Engineered Bispecific Antibodies with Exquisite HIV-1-Neutralizing Activity.

While the search for an efficacious HIV-1 vaccine remains elusive, emergence of a new generation of virus-neutralizing monoclonal antibodies (mAbs) has re-ignited the field of passive immunization for HIV-1 prevention. However, the plasticity of HIV-1 demands additional improvements to these mAbs to better ensure their clinical utility. Here, we report engineered bispecific antibodies that are the most potent and broad HIV-neutralizing antibodies to date. One bispecific antibody, 10E8V2.0/iMab, neutralized 118 HIV-1 pseudotyped viruses tested with a mean 50% inhibitory concentration (IC50) of 0.002 µg/mL. 10E8V2.0/iMab also potently neutralized 99% of viruses in a second panel of 200 HIV-1 isolates belonging to clade C, the dominant subtype accounting for ∼50% of new infections worldwide. Importantly, 10E8V2.0/iMab reduced virus load substantially in HIV-1-infected humanized mice and also provided complete protection when administered prior to virus challenge. These bispecific antibodies hold promise as novel prophylactic and/or therapeutic agents in the fight against HIV-1.

Structures of rhodopsin in complex with G-protein-coupled receptor kinase 1.

G-protein-coupled receptor (GPCR) kinases (GRKs) selectively phosphorylate activated GPCRs, thereby priming them for desensitization1. Although it is unclear how GRKs recognize these receptors2-4, a conserved region at the GRK N terminus is essential for this process5-8. Here we report a series of cryo-electron microscopy single-particle reconstructions of light-activated rhodopsin (Rho*) bound to rhodopsin kinase (GRK1), wherein the N terminus of GRK1 forms a helix that docks into the open cytoplasmic cleft of Rho*. The helix also packs against the GRK1 kinase domain and stabilizes it in an active configuration. The complex is further stabilized by electrostatic interactions between basic residues that are conserved in most GPCRs and acidic residues that are conserved in GRKs. We did not observe any density for the regulator of G-protein signalling homology domain of GRK1 or the C terminus of rhodopsin. Crosslinking with mass spectrometry analysis confirmed these results and revealed dynamic behaviour in receptor-bound GRK1 that would allow the phosphorylation of multiple sites in the receptor tail. We have identified GRK1 residues whose mutation augments kinase activity and crosslinking with Rho*, as well as residues that are involved in activation by acidic phospholipids. From these data, we present a general model for how a small family of protein kinases can recognize and be activated by hundreds of different GPCRs.

Spatial spillovers of violent conflict amplify the impacts of climate variability on malaria risk in sub-Saharan Africa.

Africa carries a disproportionately high share of the global malaria burden, accounting for 94% of malaria cases and deaths worldwide in 2019. It is also a politically unstable region and the most vulnerable continent to climate change in recent decades. Knowledge about the modifying impacts of violent conflict on climate-malaria relationships remains limited. Here, we quantify the associations between violent conflict, climate variability, and malaria risk in sub-Saharan Africa using health surveys from 128,326 individuals, historical climate data, and 17,429 recorded violent conflicts from 2006 to 2017. We observe that spatial spillovers of violent conflict (SSVCs) have spatially distant effects on malaria risk. Malaria risk induced by SSVCs within 50 to 100 km from the households gradually increases from 0.1% (not significant, P>0.05) to 6.5% (95% CI: 0 to 13.0%). SSVCs significantly promote malaria risk within the average 20.1 to 26.9 °C range. At the 12-mo mean temperature of 22.5 °C, conflict deaths have the largest impact on malaria risk, with an approximately 5.8% increase (95% CI: 1.0 to 11.0%). Additionally, a pronounced association between SSVCs and malaria risk exists in the regions with 9.2 wet days per month. The results reveal that SSVCs increase population exposure to harsh environments, amplifying the effect of warm temperature and persistent precipitation on malaria transmission. Violent conflict therefore poses a substantial barrier to mosquito control and malaria elimination efforts in sub-Saharan Africa. Our findings support effective targeting of treatment programs and vector control activities in conflict-affected regions with a high malaria risk.

Structural and Molecular Mechanisms of Cytokine-Mediated Endocrine Resistance in Human Breast Cancer Cells.

Human breast cancers that exhibit high proportions of immune cells and elevated levels of pro-inflammatory cytokines predict poor prognosis. Here, we demonstrate that treatment of human MCF-7 breast cancer cells with pro-inflammatory cytokines results in ERα-dependent activation of gene expression and proliferation, in the absence of ligand or presence of 4OH-tamoxifen (TOT). Cytokine activation of ERα and endocrine resistance is dependent on phosphorylation of ERα at S305 in the hinge domain. Phosphorylation of S305 by IKKß establishes an ERα cistrome that substantially overlaps with the estradiol (E2)-dependent ERα cistrome. Structural analyses suggest that S305-P forms a charge-linked bridge with the C-terminal F domain of ERα that enables inter-domain communication and constitutive activity from the N-terminal coactivator-binding site, revealing the structural basis of endocrine resistance. ERα therefore functions as a transcriptional effector of cytokine-induced IKKß signaling, suggesting a mechanism through which the tumor microenvironment controls tumor progression and endocrine resistance.

A tumor microenvironment-activated metal-organic framework-based nanoplatform for amplified oxidative stress-induced enhanced chemotherapy.

Engineering a highly tumor microenvironment-responsive nanoplatform toward effective chemotherapy has always been a challenge in targeted cancer treatment. Metal-organic frameworks are a promising delivery system to reformulate previously approved drugs for enhanced chemotherapy, such as disulfiram (DSF). Herein, a tumor microenvironment-activated metal-organic framework-based nanoplatform DSF@MOF-199@FA has been fabricated to realize amplified oxidative stress-induced enhanced chemotherapy. Our results unveil that the copper ions and DSF released by DSF@MOF-199@FA in an acidic environment can be converted into toxic bis(N, N-diethyl dithiocarbamate) copper and then induce cell apoptosis. Simultaneously, we determined that the apoptosis outcome is further promoted by amplified oxidative stress through effective generation of reactive oxygen species and GSH elimination. In conclusion, this work provides a promising platform for effective anticancer treatment.

Genome-wide identification, evolution, and role of SPL gene family in beet (Beta vulgaris L.) under cold stress.

BACKGROUND: SPL transcription factors play vital roles in regulating plant growth, development, and abiotic stress responses. Sugar beet (Beta vulgaris L.), one of the world's main sugar-producing crops, is a major source of edible and industrial sugars for humans. Although the SPL gene family has been extensively identified in other species, no reports on the SPL gene family in sugar beet are available. RESULTS: Eight BvSPL genes were identified at the whole-genome level and were renamed based on their positions on the chromosome. The gene structure, SBP domain sequences, and phylogenetic relationship with Arabidopsis were analyzed for the sugar beet SPL gene family. The eight BvSPL genes were divided into six groups (II, IV, V, VI, VII, and VIII). Of the BvSPL genes, no tandem duplication events were found, but one pair of segmental duplications was present. Multiple cis-regulatory elements related to growth and development were identified in the 2000-bp region upstream of the BvSPL gene start codon (ATG). Using quantitative real-time polymerase chain reaction (qRT-PCR), the expression profiles of the eight BvSPL genes were examined under eight types of abiotic stress and during the maturation stage. BvSPL transcription factors played a vital role in abiotic stress, with BvSPL3 and BvSPL6 being particularly noteworthy. CONCLUSION: Eight sugar beet SPL genes were identified at the whole-genome level. Phylogenetic trees, gene structures, gene duplication events, and expression profiles were investigated. The qRT-PCR analysis indicated that BvSPLs play a substantial role in the growth and development of sugar beet, potentially participating in the regulation of root expansion and sugar accumulation.

Susceptibility gene identification and risk evaluation model construction by transcriptome-wide association analysis for salt sensitivity of blood pressure.

BACKGROUND: Salt sensitivity of blood pressure (SSBP) is an intermediate phenotype of hypertension and is a predictor of long-term cardiovascular events and death. However, the genetic structures of SSBP are uncertain, and it is difficult to precisely diagnose SSBP in population. So, we aimed to identify genes related to susceptibility to the SSBP, construct a risk evaluation model, and explore the potential functions of these genes. METHODS AND RESULTS: A genome-wide association study of the systemic epidemiology of salt sensitivity (EpiSS) cohort was performed to obtain summary statistics for SSBP. Then, we conducted a transcriptome-wide association study (TWAS) of 12 tissues using FUSION software to predict the genes associated with SSBP and verified the genes with an mRNA microarray. The potential roles of the genes were explored. Risk evaluation models of SSBP were constructed based on the serial P value thresholds of polygenetic risk scores (PRSs), polygenic transcriptome risk scores (PTRSs) and their combinations of the identified genes and genetic variants from the TWAS. The TWAS revealed that 2605 genes were significantly associated with SSBP. Among these genes, 69 were differentially expressed according to the microarray analysis. The functional analysis showed that the genes identified in the TWAS were enriched in metabolic process pathways. The PRSs were correlated with PTRSs in the heart atrial appendage, adrenal gland, EBV-transformed lymphocytes, pituitary, artery coronary, artery tibial and whole blood. Multiple logistic regression models revealed that a PRS of P < 0.05 had the best predictive ability compared with other PRSs and PTRSs. The combinations of PRSs and PTRSs did not significantly increase the prediction accuracy of SSBP in the training and validation datasets. CONCLUSIONS: Several known and novel susceptibility genes for SSBP were identified via multitissue TWAS analysis. The risk evaluation model constructed with the PRS of susceptibility genes showed better diagnostic performance than the transcript levels, which could be applied to screen for SSBP high-risk individuals.

Variations and reduction of plastome are associated with the evolution of parasitism in Convolvulaceae.

Parasitic lifestyle can often relax the constraint on the plastome, leading to gene pseudogenization and loss, and resulting in diverse genomic structures and rampant genome degradation. Although several plastomes of parasitic Cuscuta have  been reported, the evolution of parasitism in the family Convolvulaceae which is linked to structural variations and reduction of plastome has not been well investigated. In this study, we assembled and collected 40 plastid genomes belonging to 23 species representing four subgenera of Cuscuta and ten species of autotrophic Convolvulaceae. Our findings revealed nine types of structural variations and six types of inverted repeat (IR) boundary variations in the plastome of Convolvulaceae spp. These structural variations were associated with the shift of parasitic lifestyle, and IR boundary shift, as well as the abundance of long repeats. Overall, the degradation of Cuscuta plastome proceeded gradually, with one clade exhibiting an accelerated degradation rate. We observed five stages of gene loss in Cuscuta, including NAD(P)H complex → PEP complex → Photosynthesis-related → Ribosomal protein subunits → ATP synthase complex. Based on our results, we speculated that the shift of parasitic lifestyle in early divergent time promoted relaxed selection on plastomes, leading to the accumulation of microvariations, which ultimately resulted in the plastome reduction. This study provides new evidence towards a better understanding of plastomic evolution, variation, and reduction in the genus Cuscuta.

Reactive oxygen species (ROS) modulate nitrogen signaling using temporal transcriptome analysis in foxtail millet.

Reactive oxygen species (ROS) is a chemically reactive chemical substance containing oxygen and a natural by-product of normal oxygen metabolism. Excessive ROS affect the growth process of crops, which will lead to the decrease of yield. Nitrogen, as a critical nutrient element in plants and plays a vital role in plant growth and crop production. Nitrate is the primary nitrogen source available to plants in agricultural soil and various natural environments. However, the molecular mechanism of ROS-nitrate crosstalk is still unclear. In this study, we used the foxtail millet (Setaria italica L.) as the material to figure it out. Here, we show that excessive NaCl inhibits nitrate-promoted plant growth and nitrogen use efficiency (NUE). NaCl induces ROS accumulation in roots, and ROS inhibits nitrate-induced gene expression in a short time. Surprisingly, low concentration ROS slight promotes and high concentration of ROS inhibits foxtail millet growth under long-term H2O2 treatment. These results may open a new perspective for further exploration of ROS-nitrate signaling pathway in plants.

Biosynthesis of Enfumafungin-type Antibiotic Reveals an Unusual Enzymatic Fusion Pattern and Unprecedented C-C Bond Cleavage.

Enfumafungin-type antibiotics, represented by enfumafungin and fuscoatroside, belong to a distinct group of triterpenoids derived from fungi. These compounds exhibit significant antifungal properties with ibrexafungerp, a semisynthetic derivative of enfumafungin, recently gaining FDA's approval as the first oral antifungal drug for treating invasive vulvar candidiasis. Enfumafungin-type antibiotics possess a cleaved E-ring with an oxidized carboxyl group and a reduced methyl group at the break site, suggesting unprecedented C-C bond cleavage chemistry involved in their biosynthesis. Here, we show that a 4-gene (fsoA, fsoD, fsoE, fsoF) biosynthetic gene cluster is sufficient to yield fuscoatroside by heterologous expression in Aspergillus oryzae. Notably, FsoA is an unheard-of terpene cyclase-glycosyltransferase fusion enzyme, affording a triterpene glycoside product that relies on enzymatic fusion. FsoE is a P450 enzyme that catalyzes successive oxidation reactions at C19 to facilitate a C-C bond cleavage, producing an oxidized carboxyl group and a reduced methyl group that have never been observed in known P450 enzymes. Our study thus sets the important foundation for the manufacture of enfumafungin-type antibiotics using biosynthetic approaches.

An Ultramicroelectrode Electrochemistry and Surface Plasmon Resonance Coupling Method for Cell Exocytosis Study.

Exocytosis of a single cell has been extensively researched in recent years due to its close association with numerous diseases. However, current methods only investigate exocytosis at either the single-cell or multiple-cell level, and a method for simultaneously studying exocytosis at both levels has yet to be established. In this study, a combined device incorporating ultramicroelectrode (UME) electrochemistry and surface plasmon resonance (SPR) was developed, enabling the simultaneous monitoring of single-cell and multiple-cell exocytosis. PC12 cells were cultured directly on the SPR sensing Au film, with a carboxylated carbon nanopipette (c-CNP) electrode employed for electrochemical detection in the SPR reaction cell. Upon exocytosis, the released dopamine diffuses onto the inner wall of c-CNP, undergoing an electrochemical reaction to generate a current peak. Concurrently, exocytosis can also induce changes in the refractive index of the Au film surface, leading to the SPR signal. Consequently, the device enables real-time monitoring of exocytosis from both single and multiple cells with a high spatiotemporal resolution. The c-CNP electrode exhibited excellent resistance to protein contamination, high sensitivity for dopamine detection, and the capability to continuously monitor dopamine exocytosis over an extended period. Analysis of both SPR and electrochemical signals revealed a positive correlation between changes in the SPR signal and the frequency of exocytosis. This study introduces a novel method and platform for the simultaneous investigation of single-cell and multiple-cell exocytosis.

Genome-wide identification, structural characterization and gene expression analysis of the WRKY transcription factor family in pea (Pisum sativum L.).

BACKGROUND: The WRKY gene family is one of the largest families of transcription factors in higher plants, and WRKY transcription factors play important roles in plant growth and development as well as in response to abiotic stresses; however, the WRKY gene family in pea has not been systematically reported. RESULTS: In this study, 89 pea WRKY genes were identified and named according to the random distribution of PsWRKY genes on seven chromosomes. The gene family was found to have nine pairs of tandem duplicates and 19 pairs of segment duplicates. Phylogenetic analyses of the PsWRKY and 60 Arabidopsis WRKY proteins were performed to determine their homology, and the PsWRKYs were classified into seven subfamilies. Analysis of the physicochemical properties, motif composition, and gene structure of pea WRKYs revealed significant differences in the physicochemical properties within the PsWRKY family; however, their gene structure and protein-conserved motifs were highly conserved among the subfamilies. To further investigate the evolutionary relationships of the PsWRKY family, we constructed comparative syntenic maps of pea with representative monocotyledonous and dicotyledonous plants and found that it was most recently homologous to the dicotyledonous WRKY gene families. Cis-acting element analysis of PsWRKY genes revealed that this gene family can respond to hormones, such as abscisic acid (ABA), indole-3-acetic acid (IAA), gibberellin (GA), methyl jasmonate (MeJA), and salicylic acid (SA). Further analysis of the expression of 14 PsWRKY genes from different subfamilies in different tissues and fruit developmental stages, as well as under five different hormone treatments, revealed differences in their expression patterns in the different tissues and fruit developmental stages, as well as under hormone treatments, suggesting that PsWRKY genes may have different physiological functions and respond to hormones. CONCLUSIONS: In this study, we systematically identified WRKY genes in pea for the first time and further investigated their physicochemical properties, evolution, and expression patterns, providing a theoretical basis for future studies on the functional characterization of pea WRKY genes during plant growth and development.

Medical radiation exposure in inflammatory bowel disease: an updated meta-analysis.

BACKGROUND: There have been previous studies and earlier systematic review on the relationship between inflammatory bowel disease (IBD) and radiation exposure. With the diversification of current test methods, this study intended to conduct a meta-analysis to evaluate the IBD radiation exposure in recent years. METHODS: Three databases (PUBMED, EMBASE, and MEDICINE) for relevant literature up to May 1, 2023 were searched. The statistical data meeting requirements were collated and extracted. RESULTS: 20 papers were enrolled. The overall high radiation exposure rate was 15% (95% CI = [12%, 19%]) for CD and 5% (95% CI = [3%, 7%]) for UC. The pooled result found that high radiation exposure rate was 3.44 times higher in CD than in UC (OR = 3.44, 95% CI = [2.35, 5.02]). Moreover, the average radiation exposure level in CD was 12.77 mSv higher than that in UC (WMD = 12.77, 95% CI = [9.93, 15.62] mSv). Furthermore, radiation exposure level of CD after 2012 was higher than those before 2012 (26.42 ± 39.61vs. 23.76 ± 38.46 mSv, P = 0.016), while UC did not show similar result (11.99 ± 27.66 vs. 10.01 ± 30.76 mSv, P = 0.1). Through subgroup analysis, it was found that disease duration (WMD = 2.75, 95% CI = [0.10, 5.40] mSv), complications (OR = 5.09, 95% CI = [1.50, 17.29]), and surgical history (OR = 5.46, 95% CI = [1.51, 19.69]) significantly increased the proportion of high radiation exposure. CONCLUSION: This study found that radiation exposure level of IBD patients was high, which revealed the radiation risk in the process of diagnosis and treatment of IBD patients. In the future, longer follow-up and prospective studies are needed to reveal the relationship between high radiation exposure and solid tumorigenesis.

Increased serum extrachromosomal circular DNA SORBS1circle level is associated with insulin resistance in patients with newly diagnosed type 2 diabetes mellitus.

BACKGROUND: Extrachromosomal circular DNAs (eccDNAs) exist in human blood and somatic cells, and are essential for oncogene plasticity and drug resistance. However, the presence and impact of eccDNAs in type 2 diabetes mellitus (T2DM) remains inadequately understood. METHODS: We purified and sequenced the serum eccDNAs obtained from newly diagnosed T2DM patients and normal control (NC) subjects using Circle-sequencing. We validated the level of a novel circulating eccDNA named sorbin and SH3-domain- containing-1circle97206791-97208025 (SORBS1circle) in 106 newly diagnosed T2DM patients. The relationship between eccDNA SORBS1circle and clinical data was analyzed. Furthermore, we explored the source and expression level of eccDNA SORBS1circle in the high glucose and palmitate (HG/PA)-induced hepatocyte (HepG2 cell) insulin resistance model. RESULTS: A total of 22,543 and 19,195 eccDNAs were found in serum samples obtained from newly diagnosed T2DM patients and NC subjects, respectively. The T2DM patients had a greater distribution of eccDNA on chromosomes 1, 14, 16, 17, 18, 19, 20 and X. Additionally, 598 serum eccDNAs were found to be upregulated, while 856 eccDNAs were downregulated in T2DM patients compared with NC subjects. KEGG analysis demonstrated that the genes carried by eccDNAs were mainly associated with insulin resistance. Moreover, it was validated that the eccDNA SORBS1circle was significantly increased in serum of newly diagnosed T2DM patients (106 T2DM patients vs. 40 NC subjects). The serum eccDNA SORBS1circle content was positively correlated with the levels of glycosylated hemoglobin A1C (HbA1C) and homeostasis model assessment of insulin resistance (HOMA-IR) in T2DM patients. Intracellular eccDNA SORBS1circle expression was significantly enhanced in the high glucose and palmitate (HG/PA)-induced hepatocyte (HepG2 cell) insulin resistance model. Moreover, the upregulation of eccDNA SORBS1circle in the HG/PA-treated HepG2 cells was dependent on generation of apoptotic DNA fragmentation. CONCLUSIONS: These results provide a preliminary understanding of the circulating eccDNA patterns at the early stage of T2DM and suggest that eccDNA SORBS1circle may be involved in the development of insulin resistance.

Comparison of a novel hand-held retractor-assisted transforaminal lumbar interbody fusion by the wiltse approach and posterior TLIF: a one-year prospective controlled study.

BACKGROUND: This study aims to compare the clinical outcomes and safety of a novel hand-held retractor system-assisted Wiltse TLIF with that P-TLIF and assess whether this hand-held retractor system assisted Wiltse TLIF can yield less paraspinal muscle injury. METHODS: 56 patients (P-TLIF: 26, Wiltse TLIF: 30) were included in this one year prospective controlled study. The operation time, intraoperative blood loss, postoperative drainage, mobilization time, and discharge time were recorded. The clinical outcomes were evaluated by ODI, VAS, JOA, and SF-36 scores (7 days, 3, 6, and 12 months after surgery). Paraspinal muscle injury was assessed by postoperative MRI (6 months after surgery). CK and C-reaction protein were measured pre and postoperatively, and CT or X-ray (one year postoperatively) was used to assess bony union/non-union. RESULTS: The Wiltse (study) group was associated with significantly less estimated blood loss (79.67 ± 28.59 ml vs 192.31 ± 59.48 ml, P = 0.000*), postoperative drainage (43.33 ± 27.89 ml vs 285.57 ± 123.05 ml, P = 0.000*), and shorter mobilization (4.1 ± 1.2 d vs. 3.0 ± 0.9 d, P < 0.05) and discharge times (7.7 ± 1.9 d vs. 6.1 ± 1.2 d, P = 0.002*) than the P-TLIF (control) group. Serum CK activity at 24 h postoperatively in the study group was significantly lower than in the control group (384.10 ± 141.99 U/L vs 532.76 ± 225.76 U/L, P = 0.018*). At 7 days after surgery, VAS (2.3 ± 0.6 vs 3.2 ± 0.7, P = 0.000*)and ODI scores (43.9 ± 11.9 vs 55.2 ± 12.9, P = 0.001*) were lower, while the JOA scores (18.4 ± 3.4 vs 16.3 ± 4.2, P = 0.041*) was higher in the control group than in the study group. Results observed at 3 months of follow-up were consistent with those at 7 days. After six months postoperatively, paraspinal muscle degeneration in the control group was more significant than in the study group (P = 0.008*). CONCLUSION: Our study showed that this novel hand-held retractor system assisted Wiltse approach TLIF can significantly reduce paraspinal muscle injury, postoperative drainage, and intraoperative blood loss, mobilization and discharge time, as well as yield better short-term outcomes compared to P-TLIF. TRIAL REGISTRATION: 25/09/2023 NCT06052579.

Factors influencing the job embeddedness of new graduate nurses: A multicentre cross-sectional study.

AIM: To identify factors associated with job embeddedness from the perspective of retaining new graduate nurses. DESIGN: The study was cross-sectional in design. METHODS: Convenience and stratified sampling were used to recruit 415 newly graduated nurses from 12 tertiary hospitals in China. Anonymized data were collected through self-designed sociodemographic questionnaires, job embeddedness scale, feedback-seeking behaviour scale, authentic leadership perception scale and decent work scale. Appropriate indicators were used for descriptive statistics and t-tests, ANOVA, Pearson correlation analysis and multiple linear regression to examine the influencing factors. RESULTS: The study showed that monthly income level, decent labour, authentic leadership and feedback-seeking behaviour were significant predictors of job embeddedness among new graduate nurses. CONCLUSION: The job embeddedness of new graduate nurses is moderate. Nursing managers need to construct reasonable and fair compensation incentives, adopt positive leadership styles and encourage proactive feedback-seeking behaviours to improve the job embeddedness of new graduate nurses and alleviate the nursing talent shortage. IMPACT: Exploring the factors influencing the job embeddedness of new graduate nurses provides a reference for establishing new graduate nurse retention strategies to help promote the career development of new graduate nurses and alleviate the nursing brain drain. REPORTING METHOD: We adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Two new Nb-oxide indole alkaloids with ß-hematin inhibitory activity from the stems and leaves of Rauvolfia dichotoma.

Rauvolfia dichotoma, a shrub of Apocynaceae, was collected from the Islands of SAO Tome and Principe and cultivated locally for medicinal purpose. Phytochemical investigation of 95% ethanol extract from the stems and leaves of R. dichotoma led to the isolation of two new Nb-oxide indole alkaloids, namely Nb-oxide-mitoridine (1) and Nb-oxide-raucaffricine (2), together with two known alkaloids (3-4) and eleven known lignans (5-15). Their chemical structures were elucidated by extensive NMR and HR-ESI-MS data analysis. All compounds (except 13) were tested for their ß-hematin inhibitory activity. Compounds 2, 4, 14, and 15 showed certain inhibitory activity, indicating that they may have an antimalarial effect.

Exploring the mechanism of Si-Miao-Yong-An decoction on heart failure based on molecular docking and network pharmacology.

The SwissTargetPrediction was employed to predict the potential drug targets of the active component of Si-Miao-Yong-An decoction (SMYAD). The therapeutic targets for HF were searched in the Genecard database, and Cytoscape3.9.1 software was used to construct the "drug-component-target-disease network" diagram. In addition, the String platform was used to construct Protein-Protein Interaction (PPI) network, and the DAVID database was used for GO and KEGG analysis. AutoDockTools-1.5.6 software was used for molecular docking verification. Network pharmacology studies have shown that AKT 1, ALB, and CASP 3 are the key targets of action of SMYAD against heart failure. The active compounds are quercetin and kaempferol.

"Discovering shine through feedback seeking"---feedback seeking among new graduate nurses: a qualitative study.

BACKGROUND: Feedback is critical to improving practitioners' clinical practice and professional growth. Although they are still considered junior practitioners, their feedback-seeking experiences have yet to be investigated. This study aimed to understand the fundamental thoughts and experiences of new graduate nurses regarding feedback-seeking and to identify the main factors that influence their feedback-seeking behaviors. METHODS: Conducting a descriptive phenomenological study, semi-structured in-depth interviews with newly graduated nurses from four hospitals in Zhejiang Province, China, face-to-face or via video call in the hospital conference room through purposive and snowball sampling. Interview data were evaluated using Colaizzi's 7-step phenomenological data analysis. The COREQ checklist was followed. RESULTS: A total of 15 new graduate nurses were interviewed as a sample, and 13 categories emerged from our data. They were categorized into four central elements: (1) perceptions and attitudes, (2) drivers, (3) dilemmas and needs, and (4) transformation and growth. CONCLUSIONS: This study found that new graduate nurses have various needs but face dilemmas in the feedback-seeking process. Nursing managers should be proficient at providing positive leadership, collaborating with clinical mentors to foster an atmosphere where new graduate nurses may obtain honest, transparent, and fair feedback, and exercising caution when providing negative feedback.

[Construction of the Whole Process Management Model of Hospice and Palliative Care Outpatient Clinic].

Objective To construct a scientific and practical management model of the hospice and palliative care outpatient clinic and provide a reference for the operation and development of the outpatient clinic. Methods The basic framework of the whole process management model of hospice and palliative care outpatient clinic was determined preliminarily by literature analysis,qualitative interviews and experts group meetings.Two rounds of consultation were conducted among 18 experts in hospice and palliative care and medical-nursing combined outpatient service by the Delphi method. Results The questionnaire response rates of the two rounds of expert consultation were both 100% and the authority coefficients of the two rounds of expert consultation were 0.88 and 0.91,respectively.Finally,the whole process management model of hospice and palliative care outpatient clinic was constructed,which was composed of three first-level indicators including staff composition,work structure and effect evaluation,5 second-level indicators and 62 third-level indicators. Conclusion The constructed whole process management model is scientific,innovative and continuous,which can provide a reference for the operation and development of the hospice and palliative care outpatient clinic.