Publications by authors named "Chenyang Lu"

126 Publications

MicroRNA-7a2 Contributes to Estrogen Synthesis and Is Modulated by FSH via the JNK Signaling Pathway in Ovarian Granulosa Cells.

Int J Mol Sci 2022 Aug 2;23(15). Epub 2022 Aug 2.

College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China.

MicroRNA-7a2 (miR-7a2) plays fundamental roles in the female reproductive axis, and estrogen is indispensable for maintaining ovary function. However, the interaction between miR-7a2 and ovarian function is unclear. The present study aimed to determine whether and how miR-7a2 functions in estrogen synthesis. Firstly, the results verified that miR-7a was highly expressed in ovarian granulosa cells. The knockout (KO) of miR-7a2 caused infertility and abnormal ovarian function in mice. Concomitantly, the expression and estrogen synthesis were significantly inhibited, which was validated in primary granulosa cells. The mice transplanted with miR-7a2 KO ovaries showed similar results; however, estrogen supplementation reversed infertility. In the in vitro experiment, follicle-stimulating hormone (FSH) significantly improved the expression of miR-7a and and the synthesis of estrogen. However, the miR-7a2 KO markedly reversed the function of FSH. Also, FSH upregulated miR-7a by activating the (c-Jun N-terminal kinase) JNK signaling pathway. In addition, Golgi apparatus protein 1 () was shown to be the target gene of miR-7a2. These findings indicated that miR-7a2 is essential for ovarian functions with respect to estrogen synthesis through the targeted inhibition of the expression of and then promoting expression; the physiological process was positively regulated by FSH via the JNK signaling pathway in granulosa cells.
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http://dx.doi.org/10.3390/ijms23158565DOI Listing
August 2022

Case Report: Variants Cause Primary Ciliary Dyskinesia and Infertility in Two Han Chinese Families.

Front Genet 2022 12;13:934920. Epub 2022 Jul 12.

Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder, predominantly autosomal recessive. The dynein axonemal assembly factor 4 () is mainly involved in the preassembly of multisubunit dynein protein, which is fundamental to the proper functioning of cilia and flagella. There are few reports of PCD-related pathogenic variants of , and almost no -related articles focused on sperm phenotype. Moreover, the association between and scoliosis has never been reported, to the best of our knowledge. We recruited two patients with a clinical diagnosis of PCD. One came from a consanguineous and another from a non-consanguineous family. Clinical data, laboratory test results, and imaging data were analyzed. Through whole exome sequencing, immunofluorescence, electron microscopy, high-speed video microscopy analysis, and hematoxylin-eosin (HE) staining, we identified the disease-associated variants and validated the pathogenicity. Proband 1 (P1, F1: II-1), a 19-year-old man, comes from a non-consanguineous family-I, and proband 2 (P2, F2: II-1), a 37-year-old woman, comes from a consanguineous family-II. Both had sinusitis, bronchiectasis, situs inversus, and scoliosis. P1 also had asthenoteratozoospermia, and P2 had an immature uterus. Two homozygous pathogenic variants in (NM_130810.4), c.988C > T, p.(Arg330Trp), and (NM_130810.4), c.733 C > T, p.(Arg245*), were identified through whole exome sequencing. High-speed microscopy analysis showed that most of the cilia were static in P1, with complete static of the respiratory cilia in P2. Immunofluorescence showed that the outer dynein arms (ODA) and inner dynein arms (IDA) were absent in the respiratory cilia of both probands, as well as in the sperm flagellum of P1. Transmission electron microscopy revealed the absence of ODA and IDA of respiratory cilia of P2, and HE staining showed irregular, short, absent, coiled, and bent flagella. Our study identified a novel variant c.733C > T, which expanded the spectrum of variants. Furthermore, we linked to asthenoteratozoospermia and likely scoliosis in patients with PCD. This study will contribute to a better understanding of PCD.
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http://dx.doi.org/10.3389/fgene.2022.934920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9315306PMC
July 2022

Case Report: Whole-Exome Sequencing-Based Copy Number Variation Analysis Identified a Novel Homozygous Exon Deletion in a Patient With Primary Ciliary Dyskinesia.

Front Genet 2022 6;13:940292. Epub 2022 Jul 6.

Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.

Whole-exome sequencing (WES) based copy number variation (CNV) analysis has been reported to improve the diagnostic rate in rare genetic diseases. In this study, we aim to find the disease-associated variants in a highly suspected primary ciliary dyskinesia (PCD) patient without a genetic diagnosis by routine WES analysis. We identified the CNVs using the "Exomedepth" package in an undiagnosed PCD patient with a negative result through routine WES analysis. RNA isolation, PCR amplification, and Sanger sequencing were used to confirm the variant. High-speed video microscopy analysis (HSVA) and immunofluorescence analysis were applied to detect the functional and structural deficiency of nasal cilia and sperm flagella. Papanicolaou staining was employed to characterize the morphology of sperm flagella. NC_000002.11(NM_145038.5): g.26635488_26641606del, c.156-1724_244-2550del, r.156_243del, p. (Glu53Asnfs*13), a novel homozygous CNV, was identified by WES-based CNV analysis rather than routine variants calling, in a patient from a non-consanguineous family. HSVA results showed no significant change in ciliary beating frequency but with reduced beating amplitude compared with normal control, and his spermatozoa were almost immotile. The diagnosis of multiple morphological abnormalities of the sperm flagella (MMAF) was established through sperm motility and morphology analysis. PCR amplification and Sanger sequencing confirmed the novel variant of . Immunofluorescence showed that both cilia and sperm flagella were deficient in protein expression related to the dynein regulatory complex. This report identifies a novel disease-associated variant by WES-based CNV analysis from a highly suspected PCD patient with MMAF. Our findings not only expand the genetic spectrum of PCD with MMAF but suggest that in combination with CNV analysis might improve the efficiency of genetic tests.
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http://dx.doi.org/10.3389/fgene.2022.940292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9298917PMC
July 2022

Identification of a Novel Variant in a Patient with Primary Ciliary Dyskinesia.

Pharmgenomics Pers Med 2022 11;15:697-704. Epub 2022 Jul 11.

Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People's Republic of China.

Background: encodes a protein with 1012 amino acids, which is a component of basal bodies and centrioles, essential for cilia biogenesis. was reported to be associated with X-chromosome linked dysmorphology syndrome in early studies and recent studies reported a few cases with primary ciliary dyskinesia (PCD) caused by deficiency.

Case Presentation: We report a 31-year-old man who suffered from recurrent respiratory infections with typical manifestations of primary ciliary dyskinesia. In addition to respiratory manifestations, the patient also had situs inversus, obesity, gastroesophageal reflux, and hearing impairment. Clubbing fingers and mild streblomicrodactyly were also observed.

Examination Result: We performed whole-exome sequencing to identify a novel variant c.2795delA:p.(Lys932Argfs*3) in . The hemizygous variant was predicted to be likely pathogenic by bioinformatic analysis software and ACMG guideline. High-speed video microscopy (HSVM), transmission electron microscopy (TEM), and immunofluorescence were performed to analyze the respiratory cilia. A high beating frequency and a stiff beating pattern were observed under HSVM, while there were no significant abnormalities in TEM and immunofluorescence. The sperm flagella examinations were also generally normal.

Conclusion: Our study identified a novel frameshift variant in causing PCD, enriched the genetic spectrum of variants, and verified that mutation can lead to only a PCD characteristic phenotype, while other -associated syndromic symptoms such as dysmorphic features and renal symptoms were not present.
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http://dx.doi.org/10.2147/PGPM.S365740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9285985PMC
July 2022

Novel Variants Associated With Primary Ciliary Dyskinesia-Related Infertility in Three Chinese Families.

Front Genet 2022 22;13:922287. Epub 2022 Jun 22.

Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.

The radial spoke head component 4A () is involved in the assembly of radial spokes, which is essential for motile cilia function. Asthenoteratozoospermia in primary ciliary dyskinesia (PCD) related to variants has not been reported. variants were identified and validated using whole-exome and Sanger sequencing in three unrelated Chinese families. High-speed video microscopy analysis (HSVA) was performed to measure the beating frequency and pattern of nasal cilia of the patients and healthy control. Papanicolaou staining and computer-aided sperm analysis were performed to analyze the morphology and motility of the sperm in patient 1. Immunofluorescence was adopted to confirm the structure deficiency of sperm and nasal cilia. Patient 1 from family 1 is a 22-year-old unmarried male presented with bronchiectasis. Semen analysis and sperm Papanicolaou staining confirmed asthenoteratozoospermia. Novel compound heterozygous variants c.2T>C, p.(Met1Thr) and c.1774_1775del, p.(Leu592Aspfs*5) were detected in this patient. Patients 2 and 3 are from two unrelated consanguineous families; they are both females and exhibited bronchiectasis and infertility. Two homozygous variants c.2T>C, p.(Met1Thr) and c.351dupT, p.(Pro118Serfs*2) were detected, respectively. HSVA showed that most of the cilia in patients 1 and 3 were with abnormal rotational movement. The absence of RSPH4A and RSPH1 in patient 1's sperm and patient 3's respiratory cilia was indicated by immunofluorescence. Patient 2 died of pulmonary infection and respiratory failure at the age of 35 during follow-up. Dysfunctional sperm flagellum and motile cilia in the respiratory tract and the fallopian tube were found in patients with variants. Our study enriches the genetic spectrum and clinical phenotypes of variants in PCD, and c.2T>C, p.(Met1Thr) detected in our patients may be a hotspot variant in Chinese.
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http://dx.doi.org/10.3389/fgene.2022.922287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9257073PMC
June 2022

Genetic association and single-cell transcriptome analyses reveal distinct features connecting autoimmunity with cancers.

iScience 2022 Jul 17;25(7):104631. Epub 2022 Jun 17.

Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China.

Autoimmune diseases (ADs) are at a significantly higher risk of cancers with unclear mechanism. By searching GWAS catalog database and Medline, susceptible genes for five common ADs, including systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjögren syndrome, systemic sclerosis, and idiopathic inflammatory myopathies, were collected and then were overlapped with cancer driver genes. Single-cell transcriptome analysis was performed in the comparation between SLE and related cancer. We identified 45 carcinogenic autoimmune disease risk (CAD) genes, which were mainly enriched in T cell signaling pathway and B cell signaling pathway. Integrated single-cell analysis revealed immune cell signaling was significantly downregulated in renal cancer compared with SLE, while stemness signature was significantly enriched in both renal cancer or lymphoma and SLE in specific subpopulations. Drugs targeting CAD genes were shared between ADs and cancer. Our study highlights the common and specific features between ADs and related cancers, and sheds light on a new discovery of treatments.
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http://dx.doi.org/10.1016/j.isci.2022.104631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9254016PMC
July 2022

Molecular detection and phylogeny of Anaplasma spp. closely related to Anaplasma phagocytophilum in small ruminants from China.

Ticks Tick Borne Dis 2022 Sep 24;13(5):101992. Epub 2022 Jun 24.

College of Veterinary Medicine, Henan Agricultural University, No.15 Longzihu University Area, Zhengdong, Zhengzhou, Henan 450046, PR China. Electronic address:

The genus Anaplasma comprises eight bacterial species that are obligate intracellular pathogens that affect human and animal health. The zoonotic species A. phagocytophilum is the causative agent of tick-borne fever in ruminants, and of granulocytic anaplasmosis in horses, dogs, and humans. Recently, novel strains related to A. phagocytophilum (A. phagocytophilum-like 1/Japanese variant and A. phagocytophilum-like 2/Chinese variant) have been identified. The aim of this study was to reveal the prevalence and phylogeny of A. phagocytophilum and related stains in small ruminants and ticks in China based on sequences of the 16S rRNA combined restriction fragment length polymorphism (RFLP) and groEL genes. PCR-RFLP and phylogenetic analyses based on the 16S rRNA gene showed the presence of A. phagocytophilum-like 1 and 2 variants in sampled animals from China, with prevalence rates of 22.6% (303/1338) and 0.7% (10/1338), respectively. Only A. phagocytophilum-like 1 DNA was found in Haemaphysalis longicornis. The phylogeny based on the groEL gene showed inclusion of A. phagocytophilum-like 1 and some A. phagocytophilum-like 2 strains in two unique clades distinct from, but related to, Japanese and Chinese strains of related A. phagocytophilum, respectively. One noteworthy result was that the SSAP2f/SSAP2r primers detected Ehrlichia spp. strains. Moreover, the A. phagocytophilum-like 1 and 2 strains should be considered in the differential diagnosis of caprine and ovine anaplasmosis. Further investigations should be conducted to provide additional epidemiological information about A. phagocytophilum and A. phagocytophilum-like variants in animals and ticks.
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http://dx.doi.org/10.1016/j.ttbdis.2022.101992DOI Listing
September 2022

Effects of Sporisorium reiliana polysaccharides and Phoenix dactylifera monosaccharides on the gut microbiota and serum metabolism in mice with fructose-induced hyperuricemia.

Arch Microbiol 2022 Jun 28;204(7):436. Epub 2022 Jun 28.

State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Ningbo University, Ningbo, China.

In recent decades, the prevalence of hyperuricemia has increased, and dietary fructose is an important risk factor for the development of this disease. This study investigated and compared the effects of Sphacelotheca reiliana polysaccharides and Phoenix dactylifera monosaccharides on a series of physiological and biochemical indicators and on the metagenomes and serum metabolites in mice with hyperuricemia caused by a high-fructose diet. S. reiliana polysaccharides inhibited uric acid biosynthesis and promoted uric acid excretion, thereby alleviating the hyperuricemia phenotype. In addition, hyperuricemia was closely related to the gut microbiota. After treatment with S. reiliana polysaccharides, the abundances of Bacteroidetes and Proteobacteria in the mouse intestines were decreased, the expression of genes involved in glycolysis/gluconeogenesis metabolic pathways and purine metabolism was downregulated, and the dysfunction of the gut microbiota was alleviated. With regard to serum metabolism, the abundance of hippuric acid, uridine, kynurenic acid, propionic acid and arachidonoyl decreased, and the abundances of serum metabolites in inflammatory pathways involved in kidney injury and gout, such as bile acid metabolism, purine metabolism and tryptophan metabolism pathways, decreased. P. dactylifera monosaccharides aggravated hyperuricemia. This research provides a valuable reference for the development of sugar applications.
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http://dx.doi.org/10.1007/s00203-022-03053-yDOI Listing
June 2022

Temporal Associations Between EHR-Derived Workload, Burnout, and Errors: a Prospective Cohort Study.

J Gen Intern Med 2022 Jul 16;37(9):2165-2172. Epub 2022 Jun 16.

Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, USA.

Background: The temporal progression and workload-related causal contributors to physician burnout are not well-understood.

Objective: To characterize burnout's time course and evaluate the effect of time-varying workload on burnout and medical errors.

Design: Six-month longitudinal cohort study with measurements of burnout, workload, and wrong-patient orders every 4 weeks.

Participants: Seventy-five intern physicians in internal medicine, pediatrics, and anesthesiology at a large academic medical center.

Main Measures: Burnout was measured using the Professional Fulfillment Index survey. Workload was collected from electronic health record (EHR) audit logs and summarized as follows: total time spent on the EHR, after-hours EHR time, patient load, inbox time, chart review time, note-writing time, and number of orders. Wrong-patient orders were assessed using retract-and-reorder events.

Key Results: Seventy-five of 104 interns enrolled (72.1%) in the study. A total of 337 surveys and 8,863,318 EHR-based actions were analyzed. Median burnout score across the cohort across all time points was 1.2 (IQR 0.7-1.7). Individual-level burnout was variable (median monthly change 0.3, IQR 0.1-0.6). In multivariable analysis, increased total EHR time (β=0.121 for an increase from 54.5 h per month (25th percentile) to 123.0 h per month (75th percentile), 95%CI=0.016-0.226), increased patient load (β=0.130 for an increase from 4.9 (25th percentile) to 7.1 (75th percentile) patients per day, 95%CI=0.053-0.207), and increased chart review time (β=0.096 for an increase from 0.39 (25th percentile) to 0.59 (75th percentile) hours per patient per day, 95%CI=0.015-0.177) were associated with an increased burnout score. After adjusting for the total number of ordering sessions, burnout was not statistically associated with an increased rate of wrong-patient orders (rate ratio=1.20, 95%CI=0.76-1.89).

Conclusions: Burnout and recovery were associated with recent clinical workload for a cohort of physician trainees, highlighting the elastic nature of burnout. Wellness interventions should focus on strategies to mitigate sustained elevations of work responsibilities.
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http://dx.doi.org/10.1007/s11606-022-07620-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9296727PMC
July 2022

Casein kinase 1α regulates murine spermatogenesis via p53-Sox3 signaling.

Development 2022 Jul 1;149(13). Epub 2022 Jul 1.

College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, People's Republic of China.

Casein kinase 1α (CK1α), acting as one member of the β-catenin degradation complex, negatively regulates the Wnt/β-catenin signaling pathway. CK1α knockout usually causes both Wnt/β-catenin and p53 activation. Our results demonstrated that conditional disruption of CK1α in spermatogonia impaired spermatogenesis and resulted in male mouse infertility. The progenitor cell population was dramatically decreased in CK1α conditional knockout (cKO) mice, while the proliferation of spermatogonial stem cells (SSCs) was not affected. Furthermore, our molecular analyses identified that CK1α loss was accompanied by nuclear stability of p53 protein in mouse spermatogonia, and dual-luciferase reporter and chromatin immunoprecipitation assays revealed that p53 directly targeted the Sox3 gene. In addition, the p53 inhibitor pifithrin α (PFTα) partially rescued the phenotype observed in cKO mice. Collectively, our data suggest that CK1α regulates spermatogenesis and male fertility through p53-Sox3 signaling, and they deepen our understanding of the regulatory mechanism underlying the male reproductive system.
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http://dx.doi.org/10.1242/dev.200205DOI Listing
July 2022

MicroRNA-7a2 is Required for the Development of Pituitary Stem Cells.

Stem Cells Dev 2022 Jul;31(13-14):357-368

Institute of Reproduction and Metabolism, Yangzhou University, Yangzhou, People's Republic of China.

The pituitary gland is inhabited by a subpopulation of SOX2 stem cells. However, the regulatory mechanisms underlying pituitary stem cell development remain poorly understood. In this study, we demonstrate that microRNA-7a (miR-7a) is enriched in the developing pituitary and is spatiotemporally expressed in the pituitary stem cells. Constitutive deletion of in mice results in pituitary dysplasia emerging during birth, which is primarily manifested as malformed anterior lobes. Using immunofluorescence, immunohistochemistry, or in situ hybridization, we observe that the specification of hormone-expressing cells is not impeded post deletion at birth, although the terminal differentiation of gonadotropes is inhibited. Further investigation of neonatal and adult pituitaries in knockout mice reveals an expansion of the SOX2 pituitary stem cell compartment. The inhibition of epithelial-mesenchymal like transition seems to be responsible for this phenotype, rather than abnormal proliferation or apoptosis. Furthermore, our data suggest that and are potential targets of miR-7a in pituitary stem cells. In summary, our results identify miR-7a2 as a crucial factor involved in pituitary stem cell development.
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http://dx.doi.org/10.1089/scd.2022.0023DOI Listing
July 2022

Fecal microbiota transplantation from patients with rheumatoid arthritis causes depression-like behaviors in mice through abnormal T cells activation.

Transl Psychiatry 2022 06 1;12(1):223. Epub 2022 Jun 1.

Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.

Depression is common in patients with rheumatoid arthritis (RA); however, the precise mechanisms underlying a link between depression and RA remain unclear. Accumulating evidence suggests the role of gut-microbiota-brain axis in depression. In this study, we investigated whether collagen-induced arthritis (CIA) mice produce depression-like behaviors and abnormal composition of gut microbiota. Furthermore, we investigated whether fecal microbiota transplantation (FMT) from RA patients causes depression-like phenotypes in antibiotic cocktail (ABX)-treated mice. CIA mice displayed depression-like behaviors, increased blood levels of pro-inflammatory cytokine interleukin-6 (IL-6), decreased expression of synaptic proteins in the prefrontal cortex (PFC), and abnormal composition of gut microbiota. Furthermore, FMT from RA patients caused depression-like phenotypes, alterations of gut microbiota composition, increased levels of IL-6 and tumor necrosis factor-α (TNF-α), and downregulation of synaptic proteins in the PFC compared to FMT from healthy controls. There were correlations between relative abundance of microbiota and plasma cytokines, expression of synaptic proteins in the PFC or depression-like behaviors. Interestingly, FMT from RA patients induced T cells differentiation in Peyer's patches and spleen. Reduced percentage of Treg cells with an increase of Th1/Th2 index was observed in the mice after FMT from RA patients. These findings suggest that CIA mice exhibit depression-like behaviors, systemic inflammation, and abnormal composition of gut microbiota, and that FMT from RA patients produces depression-like behaviors in ABX-treated mice via T cells differentiation. Therefore, abnormalities in gut microbiota in RA patients may contribute to depression via gut-microbiota-brain axis.
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http://dx.doi.org/10.1038/s41398-022-01993-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9160267PMC
June 2022

The Response and Survival Mechanisms of under High Salinity Stress in Salted Foods.

Foods 2022 May 22;11(10). Epub 2022 May 22.

State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Ningbo University, Ningbo 315211, China.

() has a strong tolerance to high salt stress. It is a major reason as to why the contamination of in salted food cannot be eradicated. To elucidate its response and survival mechanisms, changes in the morphology, biofilm formation, virulence, transcriptome, and metabolome of were investigated. positively regulates and participates in the formation of biofilm. Virulence was downregulated to reduce the depletion of nonessential cellular functions. Inositol phosphate metabolism was downregulated to reduce the conversion of functional molecules. The MtsABC transport system was downregulated to reduce ion transport and signaling. Aminoacyl-tRNA biosynthesis was upregulated to improve cellular homeostasis. The betaine biosynthesis pathway was upregulated to protect the active structure of proteins and nucleic acids. Within a 10% NaCl concentration, the L-proline content was upregulated to increase osmotic stability. In addition, 20 hub genes were identified through an interaction analysis. The findings provide theoretical support for the prevention and control of salt-tolerant bacteria in salted foods.
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http://dx.doi.org/10.3390/foods11101503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9140498PMC
May 2022

A directly linked COF-like conjugated microporous polymer based on naphthalene diimides for high performance supercapacitors.

Chem Commun (Camb) 2022 Jun 14;58(48):6809-6812. Epub 2022 Jun 14.

School of Chemistry and Chemical Engineering, Chongqing University, Chongqing, 400044, P. R. China.

In this work, single bond directly linked COF-like conjugated microporous polymer NDTT is constructed Stille coupling with thiophene-substituted naphthalene diimides and triazine, showing fair crystallinity. NDTT is utilized as an electrode for supercapacitor applications, exhibiting promising performance with excellent capacitance reaching 425.3 F g under a current of 0.2 A g.
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http://dx.doi.org/10.1039/d2cc02097aDOI Listing
June 2022

Novel Compound Heterozygous Variants in Associated with Primary Ciliary Dyskinesia and Multiple Morphological Abnormalities of the Sperm Flagella.

Pharmgenomics Pers Med 2022 15;15:341-350. Epub 2022 Apr 15.

Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People's Republic of China.

Primary ciliary dyskinesia (PCD) is a rare genetic disease caused by mutations of genes coding motile-cilia-related proteins. variants can cause PCD via disrupting the assembling of inner dynein and dynein regulating complex in cilia and flagella, but none has been reported associated with multiple morphological abnormalities of the sperm flagella (MMAF). We identified and validated the disease-causing variants in our patient via whole-exome and Sanger sequencing. We used high-speed video microscopy analysis (HSVA) and immunofluorescence to analyze the functional and structural deficiency of respiratory cilia. Papanicolaou staining and scanning electron microscope was applied to analyze the morphological sperm defects resulted from the PCD associated variants. We identified novel compound variants (c.901C>T, p.(Arg301*); c.2065_2068dup, p.(Ala690Glyfs*67)) in in a male patient with male infertility. HSVA revealed the rigid and stiff ciliary beating pattern. Immunofluorescence indicated loss of inner dynein arm protein DNAH2 both in cilia and the sperms of the patient. Diagnosis of MMAF was confirmed through sperm Papanicolaou staining and scanning electron microscope. We first describe a patient with a combination of PCD and MMAF associated with novel compound heterozygous variants in . Our results present initial evidence that associated with MMAF, which expands the genetic spectrum of PCD and MMAF and provides precise clinical genetic counseling to this family.
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http://dx.doi.org/10.2147/PGPM.S359821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9017783PMC
April 2022

Soluble CD13 induces inflammatory arthritis by activating the bradykinin receptor B1.

J Clin Invest 2022 06;132(11)

Division of Rheumatology and Clinical Autoimmunity Center of Excellence, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

CD13, an ectoenzyme on myeloid and stromal cells, also circulates as a shed, soluble protein (sCD13) with powerful chemoattractant, angiogenic, and arthritogenic properties, which require engagement of a G protein-coupled receptor (GPCR). Here we identify the GPCR that mediates sCD13 arthritogenic actions as the bradykinin receptor B1 (B1R). Immunofluorescence and immunoblotting verified high expression of B1R in rheumatoid arthritis (RA) synovial tissue and fibroblast-like synoviocytes (FLSs), and demonstrated binding of sCD13 to B1R. Chemotaxis, and phosphorylation of Erk1/2, induced by sCD13, were inhibited by B1R antagonists. In ex vivo RA synovial tissue organ cultures, a B1R antagonist reduced secretion of inflammatory cytokines. Several mouse arthritis models, including serum transfer, antigen-induced, and local innate immune stimulation arthritis models, were attenuated in Cd13-/- and B1R-/- mice and were alleviated by B1R antagonism. These results establish a CD13/B1R axis in the pathogenesis of inflammatory arthritis and identify B1R as a compelling therapeutic target in RA and potentially other inflammatory diseases.
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http://dx.doi.org/10.1172/JCI151827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9151693PMC
June 2022

Hydrophobic Residues at the Intracellular Domain of the M2 Protein Play an Important Role in Budding and Membrane Integrity of Influenza Virus.

J Virol 2022 05 11;96(9):e0037322. Epub 2022 Apr 11.

Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China.

M2 protein of influenza virus plays an important role in virus budding, including membrane scission and vRNP packaging. Three hydrophobic amino acids (91F, 92V, and 94I) at the intracellular domain of the M2 protein constitute a hydrophobic motif, also known as the LC3-interacting region (LIR), whereas the role of this motif remains largely unclear. To explore the role of the 91-94 hydrophobic motif for influenza virus, all three hydrophobic amino acids were mutated to either hydrophilic S or hydrophobic A, resulting in two mutant viruses (WSN-M2/SSS and WSN-M2/AAA) in the background of WSN/H1N1. The results showed that the budding ability of the M2/SSS protein was inhibited and the bilayer membrane integrity of the WSN-M2/SSS virion was impaired based on transmission electron microscopy (TEM), which in turn abolished the resistance to trypsin treatment. Moreover, the mutant WSN-M2/SSS was dramatically attenuated in mice. In contrast, the AAA mutations did not have a significant effect on the budding of the M2 proteins or the bilayer membrane integrity of the viruses, and the mutant WSN-M2/AAA was still lethal to mice. In addition, although the 91-94 motif is an LIR, knocking out of the LC3 protein of A549 cells did not significantly affect the membrane integrity of the influenza viruses propagated on the LC3KO cells, which suggested that the 91-94 hydrophobic motif affected the viral membrane integrity and budding is independent of the LC3 protein. Overall, the hydrophobicity of the 91-94 motif is crucial for the budding of M2, bilayer membrane integrity, and pathogenicity of the influenza viruses. M2 plays a crucial role in the influenza virus life cycle. However, the function of the C-terminal intracellular domain of M2 protein remains largely unclear. In this study, we explored the function of the 91-94 hydrophobic motif of M2 protein. The results showed that the reduction of the hydrophobicity of the 91-94 motif significantly affected the budding ability of the M2 protein and impaired the bilayer membrane integrity of the mutant virus. The mouse study showed that the reduction of the hydrophobicity of the 91-94 motif significantly attenuated the mutant virus. All of the results indicated that the hydrophobicity of the 91-94 motif of the M2 protein plays an important role in budding, membrane integrity, and pathogenicity of influenza virus. Our study offers insights into the mechanism of influenza virus morphogenesis, particularly into the roles of the 91-94 hydrophobic motif of M2 in virion assembly and the pathogenicity of the influenza viruses.
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http://dx.doi.org/10.1128/jvi.00373-22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9093103PMC
May 2022

Cross-trial prediction of depression remission using problem-solving therapy: A machine learning approach.

J Affect Disord 2022 07 7;308:89-97. Epub 2022 Apr 7.

Department of Medicine, University of Illinois at Chicago, United States of America. Electronic address:

Background: Psychotherapy is a standard depression treatment; however, determining a patient's prognosis with therapy relies on clinical judgment that is subject to trial-and-error and provider variability.

Purpose: To develop machine learning (ML) algorithms to predict depression remission for patients undergoing 6 months of problem-solving therapy (PST).

Method: Using data from the treatment arm of 2 randomized trials, ML models were trained and validated on ENGAGE-2 (ClinicalTrials.gov, #NCT03841682) and tested on RAINBOW (ClinicalTrials.gov, #NCT02246413) for predictions at baseline and at 2-months. Primary outcome was depression remission using the Depression Symptom Checklist (SCL-20) score < 0.5 at 6 months. Predictor variables included baseline characteristics (sociodemographic, behavioral, clinical, psychosocial) and intervention engagement through 2-months.

Results: Of the 26 candidate variables, 8 for baseline and 11 for 2-months were predictive of depression remission, and used to train the models. The best-performing model predicted remission with an accuracy significantly greater than chance in internal validation using the ENGAGE-2 cohort, at baseline [72.6% (SD = 3.6%), p < 0.0001] and at 2-months [72.3% (5.1%), p < 0.0001], and in external validation with the RAINBOW cohort at baseline [58.3% (0%), p < 0.0001] and at 2-months [62.3% (0%), p < 0.0001]. Model-agnostic explanations highlighted key predictors of depression remission at the cohort and patient levels, including female sex, lower self-reported sleep disturbance, lower sleep-related impairment, and lower negative problem orientation.

Conclusions: ML models using clinical and patient-reported data can predict depression remission for patients undergoing PST, affording opportunities for prospective identification of likely responders, and for developing personalized early treatment optimization along the patient care trajectory.
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http://dx.doi.org/10.1016/j.jad.2022.04.015DOI Listing
July 2022

Dose effect of high-docosahexaenoic acid tuna oil on dysbiosis in high-fat diet mice.

J Sci Food Agric 2022 Sep 7;102(12):5531-5543. Epub 2022 Jun 7.

State Key Laboratory for Quality and Safety of Argo-products, Ningbo University, Ningbo, China.

Background: The health benefits of tuna oil, which is different from the fish oil commonly studied, and its higher docosahexaenoic acid (DHA) content, have attracted much scientific attention in recent years. In this study, prepared tuna oil with higher DHA (HDTO) content was employed. It was the first to integrate microbiome and metabolome from a dose-effect perspective to investigate the influence of HDTO on gut dysbiosis and metabolic disorders in diet-induced obese mice.

Results: Higher DHA tuna oil was effective in reversing high-fat-diet-induced metabolic disorders and altering the composition and function of gut microbiota, but these effects were not uniformly dose dependent. The flora and metabolites that were targeted to be regulated by HDTO supplementation were Prevotella, Bifidobacterium, Olsenella, glycine, l-aspartate, l-serine, l-valine, l-isoleucine, l-threonine, l-tyrosine, glyceric acid, glycerol, butanedioic acid, and citrate, respectively. Functional pathway analysis revealed that alterations in these metabolic biomarkers were associated with six main metabolic pathways: glycine, serine, and threonine metabolism; glycerolipid metabolism; glyoxylate and dicarboxylate metabolism; alanine, aspartate, and glutamate metabolism; aminoacyl-tRNA biosynthesis, and the citrate cycle (TCA cycle).

Conclusion: Various doses of HDTO could attenuate endogenous disorders to varying degrees by regulating multiple perturbed pathways to the normal state. This explicit dose research for novel fish oil with high-DHA will provide a valuable reference for those seeking to exploit its clinical therapeutic potential. © 2022 Society of Chemical Industry.
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http://dx.doi.org/10.1002/jsfa.11908DOI Listing
September 2022

Structural Insights Into the Effects of Interactions With Iron and Copper Ions on Ferritin From the Blood Clam .

Front Mol Biosci 2022 11;9:800008. Epub 2022 Mar 11.

State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China.

In addition to its role as an iron storage protein, ferritin can function as a major detoxification component in the innate immune defense, and Cu ions can also play crucial antibacterial roles in the blood clam, . However, the mechanism of interaction between iron and copper in recombinant ferritin (TgFer) remains to be investigated. In this study, we investigated the crystal structure of TgFer and examined the effects of Fe and Cu ions on the TgFer structure and catalytic activity. The crystal structure revealed that TgFer presented a typically 4-3-2 symmetry in a cage-like, spherical shell composed of 24 identical subunits, featuring highly conserved organization in both the ferroxidase center and the 3-fold channel. Structural and biochemical analyses indicated that the 4-fold channel of TgFer could be serviced as potential binding sites of metal ions. Cu ions appear to bind preferentially with the 3-fold channel as well as ferroxidase site over Fe ions, possibly inhibiting the ferroxidase activity of TgFer. Our results present a structural and functional characterization of TgFer, providing mechanistic insight into the interactions between TgFer and both Fe and Cu ions.
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http://dx.doi.org/10.3389/fmolb.2022.800008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8961696PMC
March 2022

Effect of Carbon on Dislocation Loops Formation during Self-Ion Irradiation in Fe-Cr Alloys at High Temperatures.

Materials (Basel) 2022 Mar 17;15(6). Epub 2022 Mar 17.

Department of Nuclear Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.

In this study, two types of ferritic model alloys (Fe-9Cr and Fe-9Cr-C) were simultaneously irradiated with 3.5 MeV Fe ions at 450 °C and 550 °C to a dose of 3dpa at the peak damage region, respectively. Transmission electron microscopy (TEM) was used to investigate the microstructural evolution of the Fe-Cr alloys after irradiation. The experimental results showed that the size of the dislocation loops formed in the Fe-9Cr-C alloy was larger than that in the Fe-9Cr alloy, but the loop density of the Fe-9Cr-C alloy was lower than that of the Fe-9Cr alloy after irradiation at 450 °C. The reason for this phenomenon was attributed to the fact that loops formed in Fe-9Cr-C alloy have greater capture efficiency for interstitial atoms. Compared to Fe-Cr alloys irradiated at 450 °C, high-density loops were not observed in the Fe-Cr alloys irradiated at 550 °C; the number of dislocation loops in the Fe-Cr alloys irradiated at 550 °C significantly decreased due to the rapid conversion of the dislocation loops into network dislocations. In addition, subgrains were observed in the Fe-Cr alloys after irradiation. The underlying reason behind the formation of subgrains is discussed in detail.
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http://dx.doi.org/10.3390/ma15062211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8954294PMC
March 2022

Novel anti-hyperuricemic hexapeptides derived from hydrolysate and their modulation effects on the gut microbiota and host microRNA profile.

Food Funct 2022 Apr 4;13(7):3865-3878. Epub 2022 Apr 4.

State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China.

Hyperuricemia (HUA) is the second most common metabolic disease nowadays, and is characterized by permanently increased concentrations of serum uric acid. In this study, two novel hexapeptides (GPAGPR and GPSGRP) were identified from hydrolysate and predicted to have xanthine oxidase (XOD) inhibitory activity by molecular docking. Their XOD inhibition rates reached 37.3% and 48.6%, respectively, at a concentration of 40 mg mL. Subsequently, experiments were carried out in a HUA mouse model, and we found that both peptides reduced the serum uric acid by inhibiting uric acid biosynthesis and reabsorption, as well as alleviated renal inflammation suppressing the activation of the NLRP3 inflammasome. 16S rDNA sequencing indicated that both peptide treatments reduced the richness and diversity of the gut microbiota, altered the composition in the phylum and genus levels, but different change trends were observed in the phylum Verrucomicrobia and genera , , , Clostridium unclassified and . In addition, changes in the renal microRNA (miRNA) profiles induced by GPSGRP treatment were analyzed; 21 differentially expressed (DE) miRNAs were identified among groups, and KEGG pathway analysis indicated that their potential target genes were involved in pluripotency of stem cell regulation, mTOR signaling pathway and proteoglycans. Moreover, ten miRNAs involved in the HUA onset and alleviation were identified, which showed a high correlation with genera related to the metabolism of short-chain fatty acids, bile acids and tryptophan. This study delineated two hexapeptides as potential microbiota modulators and miRNA regulators that can ameliorate HUA.
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http://dx.doi.org/10.1039/d1fo03981dDOI Listing
April 2022

Personalized Surgical Transfusion Risk Prediction Using Machine Learning to Guide Preoperative Type and Screen Orders.

Anesthesiology 2022 07;137(1):55-66

Department of Anesthesiology and the Institute for Informatics, Washington University School of Medicine, St. Louis, Missouri.

Background: Accurate estimation of surgical transfusion risk is essential for efficient allocation of blood bank resources and for other aspects of anesthetic planning. This study hypothesized that a machine learning model incorporating both surgery- and patient-specific variables would outperform the traditional approach that uses only procedure-specific information, allowing for more efficient allocation of preoperative type and screen orders.

Methods: The American College of Surgeons National Surgical Quality Improvement Program Participant Use File was used to train four machine learning models to predict the likelihood of red cell transfusion using surgery-specific and patient-specific variables. A baseline model using only procedure-specific information was created for comparison. The models were trained on surgical encounters that occurred at 722 hospitals in 2016 through 2018. The models were internally validated on surgical cases that occurred at 719 hospitals in 2019. Generalizability of the best-performing model was assessed by external validation on surgical cases occurring at a single institution in 2020.

Results: Transfusion prevalence was 2.4% (73,313 of 3,049,617), 2.2% (23,205 of 1,076,441), and 6.7% (1,104 of 16,053) across the training, internal validation, and external validation cohorts, respectively. The gradient boosting machine outperformed the baseline model and was the best- performing model. At a fixed 96% sensitivity, this model had a positive predictive value of 0.06 and 0.21 and recommended type and screens for 36% and 30% of the patients in internal and external validation, respectively. By comparison, the baseline model at the same sensitivity had a positive predictive value of 0.04 and 0.144 and recommended type and screens for 57% and 45% of the patients in internal and external validation, respectively. The most important predictor variables were overall procedure-specific transfusion rate and preoperative hematocrit.

Conclusions: A personalized transfusion risk prediction model was created using both surgery- and patient-specific variables to guide preoperative type and screen orders and showed better performance compared to the traditional procedure-centric approach.

Editor’s Perspective:
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http://dx.doi.org/10.1097/ALN.0000000000004139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177553PMC
July 2022

Predicting physician burnout using clinical activity logs: Model performance and lessons learned.

J Biomed Inform 2022 03 5;127:104015. Epub 2022 Feb 5.

Department of Anesthesiology, School of Medicine, Washington University in St Louis, St Louis, MO, United States; Institute for Informatics, School of Medicine, Washington University in St Louis, St Louis, MO, United States. Electronic address:

Background: Burnout is a significant public health concern affecting more than half of the healthcare workforce; however, passive screening tools to detect burnout are lacking. We investigated the ability of machine learning (ML) techniques to identify burnout using passively collected electronic health record (EHR)-based audit log data.

Method: Physician trainees participated in a longitudinal study where they completed monthly burnout surveys and provided access to their EHR-based audit logs. Using the monthly burnout scores as the target outcome, we trained ML models using combinations of features derived from audit log data-aggregate measures of clinical workload, time series-based temporal measures of EHR use, and the baseline burnout score. Five ML models were constructed to predict burnout as a continuous score: penalized linear regression, support vector machine, neural network, random forest, and gradient boosting machine.

Results: 88 trainee physicians participated and completed 416 surveys; greater than10 million audit log actions were collected (Mean [Standard Deviation] = 25,691 [14,331] actions per month, per physician). The workload feature set predicted burnout score with a mean absolute error (MAE) of 0.602 (95% Confidence Interval (CI), 0.412-0.826), and was able to predict burnout status with an average AUROC of 0.595 (95% CI 0.355-0.808) and average accuracy 0.567 (95% CI 0.393-0.742). The temporal feature set had a similar performance, with MAE 0.596 (95% CI 0.391-0.826), and AUROC 0.581 (95% CI 0.343-0.790). The addition of the baseline burnout score to the workload features improved the model performance to a mean AUROC of 0.829 (95% CI 0.607-0.996) and mean accuracy of 0.781 (95% CI 0.587-0.936); however, this performance was not meaningfully different than using the baseline burnout score alone.

Conclusions: Current findings illustrate the complexities of predicting burnout exclusively based on clinical work activities as captured in the EHR, highlighting its multi-factorial and individualized nature. Future prediction studies of burnout should account for individual factors (e.g., resilience, physiological measurements such as sleep) and associated system-level factors (e.g., leadership).
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http://dx.doi.org/10.1016/j.jbi.2022.104015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8901565PMC
March 2022

Continuous real-time prediction of surgical case duration using a modular artificial neural network.

Br J Anaesth 2022 05 26;128(5):829-837. Epub 2022 Jan 26.

Department of Anesthesiology, Washington University School of Medicine in St Louis, St Louis, MO, USA; Institute for Informatics, Washington University School of Medicine in St Louis, St Louis, MO, USA.

Background: Real-time prediction of surgical duration can inform perioperative decisions and reduce surgical costs. We developed a machine learning approach that continuously incorporates preoperative and intraoperative information for forecasting surgical duration.

Methods: Preoperative (e.g. procedure name) and intraoperative (e.g. medications and vital signs) variables were retrieved from anaesthetic records of surgeries performed between March 1, 2019 and October 31, 2019. A modular artificial neural network was developed and compared with a Bayesian approach and the scheduled surgical duration. Continuous ranked probability score (CRPS) was used as a measure of time error to assess model accuracy. For evaluating clinical performance, accuracy for each approach was assessed in identifying cases that ran beyond 15:00 (commonly scheduled end of shift), thus identifying opportunities to avoid overtime labour costs.

Results: The analysis included 70 826 cases performed at eight hospitals. The modular artificial neural network had the lowest time error (CRPS: mean=13.8; standard deviation=35.4 min), which was significantly better (mean difference=6.4 min [95% confidence interval: 6.3-6.5]; P<0.001) than the Bayesian approach. The modular artificial neural network also had the highest accuracy in identifying operating theatres that would overrun 15:00 (accuracy at 1 h prior=89%) compared with the Bayesian approach (80%) and a naïve approach using the scheduled duration (78%).

Conclusions: A real-time neural network model using preoperative and intraoperative data had significantly better performance than a Bayesian approach or scheduled duration, offering opportunities to avoid overtime labour costs and reduce the cost of surgery by providing superior real-time information for perioperative decision support.
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http://dx.doi.org/10.1016/j.bja.2021.12.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9074795PMC
May 2022

Crystallographic characterization of a marine invertebrate ferritin from the sea cucumber Apostichopus japonicus.

FEBS Open Bio 2022 03 7;12(3):664-674. Epub 2022 Feb 7.

State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, China.

Ferritin is considered to be an ubiquitous and conserved iron-binding protein that plays a crucial role in iron storage, detoxification, and immune response. Although ferritin is of critical importance for almost all kingdoms of life, there is a lack of knowledge about its role in the marine invertebrate sea cucumber (Apostichopus japonicus). In this study, we characterized the first crystal structure of A. japonicus ferritin (AjFER) at 2.75 Å resolution. The structure of AjFER shows a 4-3-2 symmetry cage-like hollow shell composed of 24 subunits, mostly similar to the structural characteristics of other known ferritin species, including the conserved ferroxidase center and 3-fold channel. The 3-fold channel consisting of three 3-fold negative amino acid rings suggests a potential pathway in which metal ions can be first captured by Asp120 from the outside environment, attracted by His116 and Cys128 when entering the channel, and then transferred by Glu138 from the 3-fold channel to the ferroxidase site. Overall, the presented crystal structure of AjFER may provide insights into the potential mechanism of the metal transport pathway for related marine invertebrate ferritins.
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http://dx.doi.org/10.1002/2211-5463.13375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8886333PMC
March 2022

Correction: The gut microbiota mediates the protective effects of anserine supplementation on hyperuricaemia and associated renal inflammation.

Food Funct 2022 Jan 24;13(2):1027. Epub 2022 Jan 24.

State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China.

Correction for 'The gut microbiota mediates the protective effects of anserine supplementation on hyperuricaemia and associated renal inflammation' by Jiaojiao Han , , 2021, , 9030-9042, DOI: 10.1039/D1FO01884A.
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http://dx.doi.org/10.1039/d1fo90120fDOI Listing
January 2022

Comprehensive evaluation and analysis of the salinity stress response mechanisms based on transcriptome and metabolome of Staphylococcus aureus.

Arch Microbiol 2021 Dec 18;204(1):28. Epub 2021 Dec 18.

State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Ningbo University, Ningbo, China.

Staphylococcus aureus possesses an extraordinary ability to deal with a wide range of osmotic pressure. This study performed transcriptomic and metabolomic analyses on the potential mechanism of gradient salinity stress adaptation in S. aureus ZS01. The results revealed that CPS biosynthetic protein genes were candidate target genes for directly regulating the phenotypic changes of biofilm. Inositol phosphate metabolism was downregulated to reduce the conversion of functional molecules. The gluconeogenesis pathway and histidine synthesis were downregulated to reduce the production of endogenous glucose. The pyruvate metabolism pathway was upregulated to promote the accumulation of succinate. TCA cycle metabolism pathway was downregulated to reduce unnecessary energy loss. L-Proline was accumulated to regulate osmotic pressure. Therefore, these self-protection mechanisms can protect cells from hypertonic environments and help them focus on survival. In addition, we identified ten hub genes. The findings will aid in the prevention and treatment strategies of S. aureus infections.
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http://dx.doi.org/10.1007/s00203-021-02624-9DOI Listing
December 2021

Cinacalcet Targets the Neurokinin-1 Receptor and Inhibits PKCδ/ERK/P65 Signaling to Alleviate Dextran Sulfate Sodium-Induced Colitis.

Front Pharmacol 2021 22;12:735194. Epub 2021 Nov 22.

Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China.

Inflammatory bowel disease is an immune-mediated chronic inflammatory disease of the gastrointestinal tract for which curative drugs are currently not available. This study was performed to assess the therapeutic effects of cinacalcet on dextran sulfate sodium (DSS)-induced colitis. Primary macrophages obtained from bone marrow and the macrophage cell line RAW264.7 were used to examine the inhibitory effect of cinacalcet on cytokine production, the PKCδ/ERK/P65 signaling pathway, and NF-κB P65 translocation. Colitis was induced using DSS to assess the treatment effect of cinacalcet. Bioinformatics approaches were adopted to predict potential targets of cinacalcet, and a drug affinity responsive target stability (DARTs) assay was performed to confirm binding between cinacalcet and potential target. analysis showed that cinacalcet reduced the disease activity score, prevented shortening of the colon, diminished inflammatory cell infiltration, and protected the structural integrity of the intestinal wall. Cinacalcet also reduced production of the inflammatory cytokines TNFα, IL-1β, and IL-6 in the colon and sera of mice with DSS-induced colitis. studies revealed that cinacalcet suppressed the translocation of P65 and inhibited production of the inflammatory cytokines IL-1β and IL-6. Mechanistic studies revealed that the target of cinacalcet was neurokinin-1 receptor (NK1R) and their binding was confirmed by a DARTs assay. Furthermore, the inhibition of NK-κB P65 activation was found to occur via the suppression of PKCδ/ERK/P65 signaling mediated by cinacalcet. Cinacalcet inhibits the activation of NF-κB and reduces the production of inflammatory cytokines by suppressing the PKCδ/ERK/P65 signaling pathway via targeting NK1R, suggesting that it can be used to treat inflammatory diseases, particularly colitis.
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http://dx.doi.org/10.3389/fphar.2021.735194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8645985PMC
November 2021

Identification of Two Novel Variants in Two Consanguineous Families with Primary Ciliary Dyskinesia.

Pharmgenomics Pers Med 2021 10;14:1415-1423. Epub 2021 Nov 10.

Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.

Background: Dynein axonemal assembly factor 2 () is involved in the early preassembly of dynein in the cytoplasm, which is essential for motile cilia function. Primary ciliary dyskinesia (PCD) associated with variants has rarely been reported in females with infertility. Moreover, there is no report linking to scoliosis in human.

Materials And Methods: We recruited patients from two consanguineous families with a clinical diagnosis of PCD and collected their clinical history, laboratory tests, and radiographic data. Sequencing and bioinformatics analysis were then performed. Immunofluorescence and high-speed microscope analysis were used to support the pathogenicity of the variant.

Results: Proband 1, a 26-year-old female from family I, exhibited scoliosis, bronchiectasis, sinusitis, situs inversus, and infertility. We found a novel homozygous missense variant in , c.491T>C, p.(Leu164Pro) in this patient. Subsequent immunofluorescence indicated the absence of outer dynein arm and inner dynein arm of cilia, and high-speed microscopy analysis showed that the most of the cilia are static, which support the pathogenicity of this variant. Proband 2, a 53-year-old female, presented with bronchiectasis, sinusitis, and infertility. In this patient, a new homozygous frameshift variant , c.822del, p.(Ala275Profs*10) was identified. The disease-causing variants mentioned above are not included in the current authorized genetic databases.

Conclusion: Our findings expand the spectrum of variants and link to female infertility and likely scoliosis in patients with PCD.
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http://dx.doi.org/10.2147/PGPM.S338981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591118PMC
November 2021
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