Publications by authors named "Kai Xu"

880 Publications

Myositis specific antibodies are associated with isolated anti-Ro-52 associated interstitial lung disease.

Rheumatology (Oxford) 2021 Jun 15. Epub 2021 Jun 15.

Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Objectives: Anti-Ro-52 antibody positivity might be associated with the presence of interstitial lung disease (ILD) among patients with autoimmune features. However, the clinical significance of isolated anti-Ro-52 positivity (i.e., the presence of anti-Ro52 antibodies but the absence of anti-Ro60 antibodies; anti-Ro52+-Ro60-) in patients with ILD is not clear.

Methods: This is a prospective and observational study of Chinese ILD patients with isolated anti-Ro-52 positivity. According to their myositis-specific antibody (MSA) status, patients were split into groups, and their clinical and radiological features were compared.

Results: Of the 158 enrolled patients with ILD and isolated anti-Ro-52 positivity (isolated anti-Ro-52-ILD), there were 130 patients with a positive MSA status and 28 patients with a negative MSA status. Anti-synthetase antibodies (ASAs) were found in 61.5% of patients with MSA+ ILD, and anti-melanoma differentiated-associated protein 5 (MDA-5) antibodies were found in the remaining 38.5% of patients. The anti-nuclear antibody (ANA) pattern was associated with ASA and anti-MDA-5 positivity (χ2=70.7, P < 0.001; Cramer's value 0.47, P < 0.001): ANA negativity was associated with anti-MDA-5 positivity, and cytoplasmic ANA positivity was associated with ASA positivity. There were statistically significant differences in the high-resolution CT patterns between patients with isolated anti-Ro-52 positivity with different MSA statuses (χ2=29.8, P < 0.001; Cramer's value 0.31, P < 0.001): OP pattern was more common in patients with anti-MDA-5 antibodies than in those without anti-MDA-5 antibodies.

Conclusions: Patients with isolated anti-Ro-52-ILD showed high positivity of MSA. Isolated anti-Ro-52 positivity with cytoplasmic ANA positivity was strongly associated with ASA+-ILD, while ANA negativity was associated with anti-MDA-5+-ILD.
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http://dx.doi.org/10.1093/rheumatology/keab488DOI Listing
June 2021

Endoscopic and Microscopic Interlaminar Discectomy for the Treatment of Far-Migrated Lumbar Disc Herniation: A Retrospective Study with a 24-Month Follow-Up.

J Pain Res 2021 4;14:1593-1600. Epub 2021 Jun 4.

Department of Spine Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People's Republic of China.

Purpose: Percutaneous endoscopic lumbar discectomy for the treatment of far-migrated lumbar disc herniation (LDH) is clinically challenging. The aim of this study was to compare the efficacy and safety of interlaminar endoscopic lumbar discectomy (IELD) and interlaminar microscopic lumbar discectomy (IMLD) for the treatment of far-migrated LDH.

Materials And Methods: We retrospectively analyzed 50 consecutive cases of far-migrated LDH treated by IELD or IMLD. Clinical data and outcomes were assessed before the operation and 1 day and 3, 12, and 24 months after the surgery using the visual analog scale (VAS) and Oswestry disability index (ODI). Modified MacNab criteria were used to evaluate patient satisfaction at the 24-month follow-up.

Results: A significant reduction in leg pain and improvement in ODI (P<0.01) were observed in both groups after surgery. Lower back pain (LBP) was reduced at 24 months postsurgery in the IELD group (P<0.05) but not in the IMLD group (P>0.05). There were significant intergroup differences in VAS LBP score at 1 day and 24 months postsurgery (p=0.01 and 0.02, respectively) and in ODI at 24 months (p=0.03). The rate of excellent or good outcome was 90.32% with IELD and 78.95% with IMLD (p=0.55). Hospital stay and time to ambulation were shorter in the IELD group than in the IMLD group, but the former had a longer operative time (p<0.01). Low and comparable complication rates were reported in the IELD (16.13%) and IMLD (10.53%) groups (p=0.70).

Conclusion: Both IELD and IMLD achieve favorable clinical results in the treatment of far-migrated LDH, with only minor complications. Compared to IMLD, LBP was significantly reduced with IELD presumably because it involved less trauma.
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http://dx.doi.org/10.2147/JPR.S302717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189696PMC
June 2021

Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants.

Nature 2021 Jun 7. Epub 2021 Jun 7.

Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD, 20892, USA.

Since the start of the COVID-19 pandemic, SARS-CoV-2 has caused millions of deaths worldwide. While many vaccines have been deployed to date, the continual evolution of the viral receptor-binding domain (RBD) has challenged their efficacy. In particular, emerging variants B.1.1.7 (U.K.), B.1.351 (South Africa) and P.1 (Brazil) have compromised convalescent sera and immunotherapies that received emergency use authorization. One potential alternative to avert viral escape is the use of camelid VHHs or nanobodies, which can recognize epitopes often inaccessible to conventional antibodies. Here, we isolate anti-RBD nanobodies from llamas and "nanomice" we engineered to produce VHHs cloned from alpacas, dromedaries and camels. We identified two sets of highly neutralizing nanobodies. Group 1 circumvents antigenic drift by recognizing an RBD region that is highly conserved in coronaviruses but rarely targeted by human antibodies. Group 2 is almost exclusively focused to the RBD-ACE2 interface and fails to neutralize variants carrying E484K or N501Y substitutions. Notably however, group 2 nanobodies retain full neutralization activity against variants when expressed as homotrimers, rivaling the most potent antibodies produced to date against SARS-CoV-2. These findings suggest that multivalent nanobodies overcome SARS-CoV-2 mutations through two separate mechanisms: enhanced avidity for the ACE2 binding domain, and recognition of conserved epitopes largely inaccessible to human antibodies. Therefore, while new SARS-CoV-2 mutants will continue to emerge, nanobodies represent promising tools to prevent COVID-19 mortality when vaccines are compromised.
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http://dx.doi.org/10.1038/s41586-021-03676-zDOI Listing
June 2021

Role of lincRNA-Cox2 targeting miR-150 in regulating the viability of chondrocytes in osteoarthritis.

Exp Ther Med 2021 Aug 25;22(2):800. Epub 2021 May 25.

Department of Anesthesiology, Qingdao No. 6 People's Hospital, Qingdao, Shandong 266033, P.R. China.

Osteoarthritis (OA) is a joint disease characterised by progressive cartilage degradation and inflammation, but the detailed pathogenesis of OA remains unclear. The present study aimed to investigate the role of long intergenic non-coding RNA (lincRNA)-Cox2 in OA progression and the potential mechanism. An OA mouse model was used for experiments, and IL-1β-induced injury of mouse chondrocytes was conducted for experiments. Small interfering (si)-Cox2 was transfected into chondrocytes to elucidate the effect of lincRNA-Cox2 on OA. Quantitative reverse transcription PCR assays were conducted to detect the expression of lincRNA-Cox2 and microRNA (miR)-150. Cell proliferation and apoptosis were analysed based on an MTT assay and annexin V/propidium iodide staining, respectively. Western blotting was performed to evaluate the protein expression levels of Ki-67, PCNA, Bax, cleaved (c)-Caspase-3, c-Caspase-9 and Wnt/β-catenin pathway-associated proteins in chondrocytes. High levels of lincRNA-Cox2 were observed in cartilage tissues of the OA mouse model . In the experiments, the expression of lincRNA-Cox2 was increased in IL-1β-treated chondrocytes. Knockdown of lincRNA-Cox2 promoted the proliferation and inhibited the apoptosis of chondrocytes. Mechanistically, lincRNA-Cox2 was found to directly target miR-150, acting as a competing endogenous RNA, and the effect of si-Cox2 on the proliferation and apoptosis of chondrocytes was reversed by miR-150 inhibitors. Moreover, lincRNA-Cox2 activated the Wnt/β-catenin pathway to regulate chondrocyte proliferation and apoptosis. The present study demonstrated that silencing lincRNA-Cox2 expression plays a protective role in OA by enhancing the proliferation and suppressing the apoptosis of chondrocytes, which is related to increased miR-150 expression and activation of the Wnt/β-catenin pathway.
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http://dx.doi.org/10.3892/etm.2021.10232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170664PMC
August 2021

Identification of Novel Compound Heterozygous Mutations in Two Chinese Families with Autosomal Recessive Nonsyndromic Hearing Loss.

Neural Plast 2021 14;2021:9957712. Epub 2021 May 14.

Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

Congenital deafness is one of the most common causes of disability in humans, and more than half of cases are caused by genetic factors. Mutations of the gene are the third most common cause of hereditary hearing loss. Using next-generation sequencing combined with auditory tests, two novel compound heterozygous variants c.2802_2812del/c.5681T>C and c.5681T>C/c.6340G>A in the gene were identified in probands from two irrelevant Chinese families. Auditory phenotypes of the probands are consistent with the previously reported for recessive variants in the gene. The two novel variants, c.2802_2812del and c.5681T>C, were identified as deleterious mutations by bioinformatics analysis. Our findings extend the gene mutation spectrum and provide more information for rapid and precise molecular diagnosis of congenital deafness.
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http://dx.doi.org/10.1155/2021/9957712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140830PMC
May 2021

Evaluation of Renal Tissue Oxygenation Using Blood Oxygen Level-Dependent Magnetic Resonance Imaging in Chronic Kidney Disease.

Kidney Blood Press Res 2021 Jun 4:1-11. Epub 2021 Jun 4.

Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.

Background: Blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) has been widely used to assess renal oxygenation changes in different kidney diseases in recent years. This study was designed to evaluate and compare renal tissue oxygenation using 2 BOLD-MRI analysis methods, namely, the regional and whole-kidney region of interest (ROI) selection methods.

Methods: The study ended up with 10 healthy controls and 40 chronic kidney disease (CKD) patients without dialysis. Their renal BOLD-MRI data were analyzed using whole-kidney ROI selection method and compared with regional ROI selection method.

Results: We found the cortical, medullary, and whole-kidney R2* values were significantly higher in CKD patients than those in controls. Compared with the regional ROI selection method, the whole-kidney ROI selection method yielded higher cortical R2* values in both controls and CKD patients. The whole-kidney R2* values of deteriorating renal function group were significantly higher than those in stable renal function group.

Conclusions: Cortical and medullary oxygenation was decreased significantly in CKD patients compared with the healthy controls, particularly in the medulla. The whole-kidney R2* values were positively correlated with kidney function and inversely correlated with the estimated glomerular filtration rate and effective renal plasma flow. Whole-Kidney R2* value might effectively predict the progression of renal function in patients with CKD.
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http://dx.doi.org/10.1159/000515709DOI Listing
June 2021

USP15 participates in DBP-induced testicular oxidative stress injury through regulating the Keap1/Nrf2 signaling pathway.

Sci Total Environ 2021 Aug 9;783:146898. Epub 2021 Apr 9.

Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210009, China.

Di-n-butylphthalate (DBP) has been listed as an environmental priority pollutant in China due to its distinct biotoxicity. Epidemiological studies have shown that exposure to DBP is closely related to a series of congenital and acquired defects in the male reproductive system. The oxidative stress injury caused by DBP plays an important role in these defects. Previous studies have demonstrated that the Keap1/Nrf2 antioxidative pathway plays a protective role in DBP-induced oxidative stress injury. However, the further molecular regulation mechanism of the activation of Nrf2 pathway remains unclear. Here, we demonstrate that DBP caused testicular oxidative stress injury and Nrf2 pathway was activated in response to the injury in vivo and in vitro. Moreover, we validated that reduced level of USP15 attenuates DBP-induced oxidative stress injury through restraining the ubiquitylation and degradation of Nrf2. Notably, USP15 is confirmed as a target of miR-135b-5p and miR-135b-5p mediated inhibition of USP15 is involved in the DBP-induced oxidative stress injury. Collectively, these findings indicated that decreased level of USP15 functions a significant protective effect on the oxidative stress injury of testis caused by DBP via regulating the Keap1/Nrf2 signaling pathway.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146898DOI Listing
August 2021

The feasibility of non-contrast-enhanced zero echo time magnetic resonance angiography for characterization of intracranial atherosclerotic disease.

Quant Imaging Med Surg 2021 Jun;11(6):2442-2452

Department of Radiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.

Background: Accurate and non-invasive assessment of intracranial atherosclerotic disease (ICAD) is important because of its effect on treatment planning. The aim of this study is to investigate if zero echo time (zTE) magnetic resonance angiography (zTE-MRA) is feasible in the characterization of ICAD.

Methods: A total of 175 patients with ICAD were recruited. ZTE-MRA and time-of-flight (TOF)-MRA sequences were conducted for all participants using a 3T clinical MR system. Forty-one patients also underwent digital subtraction angiography (DSA), and were confirmed to have intracranial arterial stenosis (ICAS). Weighted kappa (κ) statistics were used to assess the inter-observer agreement and diagnostic consistency of both zTE- and TOF-MRA, using DSA as a reference. The Wilcoxon signed-rank test was used to evaluate differences in image quality between zTE- and TOF-MRA images. The nonparametric test of multiple paired samples was used to compare the results of vascular stenosis diagnosis between zTE-, TOF-MRA and DSA.

Results: Supported by high inter-observer agreement (weighted κ=0.78), zTE-MRA generated significantly higher scores than TOF-MRA for susceptibility artifact signal (mean: 3.03±0.98 2.72±1.09; P=0.017) and flow signal in parent artery (mean: 3.63±0.49 3.07±0.82; P<0.001). Additionally, zTE-MRA showed more robust diagnostic performance than TOF-MRA for patients with ICAD and degree of vascular stenosis (P<0.05), and was highly consistent with reference DSA images (weighted κ=0.80).

Conclusions: ZTE-MRA has potential for use as a routine clinical method for patients with ICAD.
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http://dx.doi.org/10.21037/qims-20-696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107310PMC
June 2021

Effects of laparoscopic-assisted gastrectomy on elderly patients with gastric cancer.

J BUON 2021 Mar-Apr;26(2):490-498

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital and Institute, Beijing, China.

Purpose: Although the acceptance of laparoscopy-assisted gastrectomy (LAG) for the treatment of gastric cancer (GC) has been increasing, it is still controversial that LAG is an applicable treatment method for elderly patients since elderly patients are usually complicated with other diseases. Therefore, this study aimed to investigate the prognostic differences between elderly patients and non-elderly patients after receiving LAG.

Methods: Patients (n = 306) who received LAG for the treatment of GC from April 2009 to December 2014 were included in the study. The patients were divided into the elderly group (≥ 65 years old, n = 120) and the non-elderly group (< 65 years old, n=186). The postoperative outcomes as well as the morbidity and the survival rates were compared between the two groups.

Results: American Society of Anesthesiologists (ASA) score and comprehensive complication index (CCI) score in the elderly group were significantly higher than those in the non-elderly group (p<0.05). In terms of surgical outcomes, there was no significant difference in blood loss or postoperative hospital stay between the elderly group and the non-elderly group. As for postoperative comorbidities, there were significant differences in intraperitoneal hemorrhage and pleural effusion between the elderly group and the non-elderly group. Moreover, the median follow-up time was 38.5 months, and the overall survival of elderly patients with comorbidities was significantly lower than that of the elderly patients without comorbidities (p<0.05).

Conclusions: LAG can be performed safely and successfully in the elderly population with acceptable postoperative and long-term results.
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June 2021

FFAR from the Gut Microbiome Crowd: SCFA Receptors in T1D Pathology.

Metabolites 2021 May 11;11(5). Epub 2021 May 11.

Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL 60612, USA.

The gut microbiome has emerged as a novel determinant of type 1 diabetes (T1D), but the underlying mechanisms are unknown. In this context, major gut microbial metabolites, short-chain fatty acids (SCFAs), are considered to be an important link between the host and gut microbiome. We, along with other laboratories, have explored how SCFAs and their cognate receptors affect various metabolic conditions, including obesity, type 2 diabetes, and metabolic syndrome. Though gut microbiome and SCFA-level changes have been reported in T1D and in mouse models of the disease, the role of SCFA receptors in T1D remains under explored. In this review article, we will highlight the existing and possible roles of these receptors in T1D pathology. We conclude with a discussion of SCFA receptors as therapeutic targets for T1D, exploring an exciting new potential for novel treatments of glucometabolic disorders.
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http://dx.doi.org/10.3390/metabo11050302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151283PMC
May 2021

Biological effects of exosome derived from Cal27 on normal human gingival fibroblasts.

Hua Xi Kou Qiang Yi Xue Za Zhi 2021 Jun;39(3):313-319

Dept. of Prosthodontics, School of Stomatology, Lanzhou University, Lanzhou 730000, China.

Objectives: The proliferation, migration capacity, and expression of activation-related proteins of NHGFs+Cal27-exo were determined by coculturing Cal27 exosome (Cal27-exo) with normal human gingival fibroblasts (NHGFs) to explore the effects of Cal27-exo on the activation and biological behavior of NHGFs.

Methods: Cal27-exo was extracted using supercentrifugation, and exosomes were identified using Western blot, transmission electron microscopy (TEM), and particle size detection. Cal27-exo was cocultured with NHGFs to detect the uptake of Cal27-exo by NHGFs, and the proliferation and migration capacity of NHGFs+Cal27-exo were detected using CCK8 and wound healing tests, respectively. The expression levels of NHGF activation-related proteins, i.e., matrix metalloproteinase-9 (MMP-9), fibroblast-activating protein (FAP), alpha smooth muscle actin (αSMA), and transforming growth factor-β (TGF-β), were detected using real-time quantitative polymerase chain reaction (qRT-PCR).

Results: Cal27-exo was extracted u-sing supercentrifugation, and Western blot showed the positive expression levels of Alix and CD63. TEM showed that Cal27-exo had a circular double-layer vesicle. The particle size was between 30 and 150 nm. Cal27-exo labeled with PKH67 entered NHGFs after the coculture method. The wound healing test showed that the migration capacity of NHGFs+Cal27-exo was stronger after the scratch compared with that of NHGFs. CCK8 results showed that the proliferation activity of NHGFs+Cal27-exo was enhanced. qRT-PCR results showed that the MMP-9 levels of NHGFs+Cal27-exo were upregulated, whereas the TGF-β and αSMA mRNA levels of NHGFs+Cal27-exo were downregulated (<0.05).

Conclusions: The proliferation and migration ability of NHGFs+Cal27-exo are enhanced, and the mRNA expression of related proteins is changed. Cal27-exo can activate NHGFs, which suggests that Cal27-exo has potential significance in tumor invasion and metastasis.
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http://dx.doi.org/10.7518/hxkq.2021.03.011DOI Listing
June 2021

Identification of a thermostable cellobiose 2-epimerase from Caldicellulosiruptor sp. Rt8.B8 and production of epilactose using Bacillus subtilis.

J Sci Food Agric 2021 May 24. Epub 2021 May 24.

College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China.

Background: Epilactose, a potential prebiotics, was derived from lactose through enzymatic catalysis. However, production and purification of epilactose are currently difficult due to powerless enzymes and inefficient downstream processing steps.

Results: The encoding gene of cellobiose 2-epimerase (CE) from Caldicellulosiruptor sp. Rt8.B8 was cloned and expressed in Escherichia coli BL21(DE3). The enzyme was purified and it was suitable for industrial production of epilactose from lactose without by-products, because of high k (197.6 s ) and preferable thermostability. The Rt8-CE gene was further expressed in the Bacillus subtilis strain. We successfully produced epilactose from 700 g L lactose in 30.4% yield by using the recombinant Bacillus subtilis whole cells. By screening of a β-galactosidase from Bacillus stearothermophilus (BsGal), a process for separating epilactose and lactose was established, which showed a purity of over 95% in a total yield of 69.2%. In addition, a mixed rare sugar syrup composed of epilactose and d-tagatose was successfully produced from lactose through the co-expression of l-arabinose isomerase and β-galactosidase.

Conclusion: Our study shed light on the efficient production of epilactose using a food-grade host expressing a novel CE enzyme. Moreover, an efficient and low-cost process was attempted to obtain high purity epilactose. In order to improve the utilization of raw materials, the production process of mixed syrup containing epilactose and d-tagatose with prebiotic properties produced from lactose was also established for the first time. © 2021 Society of Chemical Industry.
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http://dx.doi.org/10.1002/jsfa.11333DOI Listing
May 2021

Short-Term High-Intensity Interval Exercise Promotes Motor Cortex Plasticity and Executive Function in Sedentary Females.

Front Hum Neurosci 2021 23;15:620958. Epub 2021 Apr 23.

Guangdong Provincial Key Laboratory of Sports and Health Promotion, Scientific Research Center, Guangzhou Sport University, Guangzhou, China.

Previous research has demonstrated that regular exercise modulates motor cortical plasticity and cognitive function, but the influence of short-term high-intensity interval training (HIIT) remains unclear. In the present study, the effect of short-term HIIT on neuroplasticity and executive function was assessed in 32 sedentary females. Half of the participants undertook 2 weeks of HIIT. Paired-pulse transcranial magnetic stimulation (ppTMS) was used to measure motor cortical plasticity via short intracortical inhibition (SICI) and intracortical facilitation (ICF). We further adapted the Stroop task using functional near-infrared spectroscopy (fNIRS) to evaluate executive function in the participants. The results indicated that, compared with the control group, the HIIT group exhibited decreased ICF. In the Stroop task, the HIIT group displayed greater activation in the left dorsolateral prefrontal cortex (DLPFC) and left orbitofrontal cortex (OFC) even though no significant difference in task performance was observed. These findings indicate that short-term HIIT may modulate motor cortical plasticity and executive function at the neural level.
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http://dx.doi.org/10.3389/fnhum.2021.620958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102987PMC
April 2021

Preliminary study on impacts of polystyrene microplastics on the hematological system and gene expression in bone marrow cells of mice.

Ecotoxicol Environ Saf 2021 May 4;218:112296. Epub 2021 May 4.

Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, Jiangsu, China. Electronic address:

Microplastics (MPs) are currently a global environmental pollutants and health hazards that caused by MPs cannot be ignored. However, studies on MP toxicity in mammals are scare. Here, we investigated the effects of two doses (0.1 mg and 0.5 mg) of 5 µm polystyrene microplastic (PS-MP) particles on the hematological system of mice through traditional toxicology experiments and assessed the related potential biological mechanisms using transcriptome sequencing analysis. The toxicological examinations showed that the 0.5 mg dose significantly decreased white blood cell count, increased Pit count, and inhibited the growth of colony-forming unit CFU-G, CFU-M and CFU-GM. Compared with the control group, there were 41 differentially expressed genes (DEGs) in the 0.1 mg-treated group and 32 significantly changed genes in 0.5 mg-treated group. Of note, eight genes were found to be significantly altered in both the PS-MP-treated groups. Gene ontology analysis showed that DEGs were mainly involved in T cell homeostasis, response to osmotic stress, extracellular matrix and structure organization, and metabolic process of NADP and nucleotides. In addition, pathway analysis revealed that the Jak/Stat pathway, pentose and glucuronate interconversions, nicotinate and nicotinamide metabolism, biosynthesis of unsaturated fatty acids, and the pentose phosphate pathway were involved in PS-MP-induced toxicity in mice. These results indicated that PS-MP exposure can cause hematotoxicity to some extent, impact gene expression, and disturb related molecular and biological pathways in mouse bone marrow cells. Our study provides fundamental data on the hematotoxicity of PS-MPs in terrestrial mammals that will help to further assess the corresponding health risks in these mammals.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112296DOI Listing
May 2021

Ectopic tooth in maxillary sinus compressing the nasolacrimal canal: A case report.

Medicine (Baltimore) 2021 May;100(18):e25514

Department of Stomatology.

Rationale: Ectopic tooth is tooth erupting out of normal anatomical position. Ectopic tooth can occur in different positions, such as maxillary sinus and nasal cavity. In this article, we present a rare case of an ectopic tooth with a dentigerous cyst in the maxillary sinus compressing the nasolacrimal canal.

Patient Concerns: An 8-year-old girl presented with a 2-month history of spontaneous lacrimation in her right eye. When she wept, more tear shed from her right eye than that from the left one. Computed tomographic (CT) imaging showed a huge low-density image containing a tooth in the maxillary sinus in her right maxilla; the right nasolacrimal canal vanished due to the compression of the ectopic tooth.

Diagnoses: Ectopic tooth with dentigerous cyst of right maxilla, and obstruction of nasolacrimal duct.

Interventions: The patient underwent nasal endoscopic maxillary sinus cystectomy.

Outcomes: The patient recovered well after cystectomy and has been symptom-free.

Lessons: The unique finding is that this is the first report about ectopic tooth compressing the nasolacrimal canal and inducing spontaneous lacrimation. Treatment: aspect: surgery under endoscope is a minimally invasive approach to ectopic tooth.
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http://dx.doi.org/10.1097/MD.0000000000025514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104135PMC
May 2021

Microwave-Assisted Extraction Coupled with Mass Spectrometry for Determining Five Volatile Compounds from Soy Sauces.

J Anal Methods Chem 2021 5;2021:6625929. Epub 2021 Apr 5.

Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, 59Cangwu Road, Lianyungang 222005, China.

As a popular fermented condiment in oriental countries, soy sauce plays a more and more important role in modern food culture due to its unique smell and delicious taste. With the help of microwave extraction and gas chromatography-tandem mass spectrometry, the sample preparation method is aimed to determine the content of cyclohexane, benzene, toluene, chlorobenzene, and styrene in soy sauce. The method was validated by examining the linearity, accuracy, specificity, precision, the limit of detection, and quantitation. Meanwhile, three key factors have an impact on the efficiency and accuracy of the method including extracting solvent, temperature, and time which were optimized. The result shows that the recoveries of spiked analytes ranged from 80.86% to 105.71%, the relative standard deviation of intraday and interday precision was no more than 12.1% and 12.5%, and the limit of detection and quantitation were 0.25-1.00 ng/mL and 0.50-2.00 ng/mL, respectively. The results also indicated that the proposed method was a simple, reliable, and sensitive approach for the determination trace amount of five harmful volatile organic compounds from soy sauce.
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http://dx.doi.org/10.1155/2021/6625929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062169PMC
April 2021

A high-conductivity n-type polymeric ink for printed electronics.

Nat Commun 2021 Apr 21;12(1):2354. Epub 2021 Apr 21.

Laboratory of Organic Electronics, Department of Science and Technology, Linköping University, Norrköping, Sweden.

Conducting polymers, such as the p-doped poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS), have enabled the development of an array of opto- and bio-electronics devices. However, to make these technologies truly pervasive, stable and easily processable, n-doped conducting polymers are also needed. Despite major efforts, no n-type equivalents to the benchmark PEDOT:PSS exist to date. Here, we report on the development of poly(benzimidazobenzophenanthroline):poly(ethyleneimine) (BBL:PEI) as an ethanol-based n-type conductive ink. BBL:PEI thin films yield an n-type electrical conductivity reaching 8 S cm, along with excellent thermal, ambient, and solvent stability. This printable n-type mixed ion-electron conductor has several technological implications for realizing high-performance organic electronic devices, as demonstrated for organic thermoelectric generators with record high power output and n-type organic electrochemical transistors with a unique depletion mode of operation. BBL:PEI inks hold promise for the development of next-generation bioelectronics and wearable devices, in particular targeting novel functionality, efficiency, and power performance.
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http://dx.doi.org/10.1038/s41467-021-22528-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060302PMC
April 2021

Polyvinyl alcohol/chitosan composite hydrogels with sustained release of traditional Tibetan medicine for promoting chronic diabetic wound healing.

Biomater Sci 2021 May;9(10):3821-3829

College of Medicine, Southwest Jiaotong University, Chengdu, 610031, China. and Key Laboratory of Advanced Technologies of Materials (Ministry of Education), School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China.

The Tibetan eighteen flavor dangshen pills (TEP) are composed of 18 traditional Tibetan medicines, which are commonly used in the treatment of skin diseases in the Tibetan medical system. They have anti-inflammatory and analgesic effects, and healing properties. However, TEP contain large doses and have strong side effects and low bioavailability. To improve the utilization rate of TEP in skin treatment, we prepared TEP powder and then introduced it into polyvinyl alcohol/chitosan (PVA/CS) hydrogels to treat diabetic wounds by slowly releasing the active ingredients of TEP. In vitro studies showed that TEP-loaded hydrogels can effectively and continuously release the active ingredients of TEP and have antibacterial and antioxidant properties. In addition, the hydrogel system was not cytotoxic to L929 cells, and significantly promoted the proliferation of HUVECs. Moreover, when the TEP-loaded hydrogel was applied to diabetic wounds in rats, it reduced the inflammatory response and improved collagen deposition, which in turn promoted skin healing. Our results indicate that TEP-loaded hydrogels may be a new formulation for the application of traditional Tibetan medicines for the treatment of chronic wounds.
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http://dx.doi.org/10.1039/d1bm00346aDOI Listing
May 2021

Tumor-targeted Gd-doped mesoporous FeO nanoparticles for T/T MR imaging guided synergistic cancer therapy.

Drug Deliv 2021 Dec;28(1):787-799

School of Medical Imaging, Xuzhou Medical University, Xuzhou, China.

In this study, a novel intelligent nanoplatform to integrate multiple imaging and therapeutic functions for targeted cancer theranostics. The nanoplatform, [email protected] NPs, was constructed Gd-doped mesoporous FeO nanoparticles following with the doxorubicin (DOX) loading in the mesopores of the NPs. The [email protected] NPs exhibited good properties in colloidal dispersity, photothermal conversion, NIR triggered drug release, and high T/T relaxicity rate (=9.64 mMs, = 177.71 mMs). Benefiting from the high MR contrast, [email protected] NPs enabled simultaneous T/T dual-modal MR imagining on 4T1 bearing mice and the MR contrast effect was further strengthened by external magnetic field. In addition, the [email protected] NPs revealed the strongest inhibition to the growth of 4T1 and under NIR irradiation and guidance of external magnetic field. Moreover, biosafety was also validated by and tests. Thus, the prepared [email protected] NPs would provide a promising intelligent nanoplatform for dual-modal MR imagining guided synergistic therapy in cancer theranostics.
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http://dx.doi.org/10.1080/10717544.2021.1909177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079076PMC
December 2021

Complement C3 identified as a unique risk factor for disease severity among young COVID-19 patients in Wuhan, China.

Sci Rep 2021 04 12;11(1):7857. Epub 2021 Apr 12.

Institute of Experimental Immunology, University Clinic of Rheinische Friedrich-Wilhelms-University, Bonn, Germany.

Given that a substantial proportion of the subgroup of COVID-19 patients that face a severe disease course are younger than 60 years, it is critical to understand the disease-specific characteristics of young COVID-19 patients. Risk factors for a severe disease course for young COVID-19 patients and possible non-linear influences remain unknown. Data were analyzed from COVID-19 patients with clinical outcome in a single hospital in Wuhan, China, collected retrospectively from Jan 24th to Mar 27th. Clinical, demographic, treatment and laboratory data were collected from patients' medical records. Uni- and multivariable analysis using logistic regression and random forest, with the latter allowing the study of non-linear influences, were performed to investigate the clinical characteristics of a severe disease course. A total of 762 young patients (median age 47 years, interquartile range [IQR] 38-55, range 18-60; 55.9% female) were included, as well as 714 elderly patients as a comparison group. Among the young patients, 362 (47.5%) had a severe/critical disease course and the mean age was statistically significantly higher in the severe subgroup than in the mild subgroup (59.3 vs. 56.0, Student's t-test: p < 0.001). The uni- and multivariable analysis suggested that several covariates such as elevated levels of serum amyloid A (SAA), C-reactive protein (CRP) and lactate dehydrogenase (LDH), and decreased lymphocyte counts influence disease severity independently of age. Elevated levels of complement C3 (odds ratio [OR] 15.6, 95% CI 2.41-122.3; p = 0.039) are particularly associated with the risk of developing severe COVID-19 specifically in young patients, whereas no such influence seems to exist for elderly patients. Additional analysis suggests that the influence of complement C3 in young patients is independent of age, gender, and comorbidities. Variable importance values and partial dependence plots obtained using random forests delivered additional insights, in particular indicating non-linear influences of risk factors on disease severity. This study identified increased levels of complement C3 as a unique risk factor for adverse outcomes specific to young COVID-19 patients.
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http://dx.doi.org/10.1038/s41598-021-82810-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042103PMC
April 2021

Fusion peptide priming reduces immune responses to HIV-1 envelope trimer base.

Cell Rep 2021 Apr;35(1):108937

Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Soluble "SOSIP"-stabilized envelope (Env) trimers are promising HIV-vaccine immunogens. However, they induce high-titer responses against the glycan-free trimer base, which is occluded on native virions. To delineate the effect on base responses of priming with immunogens targeting the fusion peptide (FP) site of vulnerability, here, we quantify the prevalence of trimer-base antibody responses in 49 non-human primates immunized with various SOSIP-stabilized Env trimers and FP-carrier conjugates. Trimer-base responses account for ∼90% of the overall trimer response in animals immunized with trimer only, ∼70% in animals immunized with a cocktail of SOSIP trimer and FP conjugate, and ∼30% in animals primed with FP conjugates before trimer immunization. Notably, neutralization breadth in FP-conjugate-primed animals correlates inversely with trimer-base responses. Our data provide methods to quantify the prevalence of trimer-base responses and reveal that FP-conjugate priming, either alone or as part of a cocktail, can reduce the trimer-base response and improve the neutralization outcome.
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http://dx.doi.org/10.1016/j.celrep.2021.108937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070658PMC
April 2021

N-Acetylcysteine Combined With Dexamethasone Treatment Improves Sudden Sensorineural Hearing Loss and Attenuates Hair Cell Death Caused by ROS Stress.

Front Cell Dev Biol 2021 18;9:659486. Epub 2021 Mar 18.

Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Sudden sensorineural hearing loss (SSNHL) is a common emergency in the world. Increasing evidence of imbalance of oxidant-antioxidant were found in SSNHL patients. Steroids combined with antioxidants may be a potential strategy for the treatment of SSNHL. In cochlear explant experiment, we found that N-acetylcysteine (NAC) combined with dexamethasone can effectively protect hair cells from oxidative stress when they were both at ineffective concentrations alone. A clinic trial was designed to explore whether oral NAC combined with intratympanic dexamethasone (ITD) as a salvage treatment has a better therapeutic effect. 41 patients with SSNHL were randomized to two groups. 23 patients in control group received ITD therapy alone, while 18 patient s in NAC group were treated with oral NAC and ITD. The patients were followed-up on day 1st (initiation of treatment) and day 14th. Overall, there was no statistical difference in final pure-tone threshold average (PTA) improvement between those two groups. However, a significant hearing gain at 8,000 Hz was observed in NAC group. Moreover, the hearing recovery rates of NAC group is much higher than that in control group. These results demonstrated that oral NAC in combination with ITD therapy is a more effective therapy for SSNHL than ITD alone.
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http://dx.doi.org/10.3389/fcell.2021.659486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014036PMC
March 2021

Investigation of a Progressive Relaxation Training Intervention on Precompetition Anxiety and Sports Performance Among Collegiate Student Athletes.

Front Psychol 2020 17;11:617541. Epub 2021 Mar 17.

School of Physical Education & Sports Science, South China Normal University, Guangzhou, China.

This study aims to investigate whether simple and convenient progressive relaxation training (PRT) is effective in enhancing collegiate student athletes' mental health and sports performance. An experimental group of 14 (6 female) and a control group of 10 (5 female) collegiate student athletes were recruited from among track and field athletes who were preparing for provincial competition. The experimental group was exposed to a PRT intervention in 30-min sessions conducted twice per week for a duration of one month. At baseline, the Competitive State Anxiety Inventory-2 (CSAI-2), State-Trait Anxiety Inventory (STAI), and Eysenck Personality Questionnaire-Revised Short Scale for Chinese (EPQ-RSC) were completed, while only the CSAI-2 was reassessed at one, two, and three weeks after initiation of the intervention. Additionally, within half a day after completing all one's individual competition events, the CSAI-2 was again assessed in the two groups recalling their memory of their precompetition state anxiety. Then, the differences in the three dimensions of the CSAI-2 between the two groups at the five time points introduced above were compared. This study also explored whether PRT affected sports performance, defined by the athletes reaching their best records or not, by logistic regressive analysis. This study found significant between-group differences in the self-confidence dimension score at the second and third time points. Through logistic regression analysis, a positive effect of PRT was found for the enhancement of sports performance. In sum, PRT showed positive effects on precompetition state self-confidence and enhanced sports performance among collegiate student athletes.
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http://dx.doi.org/10.3389/fpsyg.2020.617541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009973PMC
March 2021

Functional Analysis of the Fusion and Attachment Glycoproteins of Mojiang Henipavirus.

Viruses 2021 03 22;13(3). Epub 2021 Mar 22.

Department of Microbiology, Uniformed Services University, Bethesda, MD 20814, USA.

Mojiang virus (MojV) is the first henipavirus identified in a rodent and known only by sequence data, whereas all other henipaviruses have been isolated from bats (Hendra virus, Nipah virus, Cedar virus) or discovered by sequence data from material of bat origin (Ghana virus). Ephrin-B2 and -B3 are entry receptors for Hendra and Nipah viruses, but Cedar virus can utilize human ephrin-B1, -B2, -A2 and -A5 and mouse ephrin-A1. However, the entry receptor for MojV remains unknown, and its species tropism is not well characterized. Here, we utilized recombinant full-length and soluble forms of the MojV fusion (F) and attachment (G) glycoproteins in membrane fusion and receptor tropism studies. MojV F and G were functionally competent and mediated cell-cell fusion in primate and rattine cells, albeit with low levels and slow fusion kinetics. Although a relative instability of the pre-fusion conformation of a soluble form of MojV F was observed, MojV F displayed significantly greater fusion activity when heterotypically paired with Ghana virus G. An exhaustive investigation of A- and B-class ephrins indicated that none serve as a primary receptor for MojV. The MojV cell fusion phenotype is therefore likely the result of receptor restriction rather than functional defects in recombinant MojV F and G glycoproteins.
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http://dx.doi.org/10.3390/v13030517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004131PMC
March 2021

[A case of IgG4-related disease with initial clinical manifestation of neck lymph nodes enlargement and literature review].

Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2021 Apr;35(4):362-364

A 58 years old male came to our hospital with chief compliant of a persistent neck mass on his right neck.The size of this neck mass was 5 cm×3 cm.After a surgery of removing two largest lymph nodes in his neck,as well as immunohistochemistry staining,the diagnosis of IgG4 related disease was reached.
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http://dx.doi.org/10.13201/j.issn.2096-7993.2021.04.018DOI Listing
April 2021

Structural basis of malaria RIFIN binding by LILRB1-containing antibodies.

Nature 2021 Apr 31;592(7855):639-643. Epub 2021 Mar 31.

Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland.

Some Plasmodium falciparum repetitive interspersed families of polypeptides (RIFINs)-variant surface antigens that are expressed on infected erythrocytes-bind to the inhibitory receptor LAIR1, and insertion of DNA that encodes LAIR1 into immunoglobulin genes generates RIFIN-specific antibodies. Here we address the general relevance of this finding by searching for antibodies that incorporate LILRB1, another inhibitory receptor that binds to β2 microglobulin and RIFINs through their apical domains. By screening plasma from a cohort of donors from Mali, we identified individuals with LILRB1-containing antibodies. B cell clones isolated from three donors showed large DNA insertions in the switch region that encodes non-apical LILRB1 extracellular domain 3 and 4 (D3D4) or D3 alone in the variable-constant (VH-CH1) elbow. Through mass spectrometry and binding assays, we identified a large set of RIFINs that bind to LILRB1 D3. Crystal and cryo-electron microscopy structures of a RIFIN in complex with either LILRB1 D3D4 or a D3D4-containing antibody Fab revealed a mode of RIFIN-LILRB1 D3 interaction that is similar to that of RIFIN-LAIR1. The Fab showed an unconventional triangular architecture with the inserted LILRB1 domains opening up the VH-CH1 elbow without affecting VH-VL or CH1-CL pairing. Collectively, these findings show that RIFINs bind to LILRB1 through D3 and illustrate, with a naturally selected example, the general principle of creating novel antibodies by inserting receptor domains into the VH-CH1 elbow.
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http://dx.doi.org/10.1038/s41586-021-03378-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068667PMC
April 2021

MdHARBI1, a MdATG8i-interacting protein, plays a positive role in plant thermotolerance.

Plant Sci 2021 May 16;306:110850. Epub 2021 Feb 16.

State Key Laboratory of Crop Stress Biology for Arid Areas/Shaanxi Key Laboratory of Apple, College of Horticulture, Northwest A&F University, Yangling, Shaanxi 712100, China. Electronic address:

Autophagy is a major degradation pathway in plants for maintaining cellular homeostasis in response to various environmental stressors. ATG8 is one of a series of autophagy-related (ATG) proteins and plays a central role in both bulk and selective autophagy. Previously, we characterized MdATG8i in apple and demonstrated that it has a positive role in apple stress resistance. Although many ATG8-interacting proteins have been found in Arabidopsis, no protein has been reported to interact with MdATG8 in apple. Here, we identified MdHARBI1 as a MdATG8i-interacting protein in apple, however, the functions of HARBI1-like proteins have not been explored in plants. Expression analysis of MdHARBI1 and pro-MdHARBI1-GUS staining of transgenic Arabidopsis exposed to high temperature demonstrated that MdHARBI1 was significantly induced by heat stress. Moreover, heat-treated MdHARBI1-trangenic tomato plants maintained higher autophagic activity, accumulated fewer ROS, and displayed stronger chlorophyll fluorescence than wild-type plants. Because these phenotypes were consistent with those displayed by MdATG8i-overexpressing apple plants under high temperature, we concluded that the MdATG8i-interacting protein MdHARBI1 plays a critical role in the basal thermotolerance of plants, mainly by influencing autophagy pathways.
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http://dx.doi.org/10.1016/j.plantsci.2021.110850DOI Listing
May 2021

The elevated expression of IL-38 serves as an anti-inflammatory factor in osteoarthritis and its protective effect in osteoarthritic chondrocytes.

Int Immunopharmacol 2021 May 25;94:107489. Epub 2021 Mar 25.

Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Orthopedics Research Institute of Zhejiang University, Hangzhou, China; Key Laboratory of Motor System Disease Research and Precision Therapy of ZheJiang Province, Hangzhou, China. Electronic address:

The objective of this study is to investigate the role of IL-38 in osteoarthritis (OA). IL-38 levels in serum and synovial fluid (SF) of patients with OA were examined to identify the correlation between IL-38 expression and OA activity and to determine its anti-inflammatory effects in IL-1β-induced chondrocytes. A total of 75 patients with OA who underwent joint replacement surgery and 25 age- and sex-matched healthy volunteers were recruited. The levels of IL-38 in serum and SF are shown to be significant elevated in OA patients compared with that of healthy controls. Serum and SF IL-38 levels of OA patients are positively correlated with Kellgren-Lawrence (K-L) grades 2 to 3, as well as with pro-inflammatory cytokines IL-6, IL-23, and TNF-α, but are negatively correlated with the anti-inflammatory cytokine IL-10 in K-L grades 3 to 4. Furthermore, overexpression of IL-38 in vitro is shown to attenuate the expression of pro-inflammatory cytokines such as COX-2, IL-6, IL-8, IL-36Ra, IL-36α/β/γ, iNOS, and TNF-α, as well as matrix degrading enzymes such as MMP3, MMP13, and ADAMTS5, and apoptosis-related indicators Bax/Bcl-2, cleaved caspase 3/pro-caspase 3, and cleaved caspase 9/pro-caspase 9. IL-38 overexpression also reduces expression of the signaling proteins p-p38, p-p65, p-JNK, and RhoA significantly. Taken together, our results show that expression of IL-38 is increased in OA tissues and OA rat chondrocytes, and is positively correlated with early disease activity. This increased IL-38 expression lead to the inactivation of MAPK, NF-κB, JNK, and RhoA signaling pathways, which might have impletion on OA chondrocytes apoptosis, degradation and inflammatory effect. Thus, IL-38 probably serves as a novel therapeutic target for the treatment of OA.
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http://dx.doi.org/10.1016/j.intimp.2021.107489DOI Listing
May 2021

Genome-wide association study and Mendelian randomization analysis provide insights for improving rice yield potential.

Sci Rep 2021 Mar 25;11(1):6894. Epub 2021 Mar 25.

Hunan Engineering & Technology Research Center for Agricultural Big Data Analysis & Decision-Making, Hunan Agricultural University, Changsha, 410128, China.

Rice yield per plant has a complex genetic architecture, which is mainly determined by its three component traits: the number of grains per panicle (GPP), kilo-grain weight (KGW), and tillers per plant (TP). Exploring ideotype breeding based on selection for genetically less complex component traits is an alternative route for further improving rice production. To understand the genetic basis of the relationship between rice yield and component traits, we investigated the four traits of two rice hybrid populations (575 + 1495 F) in different environments and conducted meta-analyses of genome-wide association study (meta-GWAS). In total, 3589 significant loci for three components traits were detected, while only 3 loci for yield were detected. It indicated that rice yield is mainly controlled by minor-effect loci and hardly to be identified. Selecting quantitative trait locus/gene affected component traits to further enhance yield is recommended. Mendelian randomization design is adopted to investigate the genetic effects of loci on yield through component traits and estimate the genetic relationship between rice yield and its component traits by these loci. The loci for GPP or TP mainly had a positive genetic effect on yield, but the loci for KGW with different direction effects (positive effect or negative effect). Additionally, TP (Beta = 1.865) has a greater effect on yield than KGW (Beta = 1.016) and GPP (Beta = 0.086). Five significant loci for component traits that had an indirect effect on yield were identified. Pyramiding superior alleles of the five loci revealed improved yield. A combination of direct and indirect effects may better contribute to the yield potential of rice. Our findings provided a rationale for using component traits as indirect indices to enhanced rice yield, which will be helpful for further understanding the genetic basis of yield and provide valuable information for improving rice yield potential.
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http://dx.doi.org/10.1038/s41598-021-86389-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994632PMC
March 2021