Convergent evolution in the supercoiling of prokaryotic flagellar filaments.

The supercoiling of bacterial and archaeal flagellar filaments is required for motility. Archaeal flagellar filaments have no homology to their bacterial counterparts and are instead homologs of bacterial type IV pili. How these prokaryotic flagellar filaments, each composed of thousands of copies of identical subunits, can form stable supercoils under torsional stress is a fascinating puzzle for which structural insights have been elusive. Advances in cryoelectron microscopy (cryo-EM) make it now possible to directly visualize the basis for supercoiling, and here, we show the atomic structures of supercoiled bacterial and archaeal flagellar filaments. For the bacterial flagellar filament, we identify 11 distinct protofilament conformations with three broad classes of inter-protomer interface. For the archaeal flagellar filament, 10 protofilaments form a supercoil geometry supported by 10 distinct conformations, with one inter-protomer discontinuity creating a seam inside of the curve. Our results suggest that convergent evolution has yielded stable superhelical geometries that enable microbial locomotion.

Clinical trial links oncolytic immunoactivation to survival in glioblastoma.

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM)1,2. Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV)3. In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue4. These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ).

The evolution of archaeal flagellar filaments.

Flagellar motility has independently arisen three times during evolution: in bacteria, archaea, and eukaryotes. In prokaryotes, the supercoiled flagellar filaments are composed largely of a single protein, bacterial or archaeal flagellin, although these two proteins are not homologous, while in eukaryotes, the flagellum contains hundreds of proteins. Archaeal flagellin and archaeal type IV pilin are homologous, but how archaeal flagellar filaments (AFFs) and archaeal type IV pili (AT4Ps) diverged is not understood, in part, due to the paucity of structures for AFFs and AT4Ps. Despite having similar structures, AFFs supercoil, while AT4Ps do not, and supercoiling is essential for the function of AFFs. We used cryo-electron microscopy to determine the atomic structure of two additional AT4Ps and reanalyzed previous structures. We find that all AFFs have a prominent 10-strand packing, while AT4Ps show a striking structural diversity in their subunit packing. A clear distinction between all AFF and all AT4P structures involves the extension of the N-terminal α-helix with polar residues in the AFFs. Additionally, we characterize a flagellar-like AT4P from Pyrobaculum calidifontis with filament and subunit structure similar to that of AFFs which can be viewed as an evolutionary link, showing how the structural diversity of AT4Ps likely allowed for an AT4P to evolve into a supercoiling AFF.

A novel RHH family transcription factor aCcr1 and its viral homologs dictate cell cycle progression in archaea.

Cell cycle regulation is of paramount importance for all forms of life. Here, we report that a conserved and essential cell cycle-specific transcription factor (designated as aCcr1) and its viral homologs control cell division in Sulfolobales. We show that the transcription level of accr1 reaches peak during active cell division (D-phase) subsequent to the expression of CdvA, an archaea-specific cell division protein. Cells over-expressing the 58-aa-long RHH (ribbon-helix-helix) family cellular transcription factor as well as the homologs encoded by large spindle-shaped viruses Acidianus two-tailed virus (ATV) and Sulfolobus monocaudavirus 3 (SMV3) display significant growth retardation and cell division failure, manifesting as enlarged cells with multiple chromosomes. aCcr1 over-expression results in downregulation of 17 genes (>4-fold), including cdvA. A conserved motif, aCcr1-box, located between the TATA-binding box and the translation initiation site of 13 out of the 17 highly repressed genes, is critical for aCcr1 binding. The aCcr1-box is present in the promoters and 5' UTRs of cdvA genes across Sulfolobales, suggesting that aCcr1-mediated cdvA repression is an evolutionarily conserved mechanism by which archaeal cells dictate cytokinesis progression, whereas their viruses take advantage of this mechanism to manipulate the host cell cycle.

Association mechanism between Arabidopsis immune coreceptor BAK1 and Pseudomonas syringae effector HopF2.

Brassinosteroid activated kinase 1 (BAK1) is a cell-surface coreceptor which plays multiple roles in innate immunity of plants. HopF2 is an effector secreted by the bacterial pathogen Pseudomonas syringae pv. tomato DC3000 into Arabidopsis and suppresses host immune system through interaction with BAK1 as well as its downstream kinase MKK5. The association mechanism of HopF2 to BAK1 remains unclear, which prohibits our understanding and subsequent interfering of their interaction for pathogen management. Herein, we found the kinase domain of BAK1 (BAK1-KD) is sufficient for HopF2 association. With a combination of hydrogen/deuterium exchange mass spectrometry and mutational assays, we found a region of BAK1-KD N-lobe and a region of HopF2 head subdomain are critical for intermolecular interaction, which is also supported by unbiased protein-protein docking with ClusPro and kinase activity assay. Collectively, this research presents the interaction mechanism between Arabidopsis BAK1 and P. syringae HopF2, which could pave the way for bactericide development that blocking the functioning of HopF2 toward BAK1.

Strain and Shell Thickness Engineering in Pd3 Pb@Pt Bifunctional Electrocatalyst for Ethanol Upgrading Coupled with Hydrogen Production.

The ethanol oxidation reaction (EOR) is an attractive alternative to the sluggish oxygen evolution reaction in electrochemical hydrogen evolution cells. However, the development of high-performance bifunctional electrocatalysts for both EOR and hydrogen evolution reaction (HER) is a major challenge. Herein, the synthesis of Pd3 Pb@Pt core-shell nanocubes with controlled shell thickness by Pt-seeded epitaxial growth on intermetallic Pd3 Pb cores is reported. The lattice mismatch between the Pd3 Pb core and the Pt shell leads to the expansion of the Pt lattice. The synergistic effects between the tensile strain and the core-shell structures result in excellent electrocatalytic performance of Pd3 Pb@Pt catalysts for both EOR and HER. In particular, Pd3 Pb@Pt with three Pt atomic layers shows a mass activity of 8.60 A mg-1 Pd+Pt for ethanol upgrading to acetic acid and close to 100% of Faradic efficiency for HER. An EOR/HER electrolysis system is assembled using Pd3 Pb@Pt for both the anode and cathode, and it is shown that low cell voltage of 0.75 V is required to reach a current density of 10 mA cm-2 . The present work offers a promising strategy for the development of bifunctional catalysts for hybrid electrocatalytic reactions and beyond.

Spatially and Temporally Programmable Transparency Evolutions in Hydrogels Enabled by Metal Coordination toward Transient Anticounterfeiting.

Hydrogels have emerged as promising candidates for anticounterfeiting materials, owing to their unique stimulus-responsive capabilities. To improve the security of encrypted information, efforts are devoted to constructing transient anticounterfeiting hydrogels with a dynamic information display. However, current studies to design such hydrogel materials inevitably include sophisticated chemistry, complex preparation processes, and particular experimental setups. Herein, a facile strategy is proposed to realize the transient anticounterfeiting by constructing bivalent metal (M2+)-coordination complexes in poly(acrylic acid) gels, where the cloud temperature (Tc) of the gels can be feasibly tuned by M2+ concentration. Therefore, the multi-Tc parts in the gel can be locally programmed by leveraging the spatially selective diffusion of M2+ with different concentrations. With the increase of temperature or the addition of a complexing agent, the transparency of the multi-Tc parts in the gel spontaneously evolves in natural light, enabling the transient information anticounterfeiting process. This work has provided a new strategy and mechanism to fabricate advanced anticounterfeiting hydrogel materials.

The rice blast fungus SR protein 1 regulates alternative splicing with unique mechanisms.

Serine/arginine-rich (SR) proteins are well known as splicing factors in humans, model animals and plants. However, they are largely unknown in regulating pre-mRNA splicing of filamentous fungi. Here we report that the SR protein MoSrp1 enhances and suppresses alternative splicing in a model fungal plant pathogen Magnaporthe oryzae. Deletion of MoSRP1 caused multiple defects, including reduced virulence and thousands of aberrant alternative splicing events in mycelia, most of which were suppressed or enhanced intron splicing. A GUAG consensus bound by MoSrp1 was identified in more than 94% of the intron or/and proximate exons having the aberrant splicing. The dual functions of regulating alternative splicing of MoSrp1 were exemplified in enhancing and suppressing the consensus-mediated efficient splicing of the introns in MoATF1 and MoMTP1, respectively, which both were important for mycelial growth, conidiation, and virulence. Interestingly, MoSrp1 had a conserved sumoylation site that was essential to nuclear localization and enhancing GUAG binding. Further, we showed that MoSrp1 interacted with a splicing factor and two components of the exon-joining complex via its N-terminal RNA recognition domain, which was required to regulate mycelial growth, development and virulence. In contrast, the C-terminus was important only for virulence and stress responses but not for mycelial growth and development. In addition, only orthologues from Pezizomycotina species could completely rescue defects of the deletion mutants. This study reveals that the fungal conserved SR protein Srp1 regulates alternative splicing in a unique manner.

Prognostic Significance of the Highest Mediastinal Lymph Node Involvement in Patients with Stage III-N2 Non-small Cell Lung Cancer.

BACKGROUND: Highest mediastinal lymph node (HMLN) involvement is a category of uncertain resection, yet the prognostic significance of HMLN involvement remains controversial. METHODS: A total of 486 patients with pathological stage III-N2 disease who underwent radical resection were enrolled from January 2015 to December 2018. Patients were allocated into two groups-HMLN involvement (219 cases) and HMLN-negative (249 cases) groups. Kaplan-Meier analysis and Cox proportional hazard regression models were used to evaluate the impact of HMLN involvement on 5-year recurrence-free survival (RFS) and overall survival (OS). RESULTS: The proportion of patients with multiple N2 diseases (72.1% vs. 23.7%; p < 0.001) and stage IIIA (87.2% vs. 77.5%; p < 0.009) were greater in the HMLN-involvement group than in the HMLN-negative group, and the survival rates of the HMLN-involvement group were significantly lower than those of the HMLN-negative group (RFS: 27.2% vs. 49.8%, p < 0.001; OS: 42.1% vs. 59.2%, p = 0.001). HMLN status was an independent factor for OS only (RFS: adjusted hazard ratio [aHR] 1.26, 95% confidence interval CI 0.94-1.68; OS: aHR 1.45, 95% CI 1.07-1.99) in the entire stage III cohort. After stratification of patients according to stage, the involvement of HMLN decreased both RFS and OS in the stage IIIA group (RFS: aHR 1.46, 95% CI 1.06-2.02; OS: aHR 1.70, 95% CI 1.19-2.42); however, no such difference was observed within the stage IIIB group. CONCLUSIONS: HMLN involvement is a prognostic factor of deteriorating survival in highly advanced N2 disease only in patients with stage IIIA.

Dysregulated dynamic time-varying triple-network segregation in children with autism spectrum disorder.

One of the remarkable characteristics of autism spectrum disorder (ASD) is the dysregulation of functional connectivity of the triple-network, which includes the salience network (SN), default mode network (DMN), and central executive network (CEN). However, there is little known about the segregation of the triple-network dynamics in ASD. This study used resting-state functional magnetic resonance imaging data including 105 ASD and 102 demographically-matched typical developing control (TC) children. We compared the dynamic time-varying triple-network segregation and triple-network functional connectivity states between ASD and TC groups, and examined the relationship between dynamic triple-network segregation alterations and clinical symptoms of ASD. The average dynamic network segregation value of the DMN with SN and the DMN with CEN in ASD was lower but the coefficient of variation (CV) of dynamic network segregation of the DMN with CEN was higher in ASD. Furthermore, partially reduced triple-network segregation associated with the DMN was found in connectivity states analysis of ASD. These abnormal average values and CV of dynamic network segregation predicted social communication deficits and restricted and repetitive behaviors in ASD. Our findings indicate abnormal dynamic time-varying triple-network segregation of ASD and highlight the crucial role of the triple-network in the neural mechanisms underlying ASD.

Targeting SUMOylation with an injectable nanocomposite hydrogel to optimize radiofrequency ablation therapy for hepatocellular carcinoma.

BACKGROUND: Incomplete radiofrequency ablation (iRFA) in hepatocellular carcinoma (HCC) often leads to local recurrence and distant metastasis of the residual tumor. This is closely linked to the development of a tumor immunosuppressive environment (TIME). In this study, underlying mechanisms and potential therapeutic targets involved in the formation of TIME in residual tumors following iRFA were explored. Then, TAK-981-loaded nanocomposite hydrogel was constructed, and its therapeutic effects on residual tumors were investigated. RESULTS: This study reveals that the upregulation of small ubiquitin-like modifier 2 (Sumo2) and activated SUMOylation is intricately tied to immunosuppression in residual tumors post-iRFA. Both knockdown of Sumo2 and inhibiting SUMOylation with TAK-981 activate IFN-1 signaling in HCC cells, thereby promoting dendritic cell maturation. Herein, we propose an injectable PDLLA-PEG-PDLLA (PLEL) nanocomposite hydrogel which incorporates self-assembled TAK-981 and BSA nanoparticles for complementary localized treatment of residual tumor after iRFA. The sustained release of TAK-981 from this hydrogel curbs the expansion of residual tumors and notably stimulates the dendritic cell and cytotoxic lymphocyte-mediated antitumor immune response in residual tumors while maintaining biosafety. Furthermore, the treatment with TAK-981 nanocomposite hydrogel resulted in a widespread elevation in PD-L1 levels. Combining TAK-981 nanocomposite hydrogel with PD-L1 blockade therapy synergistically eradicates residual tumors and suppresses distant tumors. CONCLUSIONS: These findings underscore the potential of the TAK-981-based strategy as an effective therapy to enhance RFA therapy for HCC.

Promoting a healthy lifestyle: exploring the role of social media and fitness applications in the context of social media addiction risk.

The popularity of social networks turns them into a legal method for promoting a healthy lifestyle, which benefits not only people but also different countries' governments. This research paper aimed to examine the Keep fitness app integrated into WeChat, Weibo and QQ as regards long-term improvements in health-related behaviors (physical activity, nutrition, health responsibility, spiritual growth, interpersonal relationships and stress management) and assess the associated risk of increased social media addiction. Students from Lishui University in China (N = 300) participated in this study, and they were formed into control and experimental groups. The Healthy Lifestyle Behavior Scale and Social Media Disorder Scale were used as psychometric instruments. The Keep app was found to improve respondents' scores on the parameters of physical activity, nutrition and health responsibility (P = 0.00). However, the level of dependence on social media did not change in either the control or the experimental group during the year of research (P ≥ 0.05). It is concluded that fitness apps can be an effective tool to promote healthy lifestyles among young people in China and other countries. The feasibility of government investment in fitness apps to promote healthy lifestyles is substantiated.

The predictors of short and long term urinary continence recovery after laparoscopic radical prostatectomy: a single cancer center report in China.

PURPOSE: To evaluate the predictors for short and long term urinary continence (UC) recovery after laparoscopic radical prostatectomy (LRP) from clinical and oncological variables. METHODS: We retrospectively collected data from 142 prostate cancer patients who underwent LRP between September 2014 and June 2021 at a tumor specialist diagnosis and treatment center in China. The rate of post-prostatectomy incontinence (PPI) was evaluated from immediate and at 3, 6 and 12 mo after LRP, and UC was defined as the use of no or one safety pad. Sixteen clinical and oncological variables were analyzed by univariate and multivariate regression analysis to determine whether they were associated with short (3 mo) or long term (12 mo) UC recovery after LRP. RESULTS: After eliminating patients who were lost to follow-up, 129 patients were eventually included. The mean ± SD age was 68 ± 6.3 years. The UC rates of immediate, 3, 6 and 12 mo after the operation were 27.9%, 54.3%, 75.2% and 88.4%, respectively. Multivariate analyses revealed that membranous urethral length (MUL) was a protective predictor of UC after catheter extraction(P < 0.001), and at 3 mo (P < 0.001), 6 mo (P < 0.001) and 12 mo (P = 0.009) after surgery. CONCLUSION: MUL is a significant independent factor that can contribute to short and long term UC recovery post-LRP, which may assist clinicians and their patients in counseling of treatment.

Virus-induced cell gigantism and asymmetric cell division in archaea.

Archaeal viruses represent one of the most mysterious parts of the global virosphere, with many virus groups sharing no evolutionary relationship to viruses of bacteria or eukaryotes. How these viruses interact with their hosts remains largely unexplored. Here we show that nonlytic lemon-shaped virus STSV2 interferes with the cell cycle control of its host, hyperthermophilic and acidophilic archaeon Sulfolobus islandicus, arresting the cell cycle in the S phase. STSV2 infection leads to transcriptional repression of the cell division machinery, which is homologous to the eukaryotic endosomal sorting complexes required for transport (ESCRT) system. The infected cells grow up to 20-fold larger in size, have 8,000-fold larger volume compared to noninfected cells, and accumulate massive amounts of viral and cellular DNA. Whereas noninfected Sulfolobus cells divide symmetrically by binary fission, the STSV2-infected cells undergo asymmetric division, whereby giant cells release normal-sized cells by budding, resembling the division of budding yeast. Reinfection of the normal-sized cells produces a new generation of giant cells. If the CRISPR-Cas system is present, the giant cells acquire virus-derived spacers and terminate the virus spread, whereas in its absence, the cycle continues, suggesting that CRISPR-Cas is the primary defense system in Sulfolobus against STSV2. Collectively, our results show how an archaeal virus manipulates the cell cycle, transforming the cell into a giant virion-producing factory.

A designer rice NLR immune receptor confers resistance to the rice blast fungus carrying noncorresponding avirulence effectors.

Plant nucleotide-binding and leucine-rich repeat (NLR) receptors recognize avirulence effectors directly through their integrated domains (IDs) or indirectly via the effector-targeted proteins. Previous studies have succeeded in generating designer NLR receptors with new recognition profiles by engineering IDs or targeted proteins based on prior knowledge of their interactions with the effectors. However, it is yet a challenge to design a new plant receptor capable of recognizing effectors that function by unknown mechanisms. Several rice NLR immune receptors, including RGA5, possess an integrated heavy metal-associated (HMA) domain that recognizes corresponding Magnaporthe oryzae Avrs and ToxB-like (MAX) effectors in the rice blast fungus. Here, we report a designer rice NLR receptor RGA5HMA2 carrying an engineered, integrated HMA domain (RGA5-HMA2) that can recognize the noncorresponding MAX effector AvrPib and confers the RGA4-dependent resistance to the M. oryzae isolates expressing AvrPib, which originally triggers the Pib-mediated blast resistance via unknown mechanisms. The RGA5-HMA2 domain is contrived based on the high structural similarity of AvrPib with two MAX effectors, AVR-Pia and AVR1-CO39, recognized by cognate RGA5-HMA, the binding interface between AVR1-CO39 and RGA5-HMA, and the distinct surface charge of AvrPib and RAG5-HMA. This work demonstrates that rice NLR receptors with the HMA domain can be engineered to confer resistance to the M. oryzae isolates noncorresponding but structurally similar MAX effectors, which manifest cognate NLR receptor-mediated resistance with unknown mechanisms. Our study also provides a practical approach for developing rice multilines and broad race spectrum-resistant cultivars by introducing a series of engineered NLR receptors.

Substantial accumulation of mercury in the deepest parts of the ocean and implications for the environmental mercury cycle.

Anthropogenic activities have led to widespread contamination with mercury (Hg), a potent neurotoxin that bioaccumulates through food webs. Recent models estimated that, presently, 200 to 600 t of Hg is sequestered annually in deep-sea sediments, approximately doubling since industrialization. However, most studies did not extend to the hadal zone (6,000- to 11,000-m depth), the deepest ocean realm. Here, we report on measurements of Hg and related parameters in sediment cores from four trench regions (1,560 to 10,840 m), showing that the world's deepest ocean realm is accumulating Hg at remarkably high rates (depth-integrated minimum-maximum: 24 to 220 µg ⋅ m-2 ⋅ y-1) greater than the global deep-sea average by a factor of up to 400, with most Hg in these trenches being derived from the surface ocean. Furthermore, vertical profiles of Hg concentrations in trench cores show notable increasing trends from pre-1900 [average 51 ± 14 (1σ) ng ⋅ g-1] to post-1950 (81 ± 32 ng ⋅ g-1). This increase cannot be explained by changes in the delivery rate of organic carbon alone but also need increasing Hg delivery from anthropogenic sources. This evidence, along with recent findings on the high abundance of methylmercury in hadal biota [R. Sun et al, Nat. Commun. 11, 3389 (2020); J. D. Blum et al, Proc. Natl. Acad. Sci. U. S. A. 117, 29292-29298 (2020)], leads us to propose that hadal trenches are a large marine sink for Hg and may play an important role in the regulation of the global biogeochemical cycle of Hg.

A filamentous archaeal virus is enveloped inside the cell and released through pyramidal portals.

The majority of viruses infecting hyperthermophilic archaea display unique virion architectures and are evolutionarily unrelated to viruses of bacteria and eukaryotes. The lack of relationships to other known viruses suggests that the mechanisms of virus-host interaction in Archaea are also likely to be distinct. To gain insights into archaeal virus-host interactions, we studied the life cycle of the enveloped, ∼2-µm-long Sulfolobus islandicus filamentous virus (SIFV), a member of the family Lipothrixviridae infecting a hyperthermophilic and acidophilic archaeon Saccharolobus islandicus LAL14/1. Using dual-axis electron tomography and convolutional neural network analysis, we characterize the life cycle of SIFV and show that the virions, which are nearly two times longer than the host cell diameter, are assembled in the cell cytoplasm, forming twisted virion bundles organized on a nonperfect hexagonal lattice. Remarkably, our results indicate that envelopment of the helical nucleocapsids takes place inside the cell rather than by budding as in the case of most other known enveloped viruses. The mature virions are released from the cell through large (up to 220 nm in diameter), six-sided pyramidal portals, which are built from multiple copies of a single 89-amino-acid-long viral protein gp43. The overexpression of this protein in Escherichia coli leads to pyramid formation in the bacterial membrane. Collectively, our results provide insights into the assembly and release of enveloped filamentous viruses and illuminate the evolution of virus-host interactions in Archaea.

Citrulline facilitates the glycolysis, proliferation, and metastasis of lung cancer cells by regulating RAB3C.

Lung cancer (LC) is one of the major malignant diseases threatening human health. The study aimed to identify the effect of citrulline on the malignant phenotype of LC cells and to further disclose the potential molecular mechanism of citrulline in regulating the development of LC, providing a novel molecular biological basis for the clinical treatment of LC. The effects of citrulline on the viability, proliferation, migration, and invasion of LC cells (A549, H1299) were validated by CCK-8, colony formation, EdU, and transwell assays. The cell glycolysis was assessed via determining the glucose uptake, lactate production, ATP levels, extracellular acidification rate (ECAR), and oxygen consumption rate (OCR). RNA-seq and molecular docking were performed to screen for citrulline-binding target proteins. Western blotting experiments were conducted to examine the expression of related signaling pathway molecules. In addition, the impacts of citrulline on LC growth in vivo were investigated by constructing mouse models. Citrulline augmented the viability of LC cells in a concentration and time-dependent manner. The proliferation, migration, invasion, glycolysis, and EMT processes of LC cells were substantially enhanced after citrulline treatment. Bioinformatics analysis indicated that citrulline could bind to RAB3C protein. Western blotting results indicated that citrulline activated the IL-6/STAT3 pathway by binding to RAB3C. In addition, animal experiments disclosed that citrulline promoted tumor growth in mice. Citrulline accelerated the glycolysis and activated the IL6/STAT3 pathway through the RAB3C protein, consequently facilitating the development of LC.

Efficacy of astragalus combined with renin-angiotensin-aldosterone system blockers in the treatment of stage III diabetic nephropathy: a systematic review and meta-analysis.

OBJECTIVE: To determine the efficacy and safety of Astragalus combined with renin-angiotensin-aldosterone system (RAAS) blockers in treating stage III diabetic nephropathy (DN) by meta-analysis. METHODS: PubMed, Embase, Cochrane Library, Wiley, and Web of Science databases were searched for articles published between August 2007 and August 2022. Clinical studies on Astragalus combined with RAAS blockers for the treatment of stage III DN were included. Meta-analysis was performed by RevMan 5.1 and Stata 14.3 software. RESULTS: A total of 32 papers were included in this meta-analysis, containing 2462 patients from randomized controlled trials, with 1244 receiving the combination treatment and 1218 solely receiving RAAS blockers. Astragalus combined with RAAS blockers yielded a significantly higher total effective rate (TER) (mean difference [MD] 3.63, 95% confidence interval [CI] 2.59-5.09) and significantly reduced urinary protein excretion rate (UPER), serum creatinine (Scr), blood urine nitrogen (BUN) and glycosylated hemoglobin (HbAlc) levels. In subgroup analysis, combining astragalus and angiotensin receptor blocker significantly lowered fasting plasma glucose (FPG) and 24 h urinary protein (24hUTP) levels, compared with the combined astragalus and angiotensin-converting enzyme inhibitor treatment. Meanwhile, the latter significantly decreased the urinary microprotein (ß2-MG). Importantly, the sensitivity analysis confirmed the study's stability, and publication bias was not detected for UPER, BUN, HbAlc, FPG, or ß2-MG. However, the TER, SCr, and 24hUTP results suggested possible publication bias. CONCLUSIONS: The astragalus-RAAS blocker combination treatment is safe and improves outcomes; however, rigorous randomized, large-scale, multi-center, double-blind trials are needed to evaluate its efficacy and safety in stage III DN.

Renin-angiotensin-aldosterone system (RAAS) inhibitors are commonly used to treat diabetic neuropathy (DN) and Astragalus membranaceus components are known to improve DN symptoms.We aimed to establish the efficacy and safety of using Astragalus combined with RAAS inhibitors.Astragalus combined with RAAS inhibitors enhances the total effective rate of diabetic neuropathy response to treatment and reduces urinary protein excretion rate, serum creatinine, blood urea nitrogen and HbAlc.Sensitivity analysis affirms study stability, while publication bias was detected for total effective rate, serum creatinine, and 24 h urinary protein levels.

The Social Inequality of Music: University Students from a Higher Social Class Are More Likely to Build Relationships and Feel Happiness Through Music.

The relationship between young people's music use and well-being has gained extensive interest in recent years. The relationship-building function of music is one of its most important functions. While many studies have documented the positive effects of this function, there is a lack of research discussing this topic from the perspective of social stratification. This study sampled 691(63.8% male, M age = 19.43, SD = 1.42) Chinese university students to examine the social class differences among university students in acquiring well-being through the relationship-building function of music. The results revealed that university students from a higher social class are more likely to acquire well-being through the relationship-building function of music. In addition, interdependent self-construal plays a moderating role in the mediating model. The mediating effect was only significant when university students have a higher level of interdependent self-construal. These results indicated social class differences among university students in the building of relationships with music, underscoring the need for future research and interventions to address social inequality in the context of music's functions.