Interaction Between Genetic Susceptibility and COVID-19 Pathogenesis in Pediatric Multisystem Inflammatory Disorders: The Role of Immune Responses.

Numerous studies have highlighted the emergence of coronavirus disease (COVID-19) symptoms reminiscent of Kawasaki disease in children, including fever, heightened multisystem inflammation, and multiorgan involvement, posing a life-threatening complication. Consequently, extensive research endeavors in pediatric have aimed to elucidate the intricate relationship between COVID-19 infection and the immune system. COVID-19 profoundly impacts immune cells, culminating in a cytokine storm that particularly inflicts damage on the pulmonary system. The gravity and vulnerability to COVID-19 are closely intertwined with the vigor of the immune response. In this context, the human leukocyte antigen (HLA) molecule assumes pivotal significance in shaping immune responses. Genetic scrutiny of HLA has unveiled the presence of at least one deleterious allele in children afflicted with multisystem inflammatory syndrome in children (MIS-C). Furthermore, research has demonstrated that COVID-19 exploits the angiotensin-converting enzyme 2 (ACE-2) receptor, transmembrane serine protease type 2, and various other genes to gain entry into host cells, with individuals harboring ACE-2 polymorphisms being at higher risk. Pediatric studies have employed diverse genetic methodologies, such as genome-wide association studies (GWAS) and whole exome sequencing, to scrutinize target genes. These investigations have pinpointed two specific genomic loci linked to the severity and susceptibility of COVID-19, with the HLA locus emerging as a notable risk factor. In this comprehensive review article, we endeavor to assess the available evidence and consolidate data, offering insights into current clinical practices and delineating avenues for future research. Our objective is to advance early diagnosis, stabilization, and appropriate management strategies to mitigate genetic susceptibility's impact on the incidence of COVID-19 in pediatric patients with multisystem inflammation.

Exploring myometrial microenvironment changes at the single-cell level from nonpregnant to term pregnant states.

The microenvironment and cell populations within the myometrium play crucial roles in maintaining uterine structural integrity and protecting the fetus during pregnancy. However, the specific changes occurring at the single-cell level in the human myometrium between nonpregnant (NP) and term pregnant (TP) states remain unexplored. In this study, we used single-cell RNA sequencing (scRNA-Seq) and spatial transcriptomics (ST) to construct a transcriptomic atlas of individual cells in the myometrium of NP and TP women. Integrated analysis of scRNA-Seq and ST data revealed spatially distinct transcriptional characteristics and examined cell-to-cell communication patterns based on ligand-receptor interactions. We identified and categorized 87,845 high-quality individual cells into 12 populations from scRNA-Seq data of 12 human myometrium tissues. Our findings demonstrated alterations in the proportions of five subpopulations of smooth muscle cells in TP. Moreover, an increase in monocytic cells, particularly M2 macrophages, was observed in TP myometrium samples, suggesting their involvement in the anti-inflammatory response. This study provides unprecedented single-cell resolution of the NP and TP myometrium, offering new insights into myometrial remodeling during pregnancy.NEW & NOTEWORTHY Using single-cell RNA sequencing and spatial transcriptomics, the myometrium was examined at the single-cell level during pregnancy. We identified spatially distinct cell populations and observed alterations in smooth muscle cells and increased M2 macrophages in term pregnant women. These findings offer unprecedented insights into myometrial remodeling and the anti-inflammatory response during pregnancy. The study advances our understanding of pregnancy-related myometrial changes.

[Cardiovascular complications in malaria: a review].

Malaria, one of the major global public health events, is a leading cause of mortality and morbidity among children and adults in tropical and subtropical regions(mainly in sub-Saharan Africa), threatening human health. It is well known that malaria can cause various complications including anemia, blackwater fever, cerebral malaria, and kidney damage. Conventionally, cardiac involvement has not been listed as a common reason affecting morbidity and mortality of malaria, which may be related to ignored cases or insufficient diagnosis. However, the serious clinical consequences such as acute coronary syndrome, heart failure, and malignant arrhythmia caused by malaria have aroused great concern. At present, antimalarials are commonly used for treating malaria in clinical practice. However, inappropriate medication can increase the risk of cardiovascular diseases and cause severe consequences. This review summarized the research advances in the cardiovascular complications including acute myocardial infarction, arrhythmia, hypertension, heart failure, and myocarditis in malaria. The possible mechanisms of cardiovascular diseases caused by malaria were systematically expounded from the hypotheses of cell adhesion, inflammation and cytokines, myocardial apoptosis induced by plasmodium toxin, cardiac injury secondary to acute renal failure, and thrombosis. Furthermore, the effects of quinolines, nucleoprotein synthesis inhibitors, and artemisinin and its derivatives on cardiac structure and function were summarized. Compared with the cardiac toxicity of quinolines in antimalarial therapy, the adverse effects of artemisinin-derived drugs on heart have not been reported in clinical studies. More importantly, the artemisinin-derived drugs demonstrate favorable application prospects in the prevention and treatment of cardiovascular diseases, and are expected to play a role in the treatment of malaria patients with cardiovascular diseases. This review provides reference for the prevention and treatment of malaria-related cardiovascular complications as well as the safe application of antimalarials.

Photocatalytic Intramolecular Alkene Hydroamination of N-Alkoxy Ureas: An Approach to Imidazolinones.

Imidazolinones were obtained in good yields by intramolecular hydroamination of N-alkoxy ureas in the presence of an organic photocatalyst and an inorganic base. In this reaction, the N-alkoxy urea anion generated by deprotonation undergoes photocatalyzed single-electron-transfer oxidation to generate the corresponding radical, which cyclizes to afford the imidazolinone ring. This new protocol grants access to an array of complex molecules containing a privileged imidazolinone core.

Impacts of air pollution and meteorological conditions on dry eye disease among residents in a northeastern Chinese metropolis: a six-year crossover study in a cold region.

The purpose of this study is to explore the associations among dry eye disease (DED), air pollution, and meteorological conditions in the cold region of a northeastern Chinese metropolis (i.e., Changchun). Data on ambient air pollutants and meteorological parameters as well as diagnosed DED outpatients during 2015-2021 were collected. The associations between DED and environmental factors were analysed at multiple time scales using various statistical methods (i.e., correlation, regression and machine learning). Among the 10,809 DED patients (21,617 eyes) studied, 64.60% were female and 35.40% were male. A higher frequency of DED was observed in March and April, followed by January, August and October. Individual and multiple factor models showed the positive importance of particles with aerodynamic diameters <10 µm (PM10), carbon monoxide (CO), and ozone (O3) among normal air pollutants and air pressure (AP), air temperature (AT) and wind speed (WS) among normal meteorological parameters. Air pollutants (PM10, nitrogen dioxide: NO2) and meteorological parameters (AT, AP) have combined impacts on DED occurrence. For the first time, we further explored the associations of detailed components of atmospheric particles and DED, suggesting potential emission sources, including spring dust from bare soil and roads and precursor pollutants of summer O3 formation from vehicles and industry in Northeast China. Our results revealed the quantitative associations among air pollutants, meteorological conditions and DED outpatients in cold regions, highlighting the importance of coordinated policies in air pollution control and climate change mitigation.

CDKN1C gene mutation causing familial Silver-Russell syndrome: A case report and review of literature.

BACKGROUND: Cyclin-dependent kinase inhibitor 1C (CDKN1C) is a cell proliferation inhibitor that regulates the cell cycle and cell growth through G1 cell cycle arrest. CDKN1C mutations can lead to IMAGe syndrome (CDKN1C allele gain-of-function mutations lead to intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, and genitourinary malformations). We present a Silver-Russell syndrome (SRS) pedigree that was due to a missense mutation affecting the same amino acid position, 279, in the CDKN1C gene, resulting in the amino acid substitution p.Arg279His (c.836G>A). The affected family members had an SRS phenotype but did not have limb asymmetry or adrenal insufficiency. The amino acid changes in this specific region were located in a narrow functional region that contained mutations previously associated with IMAGe syndrome. In familial SRS patients, the PCNA region of CDKN1C should be analysed. Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants. CASE SUMMARY: We describe the case of an 8-year-old girl who initially presented with short stature. Her height was 91.6 cm, and her weight was 10.2 kg. Physical examination revealed that she had a relatively large head, an inverted triangular face, a protruding forehead, a low ear position, sunken eye sockets, and irregular cracked teeth but no limb asymmetry. Family history: The girl's mother, great-grandmother, and grandmother's brother also had a prominent forehead, triangular face, and severely proportional dwarfism but no limb asymmetry or adrenal insufficiency. Exome sequencing of the girl revealed a new heterozygous CDKN1C (NM_000076. 2) c.836G>A mutation, resulting in a variant with a predicted evolutionarily highly conserved arginine substituted by histidine (p.Arg279His). The same causative mutation was found in both the proband's mother, great-grandmother, and grandmother's brother, who had similar phenotypes. Thus far, we found an SRS pedigree, which was due to a missense mutation affecting the same amino acid position, 279, in the CDKN1C gene, resulting in the amino acid substitution p.Arg279His (c.836G>A). Although the SRS-related CDKN1C mutation is in the IMAGe-related mutation hotspot region [the proliferating cell nuclear antigen (PCNA) domain], no adrenal insufficiency was reported in this SRS pedigree. The reason may be that the location of the genomic mutation and the type of missense mutation determines the phenotype. The proband was treated with recombinant human growth hormone (rhGH). After 1 year of rhGH treatment, the height standard deviation score of the proband increased by 0.93 standard deviation score, and her growth rate was 8.1 cm/year. No adverse reactions, such as abnormal blood glucose, were found. CONCLUSION: Functional mutations in CDKN1C can lead to familial SRS without limb asymmetry, and some patients may have glucose abnormalities. In familial SRS patients, the PCNA region of CDKN1C should be analysed. Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants.

Molecular epidemiology analysis of symptomatic and asymptomatic norovirus infections in Chinese infants.

BACKGROUND: Norovirus is a leading cause of acute gastroenteritis among children. Previous studies based on symptomatic infections indicated that mutations, rather than recombination drove the evolution of the norovirus ORF2. These characteristics were found in hospital-based symptomatic infections, whereas, asymptomatic infections are frequent and contribute significantly to transmission. METHODS: We conducted the first norovirus molecular epidemiology analysis covering both symptomatic and asymptomatic infections derived from a birth cohort study in the northern China. RESULTS: During the study, 14 symptomatic and 20 asymptomatic norovirus infections were detected in 32 infants. Out of the 14 strains that caused symptomatic infections, 12 strains were identified as GII.3[P12], and others were GII.4[P31]. Conversely, 17 asymptomatic infections were caused by GII.4[P31], two by GII.2[P16], and one by GII.4[P16]. Regardless of symptomatic and asymptomatic infections, the mutations were detected frequently in the ORF2 region, and almost all recombination were identified in the RdRp-ORF2 region. The majority of the mutations were located around the predefined epitope regions of P2 subdomain indicating a potential for immune evasion. CONCLUSION: The role of symptomatic as well as asymptomatic infections in the evolution of norovirus needs to be evaluated continuously.

Heat shock protein 40 of Streptococcus pneumoniae induces immune response of human dendritic cells via TLR4-dependent p38 MAPK and JNK signaling pathways.

INTRODUCTION: Heat shock protein 40 (HSP40) is a vaccine adjuvant candidate for Streptococcus pneumoniae. The mechanism by which HSP40 activates the human dendritic cells (DCs) is unclear. METHODS: DCs were isolated from human peripheral blood and their markers (HLA-DR, CD86, CD83, and CD80) were detected by flow cytometry. The messenger RNA (mRNA) and secretion levels of inflammary cytokines were measured after DCs were stimulated with recombinant HSP40 (rHSP40). Short hairpin RNAs were used to knock down toll-like receptor 2 (TLR2) and TLR4. The TLR2- or TLR4-deficient DCs were treated with lipopolysaccharides, rHSP40, or peptidoglycan, and then the secretion levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured. Moreover, the secretion levels of TNF-α and IL-6 were measured after DCs were treated with mitogen-activated protein kinase (MAPK) inhibitors including SB203580, SP600125, and U0126. In addition, the phosphorylation levels of p38 MAPK and Jun N-terminal kinase (JNK) in DC cells were determined using western blot analysis after treatment with rHSP40 for different times. RESULTS: DCs were successfully isolated and cultured. rHSP40 treatment significantly increased cytokine levels in a concentration-dependent manner. TLR4 deficiency, but not TLR2 deficiency, significantly suppressed the rHSP40-induced secretion of tumor necrosis factor-α  (TNF-α) and interleukin-6 (IL-6). SB203580 and SP600125 significantly inhibited the rHSP40-induced secretion of TNF-α and IL-6. rHSP40 significantly enhanced the phosphorylation of p38 MAPK and JNK. CONCLUSION: HPS40 stimulates the immune response of DCs via the p38 MAPK and JNK signaling pathways, which depend on TLR4.

A 7-year-old boy with recurrent cyanosis and tachypnea: A case report.

BACKGROUND: Brain tumors are the most common solid tumors in children and comprise 25% of all malignancies in children. Common presentations include headache, nausea and vomiting, gait abnormality, papilledema, and epileptic seizure; however, some symptoms can be very insidious, with atypical and misleading manifestations. CASE SUMMARY: Here, we report a 7-year-old boy who presented with recurrent cyanosis and tachypnea after exercise for 2 years. His body mass index was 26.43 kg/m2. Hepatosplenomegaly, blood gas analysis, biochemical parameters, chest computed tomography scan, and echocardiograph suggested type II respiratory failure, pulmonary heart disease, and mild liver injury. Non-invasive breathing support, antibiotics, and anti-heart failure therapy were given. The patient's pulse oxygen saturation increased to over 95% when he was awake but dropped to 50%-60%, accompanied by cyanosis, during sleep while receiving high-flow nasal cannula oxygen. Sleep-related breathing disorder was suspected. In the intensive care unit, however, polysomnography was unavailable. Brain magnetic resonance imaging revealed a space-occupying (cerebellum and brainstem) lesion, which was later confirmed to be pleomorphic xanthoastrocytoma by surgery and histopathology by tissue biopsy. CONCLUSION: When treating patients with cyanosis and tachypnea, a broad differential diagnosis should be considered, including brain tumor.

Identification and functional analysis of novel SOX11 variants in Chinese patients with Coffin-Siris syndrome 9.

SOX11 is a transcription factor belonging to the sex determining region Y-related high-mobility group box family that plays a vital role in early embryogenesis and neurogenesis. De novo variants in SOX11 have been initially reported to cause a rare neurodevelopmental disorder, mainly referred to Coffin-siris syndrome 9 (CSS9, OMIM# 615866) which is characterized with growth deficiency, intellectual disability (ID), microcephaly, coarse facies, and hypoplastic nails of the fifth fingers and/or toes. A recent large-scale cohort study suggests that SOX11 variation would result in a clinically and molecularly distinct disease from CSS. Here, we describe three unrelated Chinese cases with variable phenotype, mainly involving developmental delay, ID, short statute, microcephaly, facial deformities (i.e., prominent forehead, arched eye brow, flat nasal bridge, broad nose and short philtrum), and cryptorchidism. Whole-exome sequencing (WES) revealed three novel heterozygous variants in the SOX11 gene, including two missense variants of c.337T>C (p.Y113H) and c.425C>G (p.A142G), and one nonsense variant of c.820A>T (p. K142*). Luciferase reporting assay shows that the two missense variants impair the transcriptional activity of the SOX11 target gene GDF5. Additionally, WES uncovered a 4,300 kb deletion involving the region of 1q24.2-q25.1 (hg19,chr1:169,433,149-173,827,682) in patient 1, which also contributes to the condition of the patient. In summary, this is the first report of Chinese cases with de novo variants of SOX11. Our study partially supports the previous observation that the phenotype caused by SOX11 variants somewhat differs from classical CSS.

Rejection of Acellular Porcine Corneal Stroma Transplantation During Coronavirus Disease 2019 Pandemic.

ABSTRACT: To report 2 successfully managed cases of graft rejection with acellular porcine corneal stroma (APCS) transplantation in patients with fungal corneal ulcer. Two patients were diagnosed with fungal corneal ulcer and received APCS transplantation. Graft rejection developed due to the lost follow-up during the period of coronavirus disease 2019 outbreak. Amniotic membranes transplantation and cauterization of neovascularization was performed, respectively. The graft failure resolved successfully after the procedure. To the best of our knowledge, amniotic membranes transplantation and cauterization of new vessels are the firstly reported in treating APCS graft failure. Amniotic membranes transplantation or cauterization of neovascularization appear to be a safe and costeffective method for treating graft failure.

Damage of brown planthopper (BPH) Nilaparvata lugens and rice leaf folder (LF) Cnaphalocrocis medinalis in parent plants lead to distinct resistance in ratoon rice.

Herbivore-induced defense responses are often specific, whereas plants could induce distinct defense responses corresponding to infestation by different herbivorous insects. Brown plant hopper (BPH) Nilaparvata lugens, a phloem-feeding insect, and rice leaf folder (LF) Cnaphalocrocis medinalis, a chewing insect, are both specialist herbivores on rice. To characterize the distinct resistance primed by prior damage to these two specialist herbivores, we challenged rice plants with two herbivores during vegetative growth of parent plants and assessed plant resistance in subsequent ratoons. Here, we show that LF and BPH induce different suites of defense responses in parent rice plants, LF induced higher level of JA accumulation and OsAOS, OsCOI1 transcripts, while BPH induced higher accumulation of SA and OsPAL1 transcripts. Moreover, an apparent loss of LF resistance was observed in OsAOS, OsCOI1 RNAi lines. Ratoon plants generated from parents receiving prior LF infestation exhibited higher jasmonic acid (JA) levels and elevated levels of transcripts of defense-related genes associated with JA signaling, while ratoon generated from parents receiving prior BPH infestation exhibited higher salicylic acid (SA) levels and elevated levels of transcripts of defense-related genes associated with SA signaling. Moreover, previous LF infestation obviously elevated ratoons resistance to LF, while previous infestation by BPH led to enhanced resistance in ratoons to BPH. Pre-priming of ratoons defense to LF was significantly reduced in OsAOS and OsCOI1 RNAi plant, but silencing OsAOS and OsCOI1 did not attenuate ratoons resistance to BPH. These results suggest that infestation of two specialist herbivores with different feeding styles in parent crop led to distinct defense responses in subsequent rations, and the acquired resistance to LF in ratoons is associated with priming of jasmonic acid-dependent defense responses.

Pulmonary lymphomatoid granulomatosis in a 4-year-old girl: A case report.

BACKGROUND: Pulmonary lymphomatoid granulomatosis (PLG) is a lymphoproliferative disease associated with Epstein-Barr viral infection occurring mainly in adults and rarely in children. It is characterized by multiple pulmonary nodules. Its diagnosis depends on lung biopsy findings. Most patients are immunodeficient, and it commonly presents in children undergoing chemotherapy for leukemia. We report the case of a child with PLG caused by a mutation in the macrophage-expressed gene 1 (MPEG1), suggesting possible PLG occurrence in children undergoing treatment for pulmonary nodular lesions. CASE SUMMARY: This study reports a case of PLG without apparent immunodeficiency, suggesting the possibility of this disease occurrence during the treatment of pulmonary nodular lesions in children. Initially, the cause was assumed to be an atypical pathogen. Following conventional anti-infective treatment, chest computed tomography findings revealed that there were still multiple nodules in the lungs. Additionally, the patient was found to be infected with the Epstein-Barr virus. Histopathological examination of the resected lung revealed lymphoproliferative lesions with necrosis. Small lymphocytes, plasma cells, and histiocytes were observed in the background, although Reed-Sternberg cells were absent. Immunohistochemical staining [CD20(+), CD30(+), and CD3(+)] and EBV-encoded small RNA1/2 in situ hybridization of small lymphocytes revealed approximately 200 cells/high-power field. Whole exon sequencing of the patient revealed a mutation in the MPEG1. The patient was eventually diagnosed with PLG and transferred to the Department of Pediatric Oncology for bone marrow transplantation. CONCLUSION: As PLG is rare and fatal, it should be suspected in clinical settings when treatment of initial diagnosis is ineffective.

Genetic characterization of two G8P[8] rotavirus strains isolated in Guangzhou, China, in 2020/21: evidence of genome reassortment.

BACKGROUND: The G8 rotavirus genotype has been detected frequently in children in many countries and even became the predominant strain in sub-Saharan African countries, while there are currently no reports from China. In this study we described the genetic characteristics and evolutionary relationship between rotavirus strains from Guangzhou in China and the epidemic rotavirus strains derived from GenBank, 2020-2021. METHODS: Virus isolation and subsequent next-generation sequencing were performed for confirmed G8P[8] specimens. The genetic characteristics and evolutionary relationship were analyzed in comparison with epidemic rotavirus sequences obtained from GenBank. RESULTS: The two Guangzhou G8 strains were DS-1-like with the closest genetic distance to strains circulating in Southeast Asia. The VP7 genes of the two strains were derived from a human, not an animal G8 rotavirus. Large genetic distances in several genes suggested that the Guangzhou strains may not have been transmitted directly from Southeast Asian countries, but have emerged following reassortment events. CONCLUSIONS: We report the whole genome sequence information of G8P[8] rotaviruses recently detected in China; their clinical and epidemiological significance remains to be explored further.

High CO-Tolerant Ru-Based Catalysts by Constructing an Oxide Blocking Layer.

CO poisoning of Pt-group metal catalysts is a long-standing problem, particularly for hydrogen oxidation reaction in proton exchange membrane fuel cells. Here, we report a catalyst of Ru oxide-coated Ru supported on TiO2 (Ru@RuO2/TiO2), which can tolerate 1-3% CO, enhanced by about 2 orders of magnitude over the classic PtRu/C catalyst, for hydrogen electrooxidation in a rotating disk electrode test. This catalyst can work stably in 1% CO/H2 for 50 h. About 20% of active sites can survive even in a pure CO environment. The high CO tolerance is not via a traditional bifunctional mechanism, i.e., oxide promoting CO oxidation, but rather via hydrous metal oxide shell blocking CO adsorption. An ab initio molecular dynamics (AIMD) simulation indicates that water confined in grain boundaries of the Ru oxide layer and Ru surface can suppress the diffusion and adsorption of CO. This oxide blocking layer approach opens a promising avenue for the design of high CO-tolerant electrocatalysts for fuel cells.

Visible light-induced N-radical 5-exo/6-endo cyclization of alkenyl amides: facile access to isoindolinones/isoquinolinones.

An efficient N-centered radical intramolecular cyclization reaction of alkenyl amides induced by visible light was described. In this process, an alkenyl amide underwent 5-exo/6-endo cyclization to selectively yield two critical alkaloid structures, namely isoindolinones and isoquinolinones.

[Pharmacodynamic substances and therapeutic potential of Wuji Pills:based on UPLC-Q-TOF-MS/MS and network pharmacology].

As a classic prescription, Wuji Pills is composed of Coptidis Rhizoma, Euodiae Fructus Preparata, and stir-fried Paeo-niae Radix Alba at the ratio of 6∶1∶6. The practical application of it is limited compared with other famous Chinese medicine prescriptions. Only one company produces Wuji Pills in China. In this study, ultra-performance liquid chromatography quadrupole time of flight mass spectrometry(UPLC-Q-TOF-MS/MS) was used to analyze and identify 26 identical compounds from Wuji Pills and drug-containing plasma of rats. Based on these components, 46 potential targets were screened out with network pharmacology methods, followed by the component-target network construction, Gene Ontology(GO) term enrichment, Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment, and disease prediction. It was concluded that Wuji Pills acted on core targets such as PTGS2, PTSG1, NCOA2, HSP9 OAD1, and RXRA through magnoflorine, hydroxyevodiamine, daucosterol, and berberine and exerted pharmacodynamic effects through various pathways such as calcium ion signaling pathway, phosphatidylinositol-3-kinase-protein kinase B(PI3 K-Akt) signaling pathway, and vascular endothelial growth factor(VEGF) signaling pathway. Thus, Wuji Pills has therapeutic potential for Alzheimer's disease, diabetes mellitus, myocardial ischemia, and other diseases in addition to the conventional disease(irritable bowel syndrome, IBS). The above research results can provide a reference for the comprehensive interpretation of the pharmacodynamic basis of Wuji Pills and the expansion of clinical application. At the same time, a lot of components in serum and the in vivo transformed and metabolized components of Wuji Pills have similar structure and relative molecular weight. In theory, these components may show additive effects and the competitive/antagonistic effects on the same target. According to the hypothesis of "additive effect of multiple components for a single target" in traditional Chinese medicine, multiple similar components may exert the additive effects on local targets. This study can partly prove the scientificity of this hypothesis and provide laboratory evidence.

Prevalence and Evolution of Noroviruses between 1966 and 2019, Implications for Vaccine Design.

Noroviruses (NoVs), a group of single-stranded RNA viruses causing epidemic acute gastroenteritis in humans, are highly diverse, consisting of multiple genogroups with >30 genotypes. Their continual evolutions make NoV vaccine design and development difficult. Here, we report a study of NoV sequences obtained from a population-based diarrhea surveillance in Zhengding County of Hebei Province spanning from 2001 to 2019 and those available in the GenBank database from 1966 to 2019. NoV genotypes and/or variants that may evade immunity were screened and identified based on primary and conformational structures for vaccine design. We selected 366, 301, 139, 74 and 495 complete VP1-coding nucleotide sequences representing the predominant genotypes of GII.4, GII.2, GII.3, GII.6 and GII.17, respectively. A total of 16 distinct GII.4 variants were identified, showing a typical linear evolutionary pattern of variant replacement, while only 1-4 variants of the other genotypes were found to co-circulate over the 40-50-year period without typical variant replacement. The vaccine strain GII.4c is close to variant Sydney_2012 (0.053) in their primary structure, but they are distinct at epitopes A and E in conformations. Our data suggested GII.4 variant Sydney_2012, GII.2 variant A, a GII.3 strain, GII.6 variants B and C and GII.17 variant D are primary candidate strains for NoV vaccine development.

Resveratrol acts via melanoma-associated antigen A12 (MAGEA12)/protein kinase B (Akt) signaling to inhibit the proliferation of oral squamous cell carcinoma cells.

The present study examined how resveratrol affects cell growth and MAGEA12/Akt signaling pathway in OSCC cells. Cal-27 cells were transiently transfected with a plasmid encoding MAGEA12, and the effects of overexpression were assessed in terms of cell viability, colony formation and the epithelial-mesenchymal transition. Cal-27 cells and MAGEA12-overexpressing cells were treated with resveratrol, then the cell viability and colony formation were also assessed by CCK8 assay and microscope, respectively. Levels of MAGEA12, p-Akt, Akt, Cyclin D1, and CDK14 genes and these proteins were analyzed using quantitative reverse-transcription polymerase-chain reaction and western blot. In the present research, we first generated and transiently transfected MAGEA12 plasmid into Cal-27 cells. Our results suggested that overexpressing MAGEA12 led to an increase in levels of phospho-Akt, which was associated with increased cell viability, colony formation. Moreover, overexpressing MAGEA12 also resulted in the up-regulation of Cyclin D1 and CDK14, indicating MAGEA12 induces the cell proliferation of Cal-27 cells. In addition, these effects were partially reversed by inhibiting Akt. Furthermore, resveratrol could inhibit the proliferation and colony in Cal-27 cells and decrease the expressions of MAGEA12 and p-Akt depending on the time and concentration. These effects were also partially reversed by MAGEA12 overexpression and Akt activation. In summary, resveratrol may suppress the growth of OSCC cells by inactivating MAGEA12/Akt signaling. These findings suggest that resveratrol may be a therapeutic drug for OSCC in clinical.

Generation of an induced pluripotent stem cell line, FJMUUHi001-A, from a hereditary Parkinson's disease patient with homozygous mutation of c.189dupA in PARK7.

PARK7 mutations are accountable for the inherited Parkinson's disease. An induced pluripotent stem cell (iPSC) line FJMUUHi001-A was generated by expressing five reprogramming factors, OCT3/4, SOX2, c-MYC, KLF4 and BCL-XL, in peripheral blood mononuclear cells from a 32-year old patient carrying a homozygous mutation of c.189dupA in PARK7. The iPSCs with a normal karyotype had the abilities to differentiate into three germ layers and expressed pluripotency markers without detectable residual plasmids. The cell line FJMUUHi001-A carrying the truncating protein PARK7 could be a useful tool to help comprehend the function of PARK7 in the iPSCs and differentiated cells from them.