ScreenDMT reveals DiHOMEs are replicably inversely associated with BMI and stimulate adipocyte calcium influx.

Activating brown adipose tissue (BAT) improves systemic metabolism, making it a promising target for metabolic syndrome. BAT is activated by 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which we previously identified to be inversely associated with BMI and which directly improves metabolism in multiple tissues. Here we profile plasma lipidomics from 83 people and test which lipids' association with BMI replicates in a concordant direction using our novel tool ScreenDMT, whose power and validity we demonstrate via mathematical proofs and simulations. We find that the linoleic acid diols 12,13-diHOME and 9,10-diHOME are both replicably inversely associated with BMI and mechanistically activate calcium influx in mouse brown and white adipocytes in vitro, which implicates this signaling pathway and 9,10-diHOME as candidate therapeutic targets. ScreenDMT can be applied to test directional mediation, directional replication, and qualitative interactions, such as identifying biomarkers whose association is shared (replication) or opposite (qualitative interaction) across diverse populations.

Trait divergence and opposite above- and below-ground strategies facilitate moso bamboo invasion into subtropical evergreen broadleaf forest.

Understanding the invasion of moso bamboo (Phyllostachys edulis) into adjacent evergreen broadleaf forest based on functional traits is crucial due to its significant influence on ecosystem processes. However, existing research has primarily focused on above- or below-ground traits in isolation, lacking a comprehensive integration of both. In this study, we conducted a trait-based analysis including 23 leaf traits and 11 root traits in three forest types - bamboo forest, mixed bamboo and broadleaf forest, and evergreen broadleaf forest - to investigate trait differences, phenotypic integration, and above- and below-ground resource strategies in bamboo and broadleaf species. Our findings demonstrated significant differences in leaf and root key traits between bamboo and broadleaf species, strongly supporting the "phenotypic divergence hypothesis". Bamboo exhibited stronger trait correlations compared to broadleaf species, indicating higher phenotypic integration. Above- and below-ground strategies were characterized by trade-offs rather than coordination, resulting in a multi-dimensional trait syndrome. Specifically, a unidimensional leaf economics spectrum revealed that bamboo with higher leaf N concentrations (LNC), P concentrations (LPC), and specific leaf area (SLA) adopted a "fast acquisitive" above-ground strategy, while broadleaf species with thicker leaves employed a "slow conservative" above-ground strategy. A two-dimensional root trait syndrome indicated a "conservation" gradient with bamboo adopting a "slow conservative" below-ground strategy associated with higher root tissue density (RTD), and broadleaf species exhibiting a "fast acquisitive" below-ground strategy linked to higher root N concentrations (RNC) and P concentrations (RPC), and a "collaboration" gradient probably ranging from broadleaf species with a "do-it-yourself" strategy characterized by high specific root length (SRL), to bamboo adopting an "outsourcing" strategy with thicker roots. In conclusion, key trait divergence from coexisting broadleaf species, higher phenotypic integration, and multi-dimensional opposite above- and below-ground resource strategies confer competitive advantages to moso bamboo, shedding light on the mechanistic understanding of its invasion into subtropical evergreen broadleaf forest and providing theoretical guidance for maintaining the stability of subtropical forest ecosystem.

[Clincopathological analysis of 171 patients with osteochondroma and malignant transformation in maxillofacial bone].

PURPOSE: To investigate the clinical and pathological features of osteochondroma in maxillofacial region, and to summarize the clinicopathological features of rare osteochondroma malignant transformation in order to provide clinical guidance. METHODS: From January 2018 to September 2023, a total of 171 patients with osteochondroma were retrospectively collected in Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. Their preoperative CT and clinicopathological features were analyzed. RESULTS: Of the 171 patients with osteochondroma in maxillofacial bone, 66%（113/171） were females and 34% were male. Their age ranged from 11-76 with an average age was 44 years old. Of the 171 cases, 95.3%（163/171）in mandible condyle, 4%(7/171) in mandible processus coronoideus, and 0.5%（1/171） in zygomatic arch. The imaging findings showed that the thickness of cartilaginous cap was less than 1 cm in 98%（159/161） cases with condyle lesions. Only 2 cases(2/171, 1.1%) had malignant transformation. One was diagnosed with secondary chondrosarcoma, another developed low-grade osteosarcoma. CONCLUSIONS: Osteochondroma in maxillofacial region mostly occurs in females, and most commonly located in condylar process, with a malignant change rate of 1.1%, which is similar to that of other parts of the body. Imaging findings have important guiding significance for the diagnosis of osteochondroma malignant change.

Enhancing the autologous fascial sling procedure: A novel fixation method for treating stress urinary incontinence in female patients.

BACKGROUND: Synthetic mid-urethral sling surgery has long been the standard surgical treatment for stress urinary incontinence (SUI) worldwide. Using an autologous fascial sling is an alternative to reduce adverse events. We evaluated the treatment outcomes of a novel fixation method applied to the autologous transobturator fascial (TOF) sling procedure for female patients with SUI. METHODS: A retrospective study was conducted between 2017 and 2020, including 33 patients with SUI who underwent mid-urethral TOF sling surgery with the novel fixation method. We used a self-locking feature (V-LOC™) that was fixed to each side of skin layer above the obturator foramen, and the tension of the fascia sling was adjusted by manipulating the V-LOC™ suture. We analyzed all data collected through questionnaires, including Urinary Distress Inventory-Short Form (UDI-6), Incontinence Impact Questionnaire-Short Form (IIQ-7), Overactive Bladder Symptom Score (OABSS), and Clinical Global Impressions of Improvement (CGI-I). Adverse events were also recorded. RESULTS: This study included 33 female patients aged 39-79 (mean 59.76 years). Following the procedure, there was a significant reduction in the total scores of UDI-6, IIQ-7, and OABSS (preoperative 9.73±4.35, 10.21±5.79, 6.06±4.03 and postoperative 3.52±3.41, 0.85±3.67, 3.06±2.90, respectively) (p < 0.001). Further analysis of each sub-score of the questionnaires revealed significant improvement in certain symptoms. The mean total score of CGI-I was 2.00 ± 0.80. The maximum flow rate was documented for 18 patients, and no significant reduction was observed after the procedure (p = 0.804). Complications reported included voiding dysfunction in two patients (6.1 %), inguinal pain in one patient (3.0 %), and mild delayed wound healing in one patient (3.0 %). CONCLUSION: This modified TOF sling surgery with a novel fixation method by V-LOC™ suture offers feasibility and adjustability as its main advantages. Our study demonstrated significant improvements in patient outcomes.

Liver stiffness in hepatocellular carcinoma and chronic hepatitis patients: Hepatitis B virus infection and transaminases should be considered.

BACKGROUND: Liver condition is a crucial prognostic factor for patients with hepatocellular carcinoma (HCC), but a convenient and comprehensive method to assess liver condition is lacking. Liver stiffness (LS) measured by two-dimensional shear wave elastography may help in assessing liver fibrosis and liver condition. Chronic hepatitis B (CHB) is an important risk factor for HCC progression, but LS was found to be less reliable in assessing liver fibrosis following hepatitis viral eradication. We hypothesize that the status of hepatitis virus infection would affect the accuracy of LS in assessing the liver condition. AIM: To test the feasibility and impact factors of using LS to assess liver condition in patients with HCC and CHB. METHODS: A total of 284 patients were retrospectively recruited and classified into two groups on the basis of serum CHB virus hepatitis B virus (HBV)-DNA levels [HBV-DNA ≥ 100.00 IU/mL as Pos group (n = 200) and < 100.00 IU/mL as Neg group (n = 84)]. Correlation analyses and receiver operating characteristic analyses were conducted to evaluate the relationship between LS and liver condition. RESULTS: A significant correlation was found between LS and most of the parameters considered to have the ability to evaluate liver condition (P < 0.05). When alanine aminotransferase (ALT) concentrations were normal (≤ 40 U/L), LS was correlated with liver condition indices (P < 0.05), but the optimal cutoff of LS to identify a Child-Pugh score of 5 was higher in the Neg group (9.30 kPa) than the Pos group (7.40 kPa). When ALT levels were elevated (> 40 U/L), the correlations between LS and liver condition indices were not significant (P > 0.05). CONCLUSION: LS was significantly correlated with most liver condition indices in patients with CHB and HCC. However, these correlations varied according to differences in HBV-DNA and transaminase concentrations.

Glucocorticoid modulates oxidative and thermogenic function of rat brown adipose tissue and human brown adipocytes.

Chronic and excessive glucocorticoid (GC) exposure can cause Cushing's syndrome, resulting in fat accumulation in selected body areas. Particularly in the brown adipose tissue (BAT), GC acts negatively, resulting in whitening of the tissue. We hypothesized that dysregulation of microRNAs by GC could be an additional mechanism to explain its negative actions in BAT. Male Wistar rats were divided into two groups: (1) Control sham and (2) GC group that was administered dexamethasone 6.25 mg/200 µL via osmotic pump implantation over 28 days. After this period, the animals were euthanized and BAT tissue was properly stored. Human fat cells treated with dexamethasone were used to translate the experimental results found in animals to human biology. GC-treated rat BAT presented with large lipid droplets, severely impaired thermogenic activation, and reduced glucose uptake measured by 18F-FDG PET/CT. GC exposure induced a reduction in the mitochondrial OXPHOS system and oxygen consumption. MicroRNA profiling of BAT revealed five top-regulated microRNAs and among them miR-21-5p was the most significantly upregulated in GC-treated rats compared to the control group. Although upregulation of miR-21-5p in the tissue, differentiated primary brown adipocytes from GC-treated rats had decreased miR-21-5p levels compared to the control group. To translate these results to the clinic, human brown adipocytes were treated with dexamethasone and miR-21-5p inhibitor. In human brown cells, inhibition of miR-21-5p increased brown adipocyte differentiation and prevented GC-induced glucose uptake, resulting in a lower glycolysis rate. In conclusion, high-dose GC therapy significantly impacts brown adipose tissue function, with a notable association between glucose uptake and miR-21-5p.

Study on the change of global ecological distribution of Nicotiana tabacum L. based on MaxEnt model.

Nicotiana tabacum L. (tobacco) has extremely high economic value, medicinal value, scientific research value and some other uses. Though it has been widely cultivated throughout the world, classification and change of its suitable habitats is not that clear, especially in the context of global warming. In order to achieve rational cultivation and sustainable development of tobacco, current (average from 1970-2000) and future (2070, average from 2061-2080) potential suitable habitats of Nicotiana tabacum L. were forecasted with MaxEnt model and ArcGIS platform based on 854 occurrence data and 22 environmental factors in this study. The results revealed that mean temperature of warmest quarter (bio10), annual precipitation (bio12), solar radiation in September (Srad9), and clay content (CLAY) were the four decisive environment variables for the distribution of Nicotiana tabacum L. Under current climate conditions, suitable habitats of Nicotiana tabacum L. were mainly distributed in south-central Europe, south-central North America, most parts of South America, central Africa, south and southeast Asia, and southeast coast of Australia, and only 13.7% of these areas were highly suitable. By the year 2070, suitable habitats under SSP1-2.6, SSP3-7.0, and SSP5-8.5 climate scenarios would all increase with the largest increase found under SSP3-7.0 scenario, while suitable habitats would reduce under SSP2-4.5 climate scenario. Globally, the center of mass of suitable habitats would migrate to southeast to varying degrees within Libya under four different climate scenarios. The emergence of new habitats and the disappearance of old habitats would all occur simultaneously under each climate scenario, and the specific changes in each area, combined with the prediction results under current climate conditions, will provide an important reference for the adjustment of agronomic practices and rational cultivation of Nicotiana tabacum L. both currently and in the future.

Classification of anatomy and treatment approaches for aneurysms originating from the proximal of the A1 segment of the anterior cerebral artery in clinical settings.

Objective: To explore the spatial relationship between A1 segment proximal anterior cerebral artery aneurysms and their main trunks, classify them anatomically and develop targeted treatment strategies. Methods: This single-center retrospective analysis involved 39 patients diagnosed with aneurysms originating from the proximal of A1 segment of the anterior cerebral artery (2014-2023). Classify the patient's aneurysm into 5 types based on the location of the neck involving the carrier artery and the spatial relationship and projection direction of the aneurysm body with the carrier artery, and outcomes from treatment methods were compared. Results: Among 39 aneurysms, 18 cases underwent endovascular intervention treatment, including 6 cases of stent assisted embolization, 1 case of flow-diverter embolization, 5 cases of balloon assisted embolization, and 6 cases of simple coiling. At discharged, the mRS score of all endovascularly treated patients was 0, and the GOS score was 5 at 6 months after discharge. At discharge, the mRS score of microsurgical clipping treated patients was 0 for 15 cases, 3 for 1 case, 4 for 1 case and 5 for 2 cases. Six months after discharge, the GOS score was 5 for 16 cases, 4 for 2 cases, 3 for 2 cases, and 1 for 1 case. GOS outcomes at 6 months were better for endovascularly treated patients (p = 0.047). Conclusion: Results showed better outcomes for the endovascular treatment group compared to microsurgical clipping at 6 months after surgery. The anatomical classification of aneurysms in this region may be of help to develop effective treatment strategies.

Prevalence and Diagnostic Agreement of Sarcopenia Based on Handgrip Strength and 5-Time Chair-Stand Test Among Chinese Community-Dwelling Older Adults.

INTRODUCTION: Handgrip strength and the 5-time chair-stand test are the two important muscle strength measures run through the whole sarcopenia diagnosis algorithm. There is a lack of evidence to confirm which muscle strength measures have a higher detection rate of sarcopenia among Chinese older adults, which is a challenge for community workers to choose the muscle strength measures and to identify more sarcopenia in clinical practice. OBJECTIVE: We aimed to investigate the prevalence and diagnostic agreement of sarcopenia based on handgrip strength and the 5-time chair-stand test among Chinese community-dwelling older adults. METHODS: This cross-sectional study sampled 1027 community-dwelling older adults from Hunan, China. We used handgrip strength and the 5-time chair-stand test to assess participants' muscle strength and used gait speed and bioimpedance analysis (BIA) to assess physical performance and skeletal muscle mass, respectively. The kappa values of the agreement test were used to evaluate the agreement of handgrip strength and 5-time chair-stand tests in the assessment of sarcopenia. RESULTS: A total of 1027 participants were included in this analysis including 337 males and 690 females with an average age of 70.35 ± 7.24 years. The prevalence of possible sarcopenia, confirmed sarcopenia and severe sarcopenia based on handgrip strength was 50.8%, 20.3% and 14.5% respectively, while the corresponding prevalence for using the 5-time chair-stand test was 27.6%, 10.8% and 10.9%. The kappa value of the consistency test between handgrip strength and 5-time chair-stand test in the assessment of possible sarcopenia, confirmed and severe sarcopenia was 0.26, 0.51 and 0.62, respectively (p < 0.001 for all). CONCLUSIONS: The prevalence of possible sarcopenia, confirmed sarcopenia and severe sarcopenia based on handgrip strength was significantly higher than that of the 5-time chair-stand test. We recommend handgrip strength as the preferred method of muscle strength measurement for Chinese community-dwelling older adults and use 5-time chair-stand tests when handgrip strength is not available. IMPLICATIONS FOR PRACTICE: The findings provide information and suggestions to healthcare providers for choosing the muscle strength measures to detect more sarcopenia in clinical practice. Compared with the 5-time chair-stand test, handgrip strength has a better performance to identify sarcopenia in Chinese community-dwelling older adults.

Light-responsive adipose-hypothalamus axis controls metabolic regulation.

Light is fundamental for biological life, with most mammals possessing light-sensing photoreceptors in various organs. Opsin3 is highly expressed in adipose tissue which has extensive communication with other organs, particularly with the brain through the sympathetic nervous system (SNS). Our study reveals a new light-triggered crosstalk between adipose tissue and the hypothalamus. Direct blue-light exposure to subcutaneous white fat improves high-fat diet-induced metabolic abnormalities in an Opsin3-dependent manner. Metabolomic analysis shows that blue light increases circulating levels of histidine, which activates histaminergic neurons in the hypothalamus and stimulates brown adipose tissue (BAT) via SNS. Blocking central actions of histidine and denervating peripheral BAT blunts the effects of blue light. Human white adipocytes respond to direct blue light stimulation in a cell-autonomous manner, highlighting the translational relevance of this pathway. Together, these data demonstrate a light-responsive metabolic circuit involving adipose-hypothalamus communication, offering a potential strategy to alleviate obesity-induced metabolic abnormalities.

Promising response of proliferative glomerulonephritis with monoclonal IgG deposits to low-dose daratumumab: a case report.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a rare disease without standardized treatment modalities. Daratumumab is a human IgG monoclonal anti-CD38 antibody that has been demonstrated to be highly effective and safe in the treatment of PGNMID. This article reports a 66-year-old female who suffered from edema in both lower limbs and face for 6 years with mild proteinuria and hypoproteinemia. Renal biopsy displayed eight glomeruli, among which two presented with glomerulosclerosis, and the remaining six exhibited moderate diffuse hyperplasia of glomerular mesangial cells and stroma with endothelial cell proliferation. Immunofluorescence microscopy revealed lumpy and diffuse deposits of C3, C1q, IgG, and κ light chain in the glomerular mesangium, with strongly positive staining for IgG3 and varying degrees of weak to negative staining for IgG1, IgG2, IgG4, and λ light chain. Additionally, ultrastructural analysis unveiled that the glomerular basement membrane was segmentally thickened, accompanied by diffuse pedicle fusion, segmental tethered insertion, subendothelial deposits, and electron-dense material in tethered areas. The patient received a total dose of 800 mg of daratumumab (400 mg daily for two consecutive days), as well as daily prednisone (25 mg) and valsartan (80 mg), for treatment and achieved complete remission after three-month follow-up. This case represents an early attempt to treat PGNMID with low-dose daratumumab but requires long-term follow-up.

Convergence and divergence in neurostructural signatures of unipolar and bipolar depressions: Insights from surface-based morphometry and prospective follow-up.

BACKGROUND: Bipolar disorder (BD) is often misidentified as unipolar depression (UD) during its early stages, typically until the onset of the first manic episode. This study aimed to explore both shared and unique neurostructural changes in patients who transitioned from UD to BD during follow-up, as compared to those with UD. METHODS: This study utilized high-resolution structural magnetic resonance imaging (MRI) to collect brain data from individuals initially diagnosed with UD. During the average 3-year follow-up, 24 of the UD patients converted to BD (cBD). For comparison, the study included 48 demographically matched UD patients who did not convert and 48 healthy controls. The MRI data underwent preprocessing using FreeSurfer, followed by surface-based morphometry (SBM) analysis to identify cortical thickness (CT), surface area (SA), and cortical volume (CV) among groups. RESULTS: The SBM analysis identified shared neurostructural characteristics between the cBD and UD groups, specifically thinner CT in the right precentral cortex compared to controls. Unique to the cBD group, there was a greater SA in the right inferior parietal cortex compared to the UD group. Furthermore, no significant correlations were observed between cortical morphological measures and cognitive performance and clinical features in the cBD and UD groups. LIMITATIONS: The sample size is relatively small. CONCLUSIONS: Our findings suggest that while cBD and UD exhibit some common alterations in cortical macrostructure, numerous distinct differences are also present. These differences offer valuable insights into the neuropathological underpinnings that distinguish these two conditions.

Modulation of PD-L1 by Astragalus polysaccharide attenuates the induction of melanoma stem cell properties and overcomes immune evasion.

BACKGROUND: Melanoma is a highly aggressive form of skin cancer. The existence of cancer stem cells (CSCs) and tumor immune evasion are two major causes of melanoma progression, but no effective treatment has been found at present. Astragalus polysaccharide (APS) is a principal active component derived from Astragalus membranaceus, showing anti-tumor effects in various tumors including melanoma. However, the underlying mechanism is still unclear. METHODS: The regulation of APS on self-renewal ability and CSC markers expression in melanoma stem cells (MSCs) was measured by tumor sphere formation and tumorigenicity assays, RT-qPCR, and western blot. Flow cytometry was conducted to evaluate the activation of immune system by APS in melanoma mice. Further, the mechanism was explored based on PD-L1 overexpression and knock-down B16 cells. RESULTS: APS attenuated the tumor sphere formation of MSCs in vitro as well as the tumorigenicity in vivo. It also decreased the expression of CD133, BMI1 and CD47. Based on the PD-L1 overexpression and knock-down B16 cells, it was confirmed that APS inhibited the induction of MSCs by down-regulating PD-L1 expression. Meanwhile, APS increased the infiltration of CD4+ and CD8+T cells in tumor tissues because of its inhibitory effect on PD-L1. CONCLUSIONS: APS inhibited MSC induction and overcame tumor immune evasion through reducing PD-L1 expression. This study provided compelling evidence that APS could be a prospective therapeutic agent for treating melanoma.

Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue.

Thermogenic adipose tissue, consisting of brown and beige fat, regulates nutrient utilization and energy metabolism. Human brown fat is relatively scarce and decreases with obesity and aging. Hence, inducing thermogenic differentiation of white fat offers an attractive way to enhance whole-body metabolic capacity. Here, we show the role of endothelin 3 (EDN3) and endothelin receptor type B (EDNRB) in promoting the browning of white adipose tissue (WAT). EDNRB overexpression stimulates thermogenic differentiation of human white preadipocytes through cAMP-EPAC1-ERK activation. In mice, cold induces the expression of EDN3 and EDNRB in WAT. Deletion of EDNRB in adipose progenitor cells impairs cold-induced beige adipocyte formation in WAT, leading to excessive weight gain, glucose intolerance, and insulin resistance upon high-fat feeding. Injection of EDN3 into WAT promotes browning and improved whole-body glucose metabolism. The findings shed light on the mechanism of WAT browning and offer potential therapeutics for obesity and metabolic disorders.

OGG1: An emerging multifunctional therapeutic target for the treatment of diseases caused by oxidative DNA damage.

Oxidative DNA damage-related diseases, such as incurable inflammation, malignant tumors, and age-related disorders, present significant challenges in modern medicine due to their complex molecular mechanisms and limitations in identifying effective treatment targets. Recently, 8-oxoguanine DNA glycosylase 1 (OGG1) has emerged as a promising multifunctional therapeutic target for the treatment of these challenging diseases. In this review, we systematically summarize the multiple functions and mechanisms of OGG1, including pro-inflammatory, tumorigenic, and aging regulatory mechanisms. We also highlight the potential of OGG1 inhibitors and activators as potent therapeutic agents for the aforementioned life-limiting diseases. We conclude that OGG1 serves as a multifunctional hub; the inhibition of OGG1 may provide a novel approach for preventing and treating inflammation and cancer, and the activation of OGG1 could be a strategy for preventing age-related disorders. Furthermore, we provide an extensive overview of successful applications of OGG1 regulation in treating inflammatory, cancerous, and aging-related diseases. Finally, we discuss the current challenges and future directions of OGG1 as an emerging multifunctional therapeutic marker for the aforementioned challenging diseases. The aim of this review is to provide a robust reference for scientific researchers and clinical drug developers in the development of novel clinical targeted drugs for life-limiting diseases, especially for incurable inflammation, malignant tumors, and age-related disorders.

Genomic evidence that Ornithinicoccus soli Jiang et al. 2020 is a later heterotypic synonym of Segeticoccus rhizosphaerae Lee and Whang 2020.

The genus Segeticoccus includes only one species with validly published name, Segeticoccus rhizosphaerae. The type strain Segeticoccus rhizosphaerae YJ01T was isolated from soil in Korea, while Ornithinicoccus soli XNB-1T was isolated from soil in China. Both strains share similar phenotypic and chemotaxonomic characteristics, including predominant menaquinone MK-8(H4) and major polar lipids diphosphatidylglycerol and phosphatidylglycerol. Whole genome sequences revealed a DNA G+C content of 70.1 mol% for both strains and 100% similarity in their 16S rRNA gene sequences. Phylogenetic analysis showed they form a distinct cluster separate from other genera. Genomic comparisons showed average nucleotide identity and digital DNA-DNA hybridization values of 99.16 and 94.2%, respectively, indicating they represent a single species. Based on this genomic evidence, Ornithinicoccus soli Jiang et al. 2020 is proposed to be a later heterotypic synonym of Segeticoccus rhizosphaerae Lee and Whang 2020.

Qiliqiangxin Alleviates Imbalance of Inflammatory Cytokines in Patients with Dilated Cardiomyopathy: A Randomized Controlled Trial.

OBJECTIVE: Qiliqiangxin (QLQX) capsule- a traditional Chinese medicine used for treating heart failure (HF), can modulate inflammatory cytokines in rats with myocardial infarction. However, its immune-regulating effect on dilated cardiomyopathy (DCM) remains unknown. The aim of this study was to investigate whether QLQX has a unique regulatory role in the imbalance of pro- and anti-inflammatory cytokines in patients with DCM. METHODS: The QLQX-DCM is a randomized- double-blind trial conducted at 24 tertiary hospitals in China. A total of 345 patients with newly diagnosed virus-induced DCM were randomly assigned to receive QLQX capsules or placebo while receiving optimal medical therapy for HF. The primary endpoints were changes in plasma inflammatory cytokines and improvements in left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDd) over the 12-month treatment. RESULTS: At the 12-month follow-up, the levels of IFN-γ, IL-17, TNF-α, and IL-4 decreased significantly, while the level of IL-10 increased in both groups compared with baselines (all P<0.0001). Furthermore-these changes, coupled with improvements in LVEF, NT-proBNP and New York Heart Association (NYHA) functional classification, excluding the LVEDd in the QLQX group, were greater than those in the placebo group (all P<0.001). Additionally, compared with placebo, QLQX treatment also reduced all-cause mortality and rehospitalization rates by 2.17% and 2.28%, respectively, but the difference was not statistically significant. CONCLUSION: QLQX has the potential to alleviate the imbalance of inflammatory cytokines in patients with DCM, potentially leading to further improvements in cardiac function when combined with anti-HF standard medications.

Upgraded cellulose and xylan digestions for synergistic enhancements of biomass enzymatic saccharification and bioethanol conversion using engineered Trichoderma reesei strains overproducing mushroom LeGH7 enzyme.

Crop straws provide enormous lignocellulose resources transformable for sustainable biofuels and valuable bioproducts. However, lignocellulose recalcitrance basically restricts essential biomass enzymatic saccharification at large scale. In this study, the mushroom-derived cellobiohydrolase (LeGH7) was introduced into Trichoderma reesei (Rut-C30) to generate two desirable strains, namely GH7-5 and GH7-6. Compared to the Rut-C30 strain, both engineered strains exhibited significantly enhanced enzymatic activities, with ß-glucosidases, endocellulases, cellobiohydrolases, and xylanase activities increasing by 113 %, 140 %, 241 %, and 196 %, respectively. By performing steam explosion and mild alkali pretreatments with mature straws of five bioenergy crops, diverse lignocellulose substrates were effectively digested by the crude enzymes secreted from the engineered strains, leading to the high-yield hexoses released for bioethanol production. Notably, the LeGH7 enzyme purified from engineered strain enabled to act as multiple cellulases and xylanase at higher activities, interpreting how synergistic enhancement of enzymatic saccharification was achieved for distinct lignocellulose substrates in major bioenergy crops. Therefore, this study has identified a novel enzyme that is active for simultaneous hydrolyses of cellulose and xylan, providing an applicable strategy for high biomass enzymatic saccharification and bioethanol conversion in bioenergy crops.

A platform to deliver single and bi-specific Cas9/guide RNA to perturb genes in vitro and in vivo.

Although CRISPR-Cas9 technology is poised to revolutionize the treatment of diseases with underlying genetic mutations, it faces some significant issues limiting clinical entry. They include low-efficiency in vivo systemic delivery and undesired off-target effects. Here, we demonstrate, by modifying Cas9 with phosphorothioate-DNA oligos (PSs), that one can efficiently deliver single and bi-specific CRISPR-Cas9/guide RNA (gRNA) dimers in vitro and in vivo with reduced off-target effects. We show that PS-Cas9/gRNA-mediated gene knockout preserves chimeric antigen receptor T cell viability and expansion in vitro and in vivo. PS-Cas9/gRNA mediates gene perturbation in patient-derived tumor organoids and mouse xenograft tumors, leading to potent tumor antitumor effects. Further, HER2 antibody-PS-Cas9/gRNA conjugate selectively perturbs targeted genes in HER2+ ovarian cancer xenografts in vivo. Moreover, we created bi-specific PS-Cas9 with two gRNAs to target two adjacent sequences of the same gene, leading to efficient targeted gene disruption ex vivo and in vivo with markedly reduced unintended gene perturbation. Thus, the cell-penetrating PS-Cas9/gRNA can achieve efficient systemic delivery and precision in gene disruption.