-2) were silenced of XBP1 to conduct proteomic analysis and investigate the underlying mechanism. RESULTS: We showed a tripartite activation of UPR in injured kidneys. XBP1 expressions were attenuated after AKI and inversely correlated with the severity of post-AKI renal fibrosis. XBP1cKO mice exhibited more severe renal fibrosis in the UIRI model than wide-type littermates. Silencing XBP1 induced HK-2 cell cycle arrest in G2M phase, inhibited cell proliferation, and promoted TGF-ß1 secretion. Proteomic analysis identified TNF receptor associated protein 1 (Trap1) as the potential downstream target transcriptionally regulated by XBP1s. Trap1 overexpression can alleviate silencing XBP1 induced profibrotic factor expressions and cell cycle arrest. CONCLUSION: The loss of XBP1 in kidney injury was profibrotic, and the process was mediated by autocrine and paracrine regulations in combination. The present study identified the XBP1-Trap1 axis as an instrumental mechanism responsible for post-AKI fibrosis, which is a novel regulatory pathway.

Early elimination of uremic toxin ameliorates AKI-to-CKD transition.

Acute kidney injury (AKI)-related fibrosis is emerging as a major driver of chronic kidney disease (CKD) development. Aberrant kidney recovery after AKI is multifactorial and still poorly understood. The accumulation of indoxyl sulfate (IS), a protein-bound uremic toxin, has been identified as a detrimental factor of renal fibrosis. However, the mechanisms underlying IS-related aberrant kidney recovery after AKI is still unknown. The present study aims to elucidate the effects of IS on tubular damage and its involvement in the pathogenesis of AKI-to-CKD transition. Our results showed that serum IS started to accumulate associated with the downregulation of tubular organic anion transporter but not observed in the small-molecule uremic toxins of the unilateral ischemia-reperfusion injury (UIRI) without a contralateral nephrectomy model. Serum IS is positively correlated with renal fibrosis and binding immunoglobulin protein (BiP) and CAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) expression induction in the UIRI with a contralateral nephrectomy model (UIRI+Nx). To evaluate the effects of IS in the AKI-to-CKD transition, we administered indole, a precursor of IS, at the early stage of UIRI. Our results demonstrated IS potentiates renal fibrosis, senescence-associated secretory phenotype (SASP), and activation of endoplasmic reticulum (ER) stress, which is attenuated by synergistic AST-120 administration. Furthermore, we clearly demonstrated that IS exposure potentiated hypoxia-reperfusion (H/R) induced G2/M cell cycle arrest, epithelial-mesenchymal transition (EMT) and aggravated ER stress induction in vitro. Finally, the ER chemical chaperon, 4-phenylbutyric acid (4-PBA), successfully reversed the above-mentioned AKI-to-CKD transition. Taken together, early IS elimination in the early stage of AKI is likely to be a useful strategy in the prevention and/or treatment of the AKI-to-CKD transition.

Therapeutic Approaches Targeting Proteostasis in Kidney Disease and Fibrosis.

Pathological insults usually disturb the folding capacity of cellular proteins and lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which leads to so-called "ER stress". Increasing evidence indicates that ER stress acts as a trigger factor for the development and progression of many kidney diseases. The unfolded protein responses (UPRs), a set of molecular signals that resume proteostasis under ER stress, are thought to restore the adaptive process in chronic kidney disease (CKD) and renal fibrosis. Furthermore, the idea of targeting UPRs for CKD treatment has been well discussed in the past decade. This review summarizes the up-to-date literature regarding studies on the relationship between the UPRs, systemic fibrosis, and renal diseases. We also address the potential therapeutic possibilities of renal diseases based on the modulation of UPRs and ER proteostasis. Finally, we list some of the current UPR modulators and their therapeutic potentials.

Ochratoxin A-Induced Nephrotoxicity: Up-to-Date Evidence.

Ochratoxin A (OTA) is a mycotoxin widely found in various foods and feeds that have a deleterious effect on humans and animals. It has been shown that OTA causes multiorgan toxicity, and the kidney is the main target of OTA among them. This present article aims to review recent and latest intracellular molecular interactions and signaling pathways of OTA-induced nephrotoxicity. Pyroptosis, lipotoxicity, organic anionic membrane transporter, autophagy, the ubiquitin-proteasome system, and histone acetyltransferase have been involved in the renal toxicity caused by OTA. Meanwhile, the literature reviewed the alternative or method against OTA toxicity by reducing ROS production, oxidative stress, activating the Nrf2 pathway, through using nanoparticles, a natural flavonoid, and metal supplement. The present review discloses the molecular mechanism of OTA-induced nephrotoxicity, providing opinions and strategies against OTA toxicity.

Selective Activation of Endoplasmic Reticulum Stress by Reactive-Oxygen-Species-Mediated Ochratoxin A-Induced Apoptosis in Tubular Epithelial Cells.

Ochratoxin A (OTA), one of the major food-borne mycotoxins, impacts the health of humans and livestock by contaminating food and feed. However, the underlying mechanism of OTA nephrotoxicity remains unknown. This study demonstrated that OTA induced apoptosis through selective endoplasmic reticulum (ER) stress activation in human renal proximal tubular cells (HK-2). OTA increased ER-stress-related JNK and precursor caspase-4 cleavage apoptotic pathways. Further study revealed that OTA increased reactive oxygen species (ROS) levels, and N-acetyl cysteine (NAC) could reduce OTA-induced JNK-related apoptosis and ROS levels in HK-2 cells. Our results demonstrate that OTA induced ER stress-related apoptosis through an ROS-mediated pathway. This study provides new evidence to clarify the mechanism of OTA-induced nephrotoxicity.

Suppression of MIF-induced neuronal apoptosis may underlie the therapeutic effects of effective components of Fufang Danshen in the treatment of Alzheimer's disease.

Fufang Danshen (FFDS or Compound Danshen) consists of three Chinese herbs Danshen (Salviae miltiorrhizae radix et rhizome), Sanqi (Notoginseng radix et rhizome) and Tianranbingpian (Borneolum, or D-borneol), which has been show to significantly improve the function of the nervous system and brain metabolism. In this study we explored the possible mechanisms underlying the therapeutic effects of the combination of the effective components of FFDS (Tan IIA, NG-R1 and Borneol) in the treatment of Alzheimer's disease (AD) based on network pharmacology. We firstly constructed AD-related FFDS component protein interaction networks, and revealed that macrophage migration inhibitory factor (MIF) might regulate neuronal apoptosis through Bad in the progression of AD. Then we investigated the apoptosis-inducing effects of MIF and the impact of the effective components of FFDS in human neuroblastoma SH-SY5Y cells. We observed the characteristics of a "Pendular state" of MIF, where MIF (8 ng/mL) increased the ratio of p-Bad/Bad by activating Akt and the IKKα/ß signaling pathway to assure cell survival, whereas MIF (50 ng/mL) up-regulated the expression of Bad to trigger apoptosis of SH-SY5Y cells. MIF displayed neurotoxicity similar to Aß1-42, which was associated with the MIF-induced increased expression of Bad. Application of the FFDS composite solution significantly decreased the expression levels of Bad, suppressed MIF-induced apoptosis in SH-SY5Y cells. In a D-galactose- and AlCl3-induced AD mouse model, administration of the FFDS composite solution significantly improved the learning and memory, as well as neuronal morphology, and decreased the serum levels of INF-γ. Therefore, the FFDS composite solution exerts neuroprotective effects through down-regulating the level of Bad stimulated by MIF.

Smoking and nasopharyngeal carcinoma mortality: a cohort study of 101,823 adults in Guangzhou, China.

BACKGROUND: Nasopharyngeal carcinoma (NPC), also known as Cantonese cancer, is rare worldwide, but has particularly high incidence in North Africa and Southeast Asia, especially in Guangdong, China, such as Guangzhou. Tobacco causes head and neck cancers, but nasopharyngeal carcinoma is not included as causally related to smoking in the 2014 United States Surgeon General's report. Prospective evidence remains limited. We used Guangzhou Occupational Cohort data to conduct the first and robust prospective study on smoking and NPC mortality in an NPC high-risk region. METHODS: Information on demographic characteristics and smoking status was collected through occupational health examinations in factories and driver examination stations from March 1988 to December 1992. Vital status and causes of deaths were retrieved until the end of 1999. Cox proportional hazard model was used to assess the association of smoking with NPC mortality. RESULTS: Of 101,823 subjects included for the present analysis, 34 NPC deaths occurred during the average 7.3 years of follow up. The mean age (standard deviation) of the subjects was 41 (5.7) years. Compared with never smokers, the hazard ratio (HR) of NPC mortality was 2.95 (95% confidence interval 1.01-8.68; p=0.048) for daily smokers and 4.03 (1.29-12.58; p=0.016) for smokers with more than 10 pack-years of cumulative consumption, after adjusting for age, sex, education, drinking status, occupation and cohort status and accounting for smoking-drinking interaction. The risk of NPC mortality increased significantly with cigarettes per day (p for trend=0.01) and number of pack-years (p for trend=0.02). CONCLUSIONS: In this first and largest cohort in a high NPC risk region, smoking was associated with higher NPC mortality. The findings have shown statistically significant dose-response trend between smoking amount and smoking cumulative consumption and the risk of NPC mortality, but due to the small event number, further studies with larger sample size are needed to confirm the findings in the present study. Our results support that smoking is one of the risk factors likely to be causally associated with NPC mortality.

Modified pedicle subtraction osteotomies (mPSO) for thoracolumbar post-tubercular kyphosis in pediatric patients: retrospective clinical cases and review of the literature.

PURPOSE: The purpose of this study was to evaluate the clinical and radiographic outcomes of modified pedicle subtraction osteotomy (mPSO) for thoracolumbar post-tubercular kyphosis in pediatric patients. METHODS: From January 2008 to August 2012, 26 consecutive pediatric patients with thoracolumbar post-tubercular kyphosis underwent modified pedicle subtraction osteotomy (mPSO). The clinical and radiologic outcomes were analyzed preoperatively, postoperatively, and at the last follow-up. RESULTS: Twenty-six patients with thoracolumbar post-tubercular kyphosis underwent mPSO. The average operation time was 256 min (188~314 min). The mean follow-up was 41 months (18~56 months). The mean estimated blood loss was 870 ml (620 ~ 1020 ml). The thoracolumbar kyphotic angle ranged from 51° to 79° before operation, 60.6° in average. The mean thoracolumbar kyphotic Cobb angle was 19.7° after operation, with a mean correction of 40.9°. The C7 sagittal plumb line was 3.8 cm after operation, comparing to the 10.5 cm preoperative. The mean preoperative angle of thoracic kyphosis (TK) was 9.9° ± 1.2° and increased to 11.8° ± 1.4°, postoperatively. Lumbar lordosis (LL) improved from -22.8° ± 4.9° preoperative to -17.8° ± 2.1° postoperative. Visual analogue scale (VAS) was 8.7 ± 1.1 preoperative and 1.2 ± 0.4 postoperative, respectively. The mean Oswestry Disability Index (ODI) improved from 49.2 ± 5.3 before surgery to 10.8 ± 3.3 postoperative (P < 0.01). All patients received good bone healing, no significant loss of correction angle. Most patients (24/26) considered pain and exterior was significantly improved. CONCLUSION: Modified pedicle subtraction osteotomy (mPSO) is effective and reliable for thoracolumbar post-tubercular kyphosis in pediatric patients.

Association between social withdrawal and suicidal ideation in patients with major depressive disorder: The mediational role of emotional symptoms.

BACKGROUND: The study was designed to investigate the associations between social withdrawal, emotional symptoms, and suicide ideation in patients with major depressive disorder (MDD). METHODS: This cross-sectional study included 2678 MDD patients from the National Survey on Symptomatology of Depression (NSSD). Differences in the sociodemographic factors, clinical characteristics, suicide ideation, and emotional symptoms were compared in patients with different frequencies of social withdrawal. Pearson correlation, multiple linear regression analysis, and mediation analysis were employed to assess the contribution of social withdrawal to suicide ideation. RESULTS: MDD patients with a higher frequency of social withdrawal were prone to have a higher frequency of suicide ideation (p for trend <0.001) and history of suicide behavior (p for trend <0.001). Multiple linear regression analysis showed that there was a dose-response relationship between social withdrawal and suicide ideation in MDD patients, but this association became insignificant after adjusting for emotional symptoms. Mediation analysis suggested that all of the emotional symptoms had significant mediating effects on the association between social withdrawal and suicide ideation in MDD patients (p < 0.05). The magnitude of mediation varied between 4.3 % and 64.3 %, with the largest mediating effect in the feeling of despair (64.3 %), helplessness (41.2 %), and loneliness (40.0 %). CONCLUSION: Our study provides evidence that social withdrawal was a common clinical presentation and it may increase the risk for suicide through emotional symptoms in MDD patients. LIMITATIONS: Causal conclusions could not be drawn between social withdrawal, emotional symptoms, and suicide ideation because of the cross-sectional design of the study.

Tumor-targeting Salmonella typhimurium, a natural tool for activation of prodrug 6MePdR and their combination therapy in murine melanoma model.

The PNP/6-methylpurine 2'-deoxyriboside (6MePdR) system is an efficient gene-directed enzyme prodrug therapy system with significant antitumor activities. In this system, Escherichia coli purine nucleoside phosphorylase (ePNP) activates nontoxic 6MePdR into potent antitumor drug 6-methylpurine (6MeP). The Salmonella typhimurium PNP (sPNP) gene has a 96-% sequence homology in comparison with ePNP and also has the ability to convert 6MePdR to 6MeP. In this study, we used tumor-targeting S. typhimurium VNP20009 expressing endogenous PNP gene constitutively to activate 6MePdR and a combination treatment of bacteria and prodrug in B16F10 melanoma model. The conversion of 6MePdR to 6MeP by S. typhimurium was analyzed by HPLC and the enzyme activity of sPNP was confirmed by in vitro (tetrazolium-based colorimetric assay) MTT cytotoxicity assay. After systemic administration of VNP20009 to mice, the bacteria largely accumulated and specifically delivered endogenous sPNP in the tumor. In comparison with VNP20009 or 6MePdR treatment alone, combined administration of VNP20009 followed by 6MePdR treatment significantly delayed the growth of B16F10 tumor and increased the CD8(+) T-cell infiltration. In summary, our results demonstrated that the combination therapy of S. typhimurium and prodrug 6MePdR is a promising strategy for cancer therapy.

Influence of HbCO structure of the bar-headed goose on photolysis thermodynamics as studied by the nanosecond laser-ultrasonic technique.

The bar-headed goose, a specialized high-altitude species, has a capacity for high oxygen uptake from a hypoxic environment. It thus has a higher oxygen affinity than other bird species of lower-altitude environments. Oxygen affinity is determined by molecular structures and genetic mutations of hemoglobin (Hb), which can also influence the coordinating structures and dynamics of oxygen-Hb. To explore the structural differences in Hbs as between high and low altitude species, photolysis dynamic parameters, including quantum yield, enthalpy, and conformational volume changes in carboxy-Hbs (HbCO) for the bar-headed goose and low altitude counterparts (the Chinese goose and chicken) were investigated by the laser pumping-probing technique and photoacoustic calorimetry. Comparing the photolysis results for HbCO of the three species, the enthalpy and conformational volume changes of the bar-headed goose were much smaller than those of the others, although the quantum yields of all three species are similar. To explain the possible mechanisms of these differences, modifications of salt bridges and key residue mutations at the α ß subunit interfaces of the proteins are described and discussed briefly.

Engineering bacteriophages for enhanced host range and efficacy: insights from bacteriophage-bacteria interactions.

Bacteriophages, the most abundant organisms on earth, have the potential to address the rise of multidrug-resistant bacteria resulting from the overuse of antibiotics. However, their high specificity and limited host range can hinder their effectiveness. Phage engineering, through the use of gene editing techniques, offers a means to enhance the host range of bacteria, improve phage efficacy, and facilitate efficient cell-free production of phage drugs. To engineer phages effectively, it is necessary to understand the interaction between phages and host bacteria. Understanding the interaction between the receptor recognition protein of bacteriophages and host receptors can serve as a valuable guide for modifying or replacing these proteins, thereby altering the receptor range of the bacteriophage. Research and development focused on the CRISPR-Cas bacterial immune system against bacteriophage nucleic acids can provide the necessary tools to promote recombination and counter-selection in engineered bacteriophage programs. Additionally, studying the transcription and assembly functions of bacteriophages in host bacteria can facilitate the engineered assembly of bacteriophage genomes in non-host environments. This review highlights a comprehensive summary of phage engineering methods, including in-host and out-of-host engineering, and the use of high-throughput methods to understand their role. The main aim of these techniques is to harness the intricate interactions between bacteriophages and hosts to inform and guide the engineering of bacteriophages, particularly in the context of studying and manipulating the host range of bacteriophages. By employing advanced high-throughput methods to identify specific bacteriophage receptor recognition genes, and subsequently introducing modifications or performing gene swapping through in-host recombination or out-of-host synthesis, it becomes possible to strategically alter the host range of bacteriophages. This capability holds immense significance for leveraging bacteriophages as a promising therapeutic approach against antibiotic-resistant bacteria.

Ultra-sensitive detection of ecologically rare fish from eDNA samples based on the RPA-CRISPR/Cas12a technology.

Environmental DNA (eDNA) research holds great promise for improving biodiversity science and conservation efforts by enabling worldwide species censuses in near real-time. Current eDNA methods face challenges in detecting low-abundance ecologically important species. In this study, we used isothermal recombinase polymerase amplification (RPA)-CRISPR/Cas detection to test Ctenopharyngodon idella. RPA-CRISPR-Cas12a detected 6.0 eDNA copies/µL within 35 min. Ecologically rare species were identified in the Three Gorges Reservoir Area (TGRA) using functional distinctiveness and geographical restrictiveness, with seven fish species (9%) classified as potentially ecologically rare including three species in this investigation. RPA-CRISPR/Cas12a-FQ outperformed high-throughput sequencing (HTS) and qPCR in detecting low-abundance eDNA (AUC = 0.883∗∗). A significant linear correlation (R2 = 0.682∗∗) between RPA-CRISPR/Cas12a-FQ and HTS quantification suggests its potential for predicting species abundance and enhancing eDNA-based fish biodiversity monitoring. This study highlights the value of RPA-CRISPR/Cas12a-FQ as a tool for advancing eDNA research and conservation efforts.

Acupuncture Improved the Function of the Lower Esophageal Sphincter and Esophageal Motility in Chinese Patients with Refractory Gastroesophageal Reflux Disease Symptoms: A Randomized Trial.

Objectives: Acupuncture is therapeutic for refractory gastroesophageal reflux disease by an unclear mechanism. This study was aimed at investigating the effect of acupuncture on esophageal motility in patients with symptoms of refractory gastroesophageal reflux disease. Methods: Sixty-eight patients with refractory gastroesophageal reflux disease symptoms were prospectively enrolled from August 2014 to December 2018 and randomized into acupuncture and control groups (n = 33 and 35, respectively). The acupuncture group received acupuncture, and the control group received sham acupuncture. Pre- and post-acupuncture high-resolution manometry was performed to evaluate the effect of acupuncture on esophageal motility. The GerdQ questionnaire was used to evaluate the pre- and post-intervention symptoms. Results: After acupuncture, there was a significant increase in the length of lower esophageal sphincter (3.10 ± 1.08 cm vs. 3.78 ± 1.01 cm), length of intra-abdominal lower esophageal sphincter (2.14 ± 1.05 cm vs. 2.75 ± 1.16 cm), and mean basal pressure of lower esophageal sphincter (22.02 ± 10.03 mmHg vs. 25.06 ± 11.48 mmHg) in the acupuncture group (P = 0.014); moreover, the numbers of fragmented contraction and ineffective contraction decreased from 36 to 12 (P < 0.001) and 43 to 18 (P = 0.001), respectively, in the acupuncture group. However, no significant difference was observed in the control group. The GerdQ score decreased significantly from 9.45 ± 2.44 to 7.82 ± 2.21 points in the first week after acupuncture (P < 0.001). Conclusions: Acupuncture, which improves esophageal motility, has short-term efficacy in patients with symptoms of refractory gastroesophageal reflux disease. This trial is registered with Chinese Clinical Trial Registry (ChiCTR1800019646).

Supervised machine learning improves general applicability of eDNA metabarcoding for reservoir health monitoring.

Effective and standardized monitoring methodologies are vital for successful reservoir restoration and management. Environmental DNA (eDNA) metabarcoding sequencing offers a promising alternative for biomonitoring and can overcome many limitations of traditional morphological bioassessment. Recent attempts have even shown that supervised machine learning (SML) can directly infer biotic indices (BI) from eDNA metabarcoding data, bypassing the cumbersome calculation process of BI regardless of the taxonomic assignment of eDNA sequences. However, questions surrounding the general applicability of this taxonomy-free approach to monitoring reservoir health remain unclear, including model stability, feature selection, algorithm choice, and multi-season biomonitoring. Here, we firstly developed a novel biological integrity index (Me-IBI) that integrates multitrophic interactions and environmental information, based on taxonomy-assigned eDNA metabarcoding data. The Me-IBI can better distinguish the actual health status of the Three Gorges Reservoir (TGR) than physicochemical assessments and have a clear response to human activity. Then, taking this reliable Me-IBI as a supervised label, we compared the impact of selecting different numbers of features and SML algorithms on the stability and predictive performance of the model for predicting ecological conditions in multiple seasons using taxonomy-free eDNA metabarcoding data. We discovered that even with a small number of features, different SML algorithms can establish a stable model and obtain excellent predictive performance. Finally, we proposed a four-step strategy for standardized routine biomonitoring using SML tools. Our study firstly explores the general applicability problem of the taxonomy-free eDNA-SML approach and establishes a solid foundation for the large-scale and standardized biomonitoring application.

Efficacy and influencing factors of the four-step approach combining the situational simulation teaching method in the clinical practice of standardized training for residents.

Background and Aims: Clinical skills practice is an essential component in standardized residency training. However, traditionally skill training methods are dogmatic and not all residents are exposed to such prescribed situations during their residency. The aims of this study were to evaluate the effectiveness and influence factors of a four-step approach combining situational simulation teaching methods in clinical practice for residents. Methods: Enrolled all second-year residents from the internal medicine base between May 2017 and May 2018 (n = 94), randomly divided into two groups. Forty-eight residents were selected as experimental group, while the others 46 as the control group. Adopted traditional clinical practice method in the teaching and assessment of the control group, while used four-step approach combining situational simulation teaching method in experimental group. We compared the theoretical and skill assessment scores in preclass and postclass. Conducted a satisfaction survey after class and analyzed the influencing factors of the teaching effect evaluation. Results: There were no significant differences in the theoretical and skill assessment scores between experimental group and control group at the beginning. After the class, both the average skill assessment and Direct Observation of Procedural Skills scores of the experimental group were higher than those of the control. Satisfaction survey findings identified that the experimental group expressed higher satisfaction. Logistic regression showed that educational background, "situational simulation mode helps to improve clinical skills training," "helps to maintain attention during learning," and "helps improve the ability to exercise analysis and solve problems" were the influencing factors of learners' satisfaction. Conclusion: The application of four-step approach combining situational simulation teaching methods in the clinical practice of residents can significantly improve skills, thinking ability, decision-making ability, and teaching satisfaction. Therefore, four-step approach combining situational simulation teaching methods is worth promoting in teaching clinical skills for internal medicine residency training.

Associations between gastrointestinal symptoms, medication use, and spontaneous drug discontinuation in patients with major depressive disorder in China.

BACKGROUND: The study was designed to investigate the associations between gastrointestinal (GI) symptoms, medication use, and spontaneous drug discontinuation (SDD) in patients with major depressive disorder (MDD). METHODS: This cross-sectional study included 3256 MDD patients from the National Survey on Symptomatology of Depression (NSSD). Differences in the sociodemographic factors, clinical characteristics, medication use, and self-reported reasons for SDD were compared in patients with different frequencies of GI symptoms. A multiple logistic regression analysis was employed to assess the contribution of GI symptoms to the risk of spontaneous drug discontinuation. RESULTS: MDD patients with a higher frequency of GI symptoms were prone to have higher proportions of mood stabilizer and benzodiazepine uses (ps for trend < 0.001) but a lower proportion of SNRI use (pfor trend < 0.001). With the increase in GI symptoms, patients were prone to report worries about long-term side effects (pfor trend < 0.001), with the patients stating ineffective treatments (pfor trend = 0.002) and intolerance of adverse drug reactions (pfor trend = 0.022) as the reasons for SDD. Compared with those patients without GI symptoms, all of the MDD patients with GI symptom frequencies of several days (OR = 1.317; 95 % CI: 1.045-1.660), more than half of all days (OR = 1.305; 95 % CI: 1.005-1.695), and nearly every day (OR = 1.820; 95 %: 1.309-2.531) had an increased risk of SDD. CONCLUSION: GI symptoms are highly associated with drug discontinuation in MDD patients. These findings may have important implications for clinical treatment options, as well as for drug adherence management, in MDD patients.

Uremic Toxins and Protein-Bound Therapeutics in AKI and CKD: Up-to-Date Evidence.

Uremic toxins are defined as harmful metabolites that accumulate in the human body of patients whose renal function declines, especially chronic kidney disease (CKD) patients. Growing evidence demonstrates the deteriorating effect of uremic toxins on CKD progression and CKD-related complications, and removing uremic toxins in CKD has become the conventional treatment in the clinic. However, studies rarely pay attention to uremic toxin clearance in the early stage of acute kidney injury (AKI) to prevent progression to CKD despite increasing reports demonstrating that uremic toxins are correlated with the severity of injury or mortality. This review highlights the current evidence of uremic toxin accumulation in AKI and the therapeutic value to prevent CKD progression specific to protein-bound uremic toxins (PBUTs).