Structural basis of energy transfer in Porphyridium purpureum phycobilisome.

Photosynthetic organisms have developed various light-harvesting systems to adapt to their environments1. Phycobilisomes are large light-harvesting protein complexes found in cyanobacteria and red algae2-4, although how the energies of the chromophores within these complexes are modulated by their environment is unclear. Here we report the cryo-electron microscopy structure of a 14.7-megadalton phycobilisome with a hemiellipsoidal shape from the red alga Porphyridium purpureum. Within this complex we determine the structures of 706 protein subunits, including 528 phycoerythrin, 72 phycocyanin, 46 allophycocyanin and 60 linker proteins. In addition, 1,598 chromophores are resolved comprising 1,430 phycoerythrobilin, 48 phycourobilin and 120 phycocyanobilin molecules. The markedly improved resolution of our structure compared with that of the phycobilisome of Griffithsia pacifica5 enabled us to build an accurate atomic model of the P. purpureum phycobilisome system. The model reveals how the linker proteins affect the microenvironment of the chromophores, and suggests that interactions of the aromatic amino acids of the linker proteins with the chromophores may be a key factor in fine-tuning the energy states of the chromophores to ensure the efficient unidirectional transfer of energy.

Interface-Suppressed Nematicity and Enhanced Superconducting Pairing Strength of FeSe/NdFeO3 in the Low-Doping Regime.

The discovery of interfacial superconductivity in monolayer FeSe/oxides has spurred intensive research interest. Here we not only extend the FeSe/FeOx superconducting interface to FeSe/NdFeO3 but also establish robust interface-enhanced superconductivity at a very low doping level. Specifically, well-annealed FeSe/NdFeO3 exhibits a low doping level of 0.038-0.046 e-/Fe with a larger superconducting pairing gap without a nematic gap, indicating an enhancement of the enhanced superconducting pairing strength and suppression of nematicity by the FeSe/FeOx interface compared with those of thick FeSe films. These results improve our understanding of the roles of the oxide interface in the low-electron-doped regime.

Porphyromonas gingivalis with collagen immunization induces ACPA-positive rheumatoid arthritis in C3H mice.

The pathogenic anti-citrullinated protein antibodies (ACPA) are thought to play a vital role in the initiation and immune maintenance of rheumatoid arthritis (RA). However, it is noteworthy that ACPA is not a salient characteristic of any conventional RA animal model. Porphyromonas gingivalis (Pg) is the first microorganism identified to induce citrullination and a target of autoantibodies in early rheumatoid arthritis (RA). Thus, we employed C3H mice with specific MHC types and combined Pg infection with collagen immunity to develop an animal model of ACPA-positive RA. The resulting model exhibited citrullination characteristics, as well as pathological and immune cell changes. 1) Mice showed a significant increase in ACPA levels, and various organs and tissues exhibited elevated levels of citrullinated protein. 2) The mice experienced heightened pain, inflammation, and bone destruction. 3) The spleen and lymph nodes of the mice showed a significant increase in the proportion of Tfh-GCB cell subpopulations responsible for regulating autoantibody production. In conclusion, the C3H mouse model of Pg infection with collagen immunity demonstrated significant alterations in ACPA levels, citrullinated protein expression, and immune cell subpopulations, which could be a crucial factor leading to increased pain, inflammation, and bone destruction.

Simultaneous Detection of Aldehyde Metabolites by Light-Assisted Ambient Ionization Mass Spectrometry.

In the clinic, small-molecule metabolites (SMMs) in blood are highly convincing indicators for disease diagnosis, such as cancer. However, challenges still exist for detection of SMMs due to their low concentration and complicated components in blood. In this work, we report the design of a novel "selenium signature" nanoprobe (Se nanoprobe) for efficient identification of multiple aldehyde metabolites in blood. This Se nanoprobe consists of magnetic nanoparticles that can enrich aldehyde metabolites from a complex environment, functionalized with photosensitive "selenium signature" hydrazide molecules that can react with aldehyde metabolites. Upon irradiation with UV, the aldehyde derivatives can be released from the Se nanoprobe and further sprayed by mass spectrometry through ambient ionization (AIMS). By quantifying the selenium isotope distribution (MS/MS) from the derivatization product, accurate detection of several aldehyde metabolites, including valeraldehyde (Val), heptaldehyde (Hep), 2-furaldehyde (2-Fur), 10-undecenal aldehyde (10-Und), and benzaldehyde (Ben), is realized. This strategy reveals a new solution for quick and accurate cancer diagnosis in the clinic.

DeepION: A Deep Learning-Based Low-Dimensional Representation Model of Ion Images for Mass Spectrometry Imaging.

Mass spectrometry imaging (MSI) is a high-throughput imaging technique capable of the qualitative and quantitative in situ detection of thousands of ions in biological samples. Ion image representation is a technique that produces a low-dimensional vector embedded with significant spectral and spatial information on an ion image, which further facilitates the distance-based similarity measurement for the identification of colocalized ions. However, given the low signal-to-noise ratios inherent in MSI data coupled with the scarcity of annotated data sets, achieving an effective ion image representation for each ion image remains a challenge. In this study, we propose DeepION, a novel deep learning-based method designed specifically for ion image representation, which is applied to the identification of colocalized ions and isotope ions. In DeepION, contrastive learning is introduced to ensure that the model can generate the ion image representation in a self-supervised manner without manual annotation. Since data augmentation is a crucial step in contrastive learning, a unique data augmentation strategy is designed by considering the characteristics of MSI data, such as the Poisson distribution of ion abundance and a random pattern of missing values, to generate plentiful ion image pairs for DeepION model training. Experimental results of rat brain tissue MSI show that DeepION outperforms other methods for both colocalized ion and isotope ion identification, demonstrating the effectiveness of ion image representation. The proposed model could serve as a crucial tool in the biomarker discovery and drug development of the MSI technique.

Sub-bundle based analysis reveals the role of human optic radiation in visual working memory.

White matter (WM) functional activity has been reliably detected through functional magnetic resonance imaging (fMRI). Previous studies have primarily examined WM bundles as unified entities, thereby obscuring the functional heterogeneity inherent within these bundles. Here, for the first time, we investigate the function of sub-bundles of a prototypical visual WM tract-the optic radiation (OR). We use the 7T retinotopy dataset from the Human Connectome Project (HCP) to reconstruct OR and further subdivide the OR into sub-bundles based on the fiber's termination in the primary visual cortex (V1). The population receptive field (pRF) model is then applied to evaluate the retinotopic properties of these sub-bundles, and the consistency of the pRF properties of sub-bundles with those of V1 subfields is evaluated. Furthermore, we utilize the HCP working memory dataset to evaluate the activations of the foveal and peripheral OR sub-bundles, along with LGN and V1 subfields, during 0-back and 2-back tasks. We then evaluate differences in 2bk-0bk contrast between foveal and peripheral sub-bundles (or subfields), and further examine potential relationships between 2bk-0bk contrast and 2-back task d-prime. The results show that the pRF properties of OR sub-bundles exhibit standard retinotopic properties and are typically similar to the properties of V1 subfields. Notably, activations during the 2-back task consistently surpass those under the 0-back task across foveal and peripheral OR sub-bundles, as well as LGN and V1 subfields. The foveal V1 displays significantly higher 2bk-0bk contrast than peripheral V1. The 2-back task d-prime shows strong correlations with 2bk-0bk contrast for foveal and peripheral OR fibers. These findings demonstrate that the blood oxygen level-dependent (BOLD) signals of OR sub-bundles encode high-fidelity visual information, underscoring the feasibility of assessing WM functional activity at the sub-bundle level. Additionally, the study highlights the role of OR in the top-down processes of visual working memory beyond the bottom-up processes for visual information transmission. Conclusively, this study innovatively proposes a novel paradigm for analyzing WM fiber tracts at the individual sub-bundle level and expands understanding of OR function.

Custom-Design of Multi-Stimuli-Responsive Degradable Silica Nanoparticles for Advanced Cancer-Specific Chemotherapy.

Chemotherapy is crucial in oncology for combating malignant tumors but often encounters obatacles such as severe adverse effects, drug resistance, and biocompatibility issues. The advantages of degradable silica nanoparticles in tumor diagnosis and treatment lie in their ability to target drug delivery, minimizing toxicity to normal tissues while enhancing therapeutic efficacy. Moreover, their responsiveness to both endogenous and exogenous stimuli opens up new possibilities for integrating multiple treatment modalities. This review scrutinizes the burgeoning utility of degradable silica nanoparticles in combination with chemotherapy and other treatment modalities. Commencing the elucidation of degradable silica synthesis and degradation mechanisms, emphasis is placed on the responsiveness of these materials to endogenous (e.g., pH, redox reactions, hypoxia, and enzymes) and exogenous stimuli (e.g., light and high-intensity focused ultrasound). Moreover, this exploration delves into strategies harnessing degradable silica nanoparticles in chemotherapy alone, coupled with radiotherapy, photothermal therapy, photodynamic therapy, gas therapy, immunotherapy, starvation therapy, and chemodynamic therapy, elucidating multimodal synergies. Concluding with an assessment of advances, challenges, and constraints in oncology, despite hurdles, future investigations are anticipated to augment the role of degradable silica in cancer therapy. These insights can serve as a compass for devising more efficacious combined tumor treatment strategies.

Direct chemical induction of hepatocyte-like cells with capacity for liver repopulation.

BACKGROUND AND AIMS: Cell fate can be directly reprogrammed from accessible cell types (e.g., fibroblasts) into functional cell types by exposure to small molecule stimuli. However, no chemical reprogramming method has been reported to date that successfully generates functional hepatocyte-like cells that can repopulate liver tissue, casting doubt over the feasibility of chemical reprogramming approaches to obtain desirable cell types for therapeutic applications. APPROACH AND RESULTS: Here, through chemical induction of phenotypic plasticity, we provide a proof-of-concept demonstration of the direct chemical reprogramming of mouse fibroblasts into functional hepatocyte-like cells using exposure to small molecule cocktails in culture medium to successively stimulate endogenous expression of master transcription factors associated with hepatocyte development, such as hepatocyte nuclear factor 4a, nuclear receptor subfamily 1, group I, member 2, and nuclear receptor subfamily 1, group H, member 4. RNA sequencing analysis, metabolic assays, and in vivo physiological experiments show that chemically induced hepatocytes (CiHeps) exhibit comparable activity and function to primary hepatocytes, especially in liver repopulation to rescue liver failure in fumarylacetoacetate hydrolase -/- recombination activating gene 2 -/- interleukin 2 receptor, gamma chain -/- mice in vivo . Single-cell RNA-seq further revealed that gastrointestinal-like and keratinocyte-like cells were induced along with CiHeps, resembling the activation of an intestinal program within hepatic reprogramming as described in transgenic approaches. CONCLUSIONS: Our findings show that direct chemical reprogramming can generate hepatocyte-like cells with high-quality physiological properties, providing a paradigm for establishing hepatocyte identity in fibroblasts and demonstrating the potential for chemical reprogramming in organ/tissue repair and regeneration therapies.

Epidemiological and clinical features of malignant hyperthermia: A scoping review.

Malignant hyperthermia (MH) is a potentially fatal inherited pharmacogenetic disorder related to pathogenic variants in the RYR1, CACNA1S, or STAC3 genes. Early recognition of the occurrence of MH and prompt medical treatment are indispensable to ensure a positive outcome. The purpose of this study was to provide valuable information for the early identification of MH by summarizing epidemiological and clinical features of MH. This scoping review followed the methodological framework recommended by Arksey and O'Malley. PubMed, Embase, and Web of science databases were searched for studies that evaluated the epidemical and clinical characteristics of MH. A total of 37 studies were included in this review, of which 26 were related to epidemiology and 24 were associated with clinical characteristics. The morbidity of MH varied from 0.18 per 100 000 to 3.9 per 100 000. The mortality was within the range of 0%-18.2%. Identified risk factors included sex, age, disorders associated with MH, and others. The most frequent initial clinical signs included hyperthermia, sinus tachycardia, and hypercarbia. The occurrence of certain signs, such as hypercapnia, delayed first temperature measurement, and peak temperature were associated with poor outcomes. The epidemiological and clinical features of MH varied considerably and some risk factors and typical clinical signs were identified. The main limitation of this review is that the treatment and management strategies were not assessed sufficiently due to limited information.

Dynamically Encircling Exceptional Points in Different Riemann Sheets for Orbital Angular Momentum Topological Charge Conversion.

Orbital angular momentum (OAM) provides an additional degree of freedom for optical communication systems, and manipulating on-chip OAM is important in integrated photonics. However, there is no effective method to realize OAM topological charge conversion on chip. In this Letter, we propose a way to convert OAM by encircling two groups of exceptional points in different Riemann sheets. In our framework, any OAM conversion can be achieved on demand just by manipulating adiabatic and nonadiabatic evolution of modes in two on-chip waveguides. More importantly, the chiral OAM conversion is realized, which is of great significance since the path direction can determine the final topological charge order. Our Letter presents a special chiral behavior and provides a new method to manipulate OAM on the chip.

Association between Constipation and the Risk of Parkinson's Disease among Participants in the UK Biobank.

INTRODUCTION: Constipation is common in patients with Parkinson's disease (PD), but its impact on incident PD remains uncertain. We aimed to prospectively investigate constipation symptoms and the risk of PD. METHODS: Participants without PD at baseline from the UK Biobank were included in the study. Information on the regular use of laxatives, bowel movement frequency, and the frequency of hard or lumpy stools was collected. Incident PD was defined by the ICD-10 code. Cox proportional hazards models were used to assess the association between constipation symptoms and incident PD. RESULTS: In the analysis of regular laxative use and PD, 490,797 participants were included and 2,735 incident PD were detected. The multivariable adjusted HR of PD in participants who regularly used laxatives was 1.99 (95% confidence interval [CI], 1.70-2.33) compared with those who did not. In the analysis of bowel movement frequency and hard or lumpy stools and PD, 170,017 participants were included and 519 incident PD were detected. The multivariable adjusted HRs were 2.16 (95% CI, 1.74-2.68) and 2.57 (95% CI, 2.00-3.31) for participants with a bowel movement frequency of 3-6 times/week and <3 times/week, respectively, compared with those with a bowel movement frequency of ≥7 times/week; compared with participants who never had hard or lumpy stools, multivariable adjusted HRs were 1.31 (95% CI, 1.07-1.60), 2.32 (95% CI, 1.77-3.05), and 2.94 (95% CI, 2.14-4.05) for those who sometimes had hard or lumpy stools, often had hard or lumpy stools, and most of time/always had hard or lumpy stools, respectively. CONCLUSIONS: Constipation measured by the regular use of laxatives, bowel movement frequency, and the frequency of hard or lumpy stools was significantly associated with an increased risk of incident PD.

Association between Physical Activity and Parkinson's Disease: A Prospective Cohort Study.

BACKGROUND: The burden of Parkinson's disease (PD) is still increasing, and physical activity is a modifiable factor for health benefits. The benefits of physical activity in PD are not well established. Therefore, this study aimed to investigate the association between various types of physical activity and the risk of developing PD. METHODS: Data from 432,497 participants in UK Biobank, who were free of PD at baseline, were analyzed. Physical activity levels were assessed by measuring the duration of walking for pleasure, light and heavy do-it-yourself (DIY) activities, strenuous sports, and other exercises. Physical activity was categorized into daily living activities (walking for pleasure, light DIY, and heavy DIY) and structured exercises (strenuous sports and other exercises). Association between different types of physical activity and PD risk was examined using multivariable adjusted restricted cubic splines and Cox proportional risk models. RESULTS: Over a median follow-up of 13.7 years, 2,350 PD cases were identified. Cubic spline analyses revealed negative linear associations between PD risk and total physical activity, daily living activities, and structured exercise. After multivariable adjustment, the hazard ratios and 95% confidence intervals for incident PD associated with the highest quartile of total physical activity, daily living activities, and structured exercise were 0.72 (0.64-0.81), 0.75 (0.67-0.84), and 0.78 (0.67-0.90), respectively, compared to those in the lowest quartile. Sensitivity analysis confirmed these findings. CONCLUSIONS: Higher levels of both daily living activities and structured exercise were associated with a reduced incidence of PD, underscoring the importance of maintaining physical activity to prevent PD.

Structural basis for SARS-CoV-2 neutralizing antibodies with novel binding epitopes.

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) threatens global public health and economy unprecedentedly, requiring accelerating development of prophylactic and therapeutic interventions. Molecular understanding of neutralizing antibodies (NAbs) would greatly help advance the development of monoclonal antibody (mAb) therapy, as well as the design of next generation recombinant vaccines. Here, we applied H2L2 transgenic mice encoding the human immunoglobulin variable regions, together with a state-of-the-art antibody discovery platform to immunize and isolate NAbs. From a large panel of isolated antibodies, 25 antibodies showed potent neutralizing activities at sub-nanomolar levels by engaging the spike receptor-binding domain (RBD). Importantly, one human NAb, termed PR1077, from the H2L2 platform and 2 humanized NAb, including PR953 and PR961, were further characterized and subjected for subsequent structural analysis. High-resolution X-ray crystallography structures unveiled novel epitopes on the receptor-binding motif (RBM) for PR1077 and PR953, which directly compete with human angiotensin-converting enzyme 2 (hACE2) for binding, and a novel non-blocking epitope on the neighboring site near RBM for PR961. Moreover, we further tested the antiviral efficiency of PR1077 in the Ad5-hACE2 transduction mouse model of COVID-19. A single injection provided potent protection against SARS-CoV-2 infection in either prophylactic or treatment groups. Taken together, these results shed light on the development of mAb-related therapeutic interventions for COVID-19.

Extracellular vesicles in the HCC microenvironment: Implications for therapy and biomarkers.

Hepatocellular carcinoma (HCC) stands as the sixth most prevalent cancer and the third leading cause of cancer mortality globally. Despite surgical resection being the preferred approach for early-stage HCC, most patients are diagnosed at intermediate to advanced stages, limiting treatment options to chemotherapy and immunotherapy, which often yield poor outcomes. Extracellular vesicles (EVs), minute lipid-bilayered particles released by diverse cells under various physiological and pathological conditions, are crucial for mediating communication between cells. Mounting evidence indicates that EVs sourced from different cells can profoundly influence the HCC tumor microenvironment (TME), thereby affecting the progression of HCC. Given their immunogenicity and liver-targeting properties, these EVs not only hold promise for HCC treatment but also provide avenues for advancing early diagnostic methods and assessing prognosis. This review not only describes the function of EVs within the HCC tumor microenvironment but also analyzes their therapeutic advantages and explores their significance in various therapeutic approaches for HCC, including chemotherapy, immunotherapy, combination therapy, and their role as innovative drug delivery carriers. Furthermore, it highlights the potential of EVs as biomarkers for the diagnosis and prognosis of HCC.

Tracking the Helicobacter pylori Epidemic in Adults and Children in China.

BACKGROUND: The Helicobacter pylori epidemic in China accounts for up to a third of gastric cancers worldwide. We aim to monitor the temporal and spatial dynamics of H. pylori infection in both adults and children across China. MATERIALS AND METHODS: We developed a surveillance system consisting of a data collection component that harnessed survey reports in natural populations and an analysis component that accounted for the differences in survey time and location, population age structure, and H. pylori detection method. System outputs were estimates of the prevalence of H. pylori in adults and children (aged ≤ 14 years) presented at three hierarchical levels (regional, provincial, and prefectural). RESULTS: The overall prevalence of H. pylori infection declined sharply in adults (63.3%, 52.5%, 43.4%, and 38.7%) and less sharply in children (23.1%, 26.1%, 16.0%, and 15.7%) in 1983-1999, 2000-2009, 2010-2014, and 2015-2019, respectively. The changes were asynchronous across regions, with the most marked declines in the Northwest, the Hong Kong-Macao-Taiwan region, and the East. We estimated that 457.6 million adults and 44.5 million children have been infected with H. pylori, with cross-province disparities in prevalence ranging from 24.3% to 69.3% among adults and 2.9% to 46.3% among children. In general, the risk level of gastric cancer increased as the prevalence of H. pylori increased. The correlation was statistically significant for both adult men (Spearman coefficient of correlation: 0.393, p = 0.0146) and women (0.470, p = 0.0029). CONCLUSIONS: The tracking system would be important for the continuous and stratified tracking of the Helicobacter pylori epidemic across China and can be used to furnish an evidence base for the formulation of tailored prevention strategies.

The effects of low-dose IL-2 on Th17/Treg cell imbalance in primary biliary cholangitis mouse models.

BACKGROUND/AIMS: Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The imbalance of Th17/Treg cells has been reported in PBC patients. Low-dose IL-2 can alleviate disease severity through modulating CD4 + T cell subsets in patients with autoimmune diseases. Hence, the present study aimed to examine the effects and mechanism of low-dose IL-2 in PBC mouse models. METHODS: PBC models were induced in female C57BL/6 mice by two immunizations with 2OA-BSA at two-week intervals, and poly I: C every three days. PBC mouse models were divided into the IL-2 treated and untreated groups and low-dose IL-2 was injected at three different time points. Th17 and Tregs were analyzed by flow cytometry, and the related cytokines were analyzed by ELISA. Liver histopathology was examined by H&E and immunohistochemical staining. RESULTS: Twelve weeks after modeling, the serum AMA was positive and the ALP was significantly increased in PBC mouse models (P<0.05). The pathology showed lymphocyte infiltration in the portal area, damage, and reactive proliferation of the small bile duct (P<0.05). The flow cytometric showed the imbalance of Th17/Treg cells in the liver of PBC mouse models, with decreased Treg cells, increased Th17 cells, and Th17/Treg ratio (P < 0.05). After the low-dose IL-2 intervention, biochemical index and liver pathologies showed improvement at 12 weeks. Besides, the imbalance of Th17 and Treg cells recovered. Public database mining showed that Th17 cell differentiation may contribute to poor response in PBC patients. CONCLUSION: Low-dose IL-2 can significantly improve liver biochemistry and pathology by reversing the imbalance of Th17 and Treg cells, suggesting that it may be a potential therapeutic target for PBC.

Improved Cell Adhesion on Self-Assembled Chiral Nematic Cellulose Nanocrystal Films.

Chirality is ubiquitous in nature, and closely related to biological phenomena. Nature-originated nanomaterials such as cellulose nanocrystals (CNCs) are able to self-assemble into hierarchical chiral nematic CNC films and impart handedness to nano and micro scale. However, the effects of the chiral nematic surfaces on cell adhesion are still unknown. Herein, this work presents evidence that the left-handed self-assembled chiral nematic CNC films (L-CNC) significantly improve the adhesion of L929 fibroblasts compared to randomly arranged isotropic CNC films (I-CNC). The fluidic force microscopy-based single-cell force spectroscopy is introduced to assess the cell adhesion forces on the substrates of L-CNC and I-CNC, respectively. With this method, a maximum adhesion force of 133.2 nN is quantified for mature L929 fibroblasts after culturing for 24 h on L-CNC, whereas the L929 fibroblasts exert a maximum adhesion force of 78.4 nN on I-CNC under the same condition. Moreover, the instant SCFS reveals that the integrin pathways are involved in sensing the chirality of substrate surfaces. Overall, this work offers a starting point for the regulation of cell adhesion via the self-assembled nano and micro architecture of chiral nematic CNC films, with potential practical applications in tissue engineering and regenerative medicine.

Relationship between Serum Irisin Level, All-Cause Mortality, and Cardiovascular Mortality in Peritoneal Dialysis Patients.

INTRODUCTION: This study aimed to investigate the prospective role of serum irisin - a novel adipo-myokine - in all-cause mortality and cardiovascular (CV) mortality in patients on peritoneal dialysis (PD). METHODS: A prospectively observational study was conducted with 154 PD patients. Baseline clinical data were collected from the medical records. Serum irisin concentrations were determined using enzyme-linked immunosorbent assay. Patients were divided into the high irisin group (serum irisin ≥113.5 ng/mL) and the low irisin group (serum irisin <113.5 ng/mL) based on the median value of serum irisin. A body composition monitor was used to monitor body composition. Cox regression analysis was utilized to find the independent risk factors of all-cause and CV mortality in PD patients. RESULTS: The median serum irisin concentration was 113.5 ng/mL (interquartile range, 106.2-119.8 ng/mL). Patients in the high irisin group had significantly higher muscle mass and carbon dioxide combining power (CO2CP) than those in the low irisin group (p < 0.05). Serum irisin was positively correlated with pulse pressure, CO2CP, and muscle mass, while negatively correlated with body fat percentage (p < 0.05). During a median of follow-up for 60.0 months, there were 55 all-cause deaths and 26 CV deaths. Patients in the high irisin group demonstrated a higher CV survival rate than those in the low irisin group (p = 0.016). Multivariate Cox regression analysis showed that high irisin level (hazard ratio [HR], 0.341; 95% confidence interval [CI], 0.135-0.858; p = 0.022), age, and diabetic mellitus were independently associated with CV mortality in PD patients. However, serum irisin level failed to demonstrate a statistically significant relationship with all-cause mortality. CONCLUSION: Low serum irisin levels at baseline were independently predictive of CV mortality but not all-cause mortality in PD patients. Therefore, serum irisin could be a potential target for monitoring CV outcomes in PD patients.

SPTLC2 ameliorates chondrocyte dysfunction and extracellular matrix metabolism disturbance in vitro and in vivo in osteoarthritis.

Disturbances in chondrocyte extracellular matrix (ECM) metabolism in osteoarthritis (OA) are a major cause of OA and potentially lead to personal disability, placing a huge burden on society. Chondrocyte apoptosis and ECM catabolism have a major role in the OA process. Firstly, bioinformatics analysis was performed to screen differentially expressed genes (DEGs) in OA, and serine palmitoyltransferase subunit 2 (SPTLC2) was chosen, which had high-level expression in the OA cartilage tissues and OA chondrocytes. Overexpression and knockdown of SPTLC2 were achieved in OA chondrocytes and normal chondrocytes respectively to study the effect of SPTLC2 upon ECM metabolism of chondrocytes. Cell viability and apoptosis were measured using MTT and flow cytometry analyses; SPTLC2 overexpression enhanced the OA chondrocyte viability and decreased apoptotic rate. In addition, Western blot detection of ECM-related factors (Collagen I, Collage II, MMP-1, MMP-3, and MMP-13) revealed that SPTLC2 overexpression promoted the expression of collagens (Collagen I and Collage II) and suppressed matrix metalloproteinase (MMP-1, MMP-3, and MMP-13) level. In contrast, SPTLC2 knockdown in normal chondrocytes showed opposite effects on cell viability, apoptosis, and ECM degeneration. The articular cartilage of OA rats was transfected with lentivirus overexpressing SPTLC2; HE and Safranin-O fast green demonstrated that SPTLC2 overexpression could alleviate chondrocyte injuries and slow down the development of OA. In conclusion, SPTLC2 plays a role in OA and may be a potential target gene for the treatment of OA.

Linking clinical manifestations and causative organisms may provide clues for the treatment of peritoneal dialysis-associated peritonitis.

INTRODUCTION: Different initial manifestations of peritoneal dialysis-associated peritonitis (PDAP) may depend on the type of pathogenic organism. We investigated the association between the clinical characteristics of PDAP and susceptibility to vancomycin and investigated the possibility of using vancomycin monotherapy alone as an initial treatment regimen for some PDAP patients to avoid unnecessary antibiotic exposure and secondary infection. METHODS: Patients with culture-positive PDAP were retrospectively analyzed and divided into two groups: peritonitis with only cloudy effluent (PDAP-cloudy) or with cloudy effluent, abdominal pain and/or fever (PDAP-multi). The bacterial culture of PD effluent and antibiotic sensitivity test results were compared between groups. Logistic regression was used to investigate factors predicting susceptibility to vancomycin. RESULTS: Of 162 episodes of peritonitis which had a positive bacterial culture of PD fluid, 30 peritonitis were in the PDAP-cloudy group, and 132 peritonitis were in the PDAP-multi group. Thirty (100%) peritonitis in the PDAP-cloudy group had gram-positive bacterial infections, which was significantly greater than that in the PDAP-multi group (51.5%) (P < 0.001). Twenty-nine (96.7%) peritonitis in the PDAP-cloudy group were susceptible to vancomycin, compared to 67 (50.8%) in the PDAP-multi group (P < 0.001). The specificity of PDAP-cloudy for vancomycin-sensitive peritonitis was 98.48%. Only one patient (3.3%) in the PDAP-cloudy group experienced vancomycin-resistant peritonitis caused by Enterococcus gallinarum, which could neither be covered by vancomycin nor by the initial antibiotic regimen recommended by the current ISPD guidelines. The presence of only cloudy effluent was an independent predictor of susceptibility to vancomycin according to multivariate analysis (OR = 27.678, 95% CI 3.191-240.103, p = 0.003), in addition to PD effluent WBC counts (OR = 0.988, 95% CI 0.980-0.996, p = 0.004), diabetes mellitus (OR = 3.646, 95% CI 1.580-8.416, p = 0.002), first episode peritonitis (OR = 0.447, 95% CI 0.207-0.962, p = 0.039) and residual renal creatinine clearance (OR = 0.956, 95% CI 0.918-0.995, p = 0.027). Addition of these characteristics increased the AUC to 0.813 (95% CI 0.0.749-0.878, P < 0.001). The specificity of presenting with only cloudy effluent for vancomycin-sensitive peritonitis was 98.48%. CONCLUSIONS: Cloudy dialysate, as the only symptom at PDAP onset, was an independent predictor of vancomycin-sensitive PDAP, which is an important new insight that may guide the choice of initial antibiotic treatment.