The impact of maternal anxiety during pregnancy on children's eczema and allergic rhinitis: The Ma'anshan birth cohort study.

OBJECTIVE: The objective of this study was to investigate the associations between maternal exposure to anxiety during pregnancy and the susceptibility of offspring to eczema and allergic rhinitis and the possibility of sensitivity periods and cumulative effects. METHODS: The study's sample consisted of 3160 mother-child pairs from the Ma'anshan Birth Cohort Study. Maternal anxiety was repeatedly measured in the 1st, 2nd, and 3rd trimesters of pregnancy using the Chinese version of the Pregnancy-Related Anxiety Scale. Information regarding children's eczema and allergic rhinitis diagnoses was collected through parental reports at 12, 24, 36 and 48 months of age. Binary logistic regression models were used for statistical analysis and corrected for multiple comparisons using the false discovery rate (FDR) method. RESULTS: Children whose mothers experienced anxiety throughout pregnancy had the highest odds of developing total eczema (aOR 1.45, 95% CI 1.02-2.07) and total allergic rhinitis (aOR 1.67, 95% CI 1.17-2.37) between the ages of 6 and 48 months. The higher the trajectory of the maternal anxiety scores throughout pregnancy, the higher the odds of total eczema (aOR 1.65, 95% CI 1.14-2.40) and allergic rhinitis (aOR 1.84, 95% CI 1.28-2.66) in their offspring. The association between maternal anxiety and children's eczema was mainly concentrated in the first 24 months, whereas the association with allergic rhinitis was mainly concentrated in the 36-48 months. CONCLUSION: Maternal anxiety during any trimester of pregnancy, especially with a consistently high trajectory of anxiety scores, was associated with higher odds of children's eczema and allergic rhinitis.

Association between maternal fasting glucose levels throughout pregnancy and preschoolers' refractive errors.

PURPOSE: We aimed to investigate the association between maternal fasting plasma glucose (FPG) trajectories during pregnancy and children's refractive errors at 6 years old. DESIGN: Based on the Ma'anshan Birth Cohort (MABC) in China, a total of 1987 mother-child pairs were included in this study. METHODS: Using the group-based trajectory model, trajectory fitting was performed on fasting blood glucose levels during the first, second, and third trimesters of pregnancy. Children's vision was measured at 6 years of age using the standard logarithmic visual acuity E-chart and cycloplegic refraction examination. Logistic regression models and multi-informant generalized estimating equations were used to analyze the association between maternal blood glucose level and 6-year-old children's visual acuity. RESULTS: Children born of mothers with high level FPG trajectory had a higher risk of developing refractive error [OR=1.46 (95% CI 1.08 1.97)], hypermetropia [OR=1.64 (95% CI 1.09, 2.46)] and astigmatism [OR=1.60 (95% CI 1.06, 2.41)] at age six compared to those with low level trajectory. Maternal blood glucose level in the first [ß=-0.012 (95% CI -0.024, -0.001)] and the second [ß=-0.016 (95% CI -0.025, -0.006)] trimesters was associated with 6 year children's distance vision value. CONCLUSIONS: High level of fasting plasma glucose trajectories during pregnancy has been observed to be associated with 6-year-old children's refractive error, hypermetropia and astigmatism. The first and the second trimesters may be critical periods for the effects of maternal blood glucose on children's vision. The long-term effect of maternal glucose metabolism on children's visual development deserves further study.

Sex-specific association between maternal mild anemia and children's behavioral development: a birth cohort study.

There has been limited research on maternal anemia affecting children's behavioral development, with a lack of studies focusing on sex differences in this association. Based on the Ma'anshan Birth Cohort, 2132 mother-child pairs were included. Maternal anemia was evaluated based on the hemoglobin concentration and children's behavioral development was assessed by Achenbach Child Behavior Checklist 1.5-5. Binary logistic regression models indicated that compared with children born of mothers without anemia throughout pregnancy, maternal mild anemia during pregnancy or only anemia in the 3rd trimester was associated with increased risks of aggressive behaviors in boys. Maternal mild anemia only in the 2nd trimester was associated with increased risks of attention problems in boys. In girls, maternal mild anemia during pregnancy was associated with increased risks of withdrawn, internalizing problems and total problems. Girls born of mothers with mild anemia only in the 2nd trimester had higher risks of total problems. Maternal mild anemia in both 2nd and 3rd trimesters was associated with increased risks of internalizing problems in girls. Our study identified sex-specific effects of maternal mild anemia during pregnancy on children's behavioral development problems.

Association between hyperglycemia during pregnancy and offspring's refractive error: A focused review.

This review article explores the relationship between hyperglycemia during pregnancy and the visual development of offspring, specifically focusing on refractive error. The authors conducted a comprehensive search for relevant articles in various databases and assessed the methodological quality of the included studies. The findings consistently indicate that hyperglycemia during pregnancy can have a detrimental impact on the structural and functional aspects of visual development in offspring. The intrauterine hyperglycemic environment appears to negatively affect the retina and lens, leading to refractive errors. In conclusion, there is likely an association between hyperglycemia during pregnancy and the development of refractive errors in offspring.

Hyaluronic acid/dextran-based polymeric micelles co-delivering ursolic acid and doxorubicin to mitochondria for potentiating chemotherapy in MDR cancer.

Cancer multidrug resistance (MDR) dramatically hindered the efficiency of standard chemotherapy. Mitochondria are highly involved in the occurrence and development of MDR; thus, inducing its malfunction will be an appealing strategy to treat MDR tumors. In this paper, a natural polysaccharides-based nanoplatform (TDTD@UA/HA micelles) with cell and mitochondria dual-targeting ability was facilely fabricated to co-deliver ursolic acid (UA) and doxorubicin (DOX) for combinatorial MDR therapy. TDTD@UA/HA micelles featured a spherical morphology, narrow size distribution (∼140 nm), as well as favorable drug co-loading capacity (DOX: 8.41 %, UA: 9.06 %). After hyaluronic acid (HA)-mediated endocytosis, the lysosomal hyaluronidase promoted the degradation of HA layer and then the positive triphenylphosphine groups were exposed, which significantly enhanced the mitochondria-accumulation of nano micelles. Subsequently, DOX and UA were specifically released into mitochondria under the trigger of endogenous reactive oxygen species (ROS), followed by severe mitochondrial destruction through generating ROS, exhausting mitochondrial membrane potential, and blocking energy supply, etc.; ultimately contributing to the susceptibility restoration of MCF-7/ADR cells to chemotherapeutic agents. Importantly, TDTD@UA/HA micelles performed potent anticancer efficacy without distinct toxicity on the MDR tumor-bearing nude mice model. Overall, the versatile nanomedicine represented a new therapeutic paradigm and held great promise in overcoming MDR-related cancer.

Are there bidirectional associations between maternal thyroid function and glucose metabolism in singleton live births? A birth cohort study.

(1) Aims: To examine the associations between maternal thyroid function and glucose metabolism during pregnancy. (2) Methods: This study was based on Ma' anshan Birth Cohort in China. Totally 2375 pregnant women were included in data analysis. Maternal thyroid-stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb) and fasting plasma glucose (FPG) levels during the first, second and third trimesters of pregnancy were measured retrospectively. Mplus 8.0 was used to construct a cross-lagged panel model to examine the potential bidirectional association between thyroid function and FPG levels throughout pregnancy. (3) Results: FT4 levels were positively correlated with FPG levels in the first trimester and negatively correlated with FPG levels in the second trimester. TSH levels were negatively associated with FPG levels in the second trimester, and in the first trimester, it could positively predict FPG levels in the second trimester. No significant association was found between TPOAb levels and FPG levels during pregnancy. (4) Conclusions: There was a non-bidirectional association between maternal thyroid function and glucose metabolism during pregnancy. FT4 and TSH levels influence FPG concentrations in the first and second trimesters of pregnancy.

Hemizygous splicing variant in CNKSR2 results in X-linked intellectual developmental disorder.

BACKGROUND: Intellectual disability (ID) refers to a childhood-onset neurodevelopmental disorder with a prevalence of approximately 1%-3%. METHODS: We performed whole exome sequencing for the patient with ID. And the splicing variant we found was validated by minigene assay. RESULTS: Here, we report a boy with ID caused by a variant of CNKSR2. His neurological examination revealed hypsarrhythmia via electroencephalography and a right temporal polar arachnoid cyst via brain magnetic resonance imaging. A novel splicing variant in the CNKSR2 gene (NM_014927.5, c.1657+1G>A) was discovered by exome sequencing. The variant caused a 166 bp intron retention between exons 14 and 15, which was validated by a minigene assay. The variant was not reported in public databases such as gnomAD and the Exome Aggregation Consortium. CONCLUSIONS: The variant was predicted to be damaging to correct the translation of the CNKRS2 protein and was classified as likely pathogenic according to the ACMG guidelines.

Association of gestational weight gain rate in pregnant women with children's cognitive and behavioral development: A birth cohort study.

BACKGROUND: The evidences on the relationship between gestational weight gain rate (GWGR) and children's cognitive and behavioral development have been limited. METHODS: A total of 3273 singleton live birth mother-child pairs from the Ma'anshan Birth Cohort in China were included in the study. Maternal GWGR was calculated based on the weights measured at multiple antenatal checkups. Children's cognitive and behavioral development were assessed by Chinese version of Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition and Achenbach Child Behavior Checklist 1.5-5. Then generalized linear models were performed for analyses. RESULTS: In the field of children's cognitive development, excessive GWGR in the second trimester was associated with increased visual space index (VSI), fluid reasoning index (FRI) and full scale intelligence quotient (FSIQ) scores, while excessive GWGR in the third trimester was associated with decreased VSI, working memory index (WMI) and FSIQ scores. In the field of children's behavioral development, excessive GWGR in the second trimester was associated with decreased aggressive behaviors and externalizing problems scores. LIMITATIONS: Children's behavioral development was assessed by main caregivers and might cause a certain degree of bias. There might be other potential confounders that we did not take into account. CONCLUSIONS: A high GWGR in the second trimester might be beneficial for children's cognitive and behavioral development, while a high GWGR in the third trimester might be harmful.

Thyroid function test abnormalities-isolated TPOAb+, SCH and hypothyroxinemia and preschool children's neurodevelopment.

OBJECTIVE: Thyroid function test abnormalities are frequent and associated with the offspring's adverse neurodevelopment. This study aimed to examine the relationship between maternal thyroid function test abnormalities before 20 gestational weeks and children's cognitive, emotional and behavioural development at 3-6 years of age. PATIENTS AND MEASUREMENTS: A total of 2243 mother-child pairs were included in the final analysis. Maternal thyroid function was evaluated retrospectively during the children's preschool period. The serum thyrotrophin, free thyroxine and thyroid peroxidase antibodies (TPOAb) were detected by chemiluminescence immunoassay during the follow-up period. The neurodevelopmental status of preschoolers aged 3-6 years was evaluated by parental versions of The Behavior Rating Inventory of Executive Function-Preschool and The Strengths and Difficulties Questionnaires. The associations between maternal thyroid function test abnormalities and preschoolers' neurodevelopment were examined using Poisson regression models. RESULTS: After adjusting for potential confounders in Poisson regression analyses, it showed that maternal isolated TPOAb positivity before 20 gestational weeks may be associated with the increased risk of abnormalities in peer problems (odds ratio [OR] = 1.90, 95% confidence interval [CI]: 1.26, 287). Maternal isolated SCH before 20 gestational weeks was observed to be related with increased risk of abnormalities in inhibition (OR = 2.73, 95% CI: 1.37, 5.41), working memory (OR = 1.67, 95% CI: 1.04, 2.70), conduct problems (OR = 1.80, 95% CI: 1.05, 3.09), hyperactivity (OR = 1.94, 95% CI:1.08, 3.49) and total difficulties (OR = 1.94, 95% CI: 1.13, 3.34). Maternal isolated hypothyroxinemia before 20 gestational was observed to be related with increased risk of abnormalities in peer problems (OR = 2.71, 95% CI: 1.17, 6.27). CONCLUSIONS: Thyroid function test abnormalities before 20 gestational weeks may be associated with children's neurodevelopment at 3-6 years of age.

Maternal anxiety during pregnancy and children's asthma in preschool age: The Ma'anshan birth cohort study.

BACKGROUND: The fetal immune system and consequent elevated risk of asthma in childhood may be impacted by maternal anxiety during pregnancy. Limited studies have evaluated whether there was a sensitive period and cumulative effect of the relationship between prenatal anxiety and children's asthma. METHODS: 3131 mother-child pairs made up the study's sample from the Ma'anshan Birth Cohort Study in China. Maternal anxiety status was repeated three times using the pregnancy-related anxiety questionnaire in the 1st, 2nd and 3rd trimesters of pregnancy. Diagnostic information on asthma was collected three times at 24, 36, and 48 months of age. RESULTS: After adjusting for confounders, children born to mothers with anxiety in the 1st, 2nd and 3rd trimesters of pregnancy all had an elevated risk of total asthma from 12 to 48 months of age. After further adjusting prenatal anxiety in the other trimesters, no association was observed between prenatal anxiety in any trimester and preschoolers' asthma. Children of mothers with persistently high anxiety score trajectory during pregnancy had an elevated risk of total asthma and high prevalence trajectory of asthma. Cumulative effects analysis showed that the more frequent the mother's anxiety, the higher the risk of her offspring developing a high prevalence trajectory of asthma from 12 to 48 months of age. The results of the subgroup analysis by age showed similar associations overall. CONCLUSIONS: Maternal antenatal anxiety was associated with an elevated risk of preschool children's asthma, and a possible cumulative effect was observed. Maternal mental health conditions during pregnancy should receive constant attention throughout pregnancy, not just during one period.

A Heterozygous Variant of FGF13 Caused X-Linked Developmental and Epileptic Encephalopathy 90 in a Chinese Family.

Developmental and epileptic encephalopathy (DEE) refers to a group of severe epilepsy encephalopathy and development disorders, and its typical clinical features include seizures, drug resistance, and developmental delay or regression. To date, limited studies have reported DEEs driven by FGF13. Here, we reported a girl with developmental and epileptic encephalopathy 90 caused by variant of FGF13. Her electroencephalogram (EEG) showed discontinuous hypsarrhythmia, and a heterozygous nonsynonymous variant in FGF13 [NM_004114.4: c.5C>G, p.(Ala2Gly)] was identified from the proband. The variant was not reported in public databases such as gnomAD and Exome Aggregation Consortium (ExAC), and was predicted to be damaging to proteins and classified as likely pathogenic according to the ACMG guidelines. The seizure was finally controlled by a combination of ACTH + zonisamide (10 mg/kg.d) + levetiracetam (52 mg/kg.d) + clonazepam (0.7 mg/kg.d).

Video-based evaluation system for tic action in Tourette syndrome: modeling, detection, and evaluation.

Behavioral ratings based on clinical observations are still the gold standard for screening, diagnosing, and assessing outcomes in Tourette syndrome. Detecting tic symptoms plays an important role in patient treatment and evaluation; accurate tic identification is the key to clinical diagnosis and evaluation. In this study, we proposed a tic action detection method using face video feature recognition for tic and control groups. Through facial ROI extraction, a 3D convolutional neural network was used to learn video feature representations, and multi-instance learning anomaly detection strategy was integrated to construct the tic action analysis and discrimination framework. We applied this tic recognition framework in our video dataset. The model evaluation results achieved average tic detection accuracy of 91.02%, precision of 77.07% and recall of 78.78%. And the tic score curve with postprocessing provided information of how the patient's twitches change over time. The detection results at the individual level indicated that our method can effectively detect tic actions in videos of Tourette patients without the need for fine labeling, which is significant for the long-term evaluation of patients with Tourette syndrome.

Generation of a human iPSC line (ZJSHDPi001-A) from peripheral blood mononuclear cells of a patient with Developmental epileptic encephalopathy-47 carrying FGF12 gene mutation (c.334G > A).

Developmental epileptic encephalopathy-47 (DEE47) is a nervous system disease characterized by the onset of intractable seizures that appear the first days or weeks after birth. FGF12 is the disease-causing gene of DEE47 that encodes a small cytoplasm protein, which is a member of the fibroblast growth factor homologous factor (FGF) family. The FGF12-encoded protein interacts with the cytoplasmic tail of voltage-gated sodium channels to enhance the voltage dependence of rapid inactivation of sodium channels in neurons. This study used non-insertion Sendai virus transfection to establish the induced pluripotent stem cells(iPSCs)line with FGF12 mutation. The cell line was obtained from a 3-year-old boy carrying the c.334G > A heterozygous mutation in the FGF12 gene. This iPSC line could facilitate the investigations of pathogeneses of complex nervous system diseases such as developmental epileptic encephalopathy.

Maternal pregnancy-related anxiety and children's physical growth: the Ma'anshan birth cohort study.

BACKGROUND: Epidemiological studies have identified maternal antenatal anxiety and several adverse birth outcomes, but limited studies have focused on the relationship with the long-term physical growth of children. The study aimed to assess the influence of maternal pregnancy-related anxiety on physical growth in children at different exposure periods during pregnancy. METHODS: 3,154 mother-child pairs were included based on the Ma'anshan birth cohort study. Maternal prenatal anxiety was obtained by administering a questionnaire using the pregnancy-related anxiety questionnaire (PRAQ) scale during the 1st, 2nd and 3rd trimesters of pregnancy. Body fat (BF) (48 to 72 months) and Body Mass Index (BMI) (birth to 72 months) were collected repeatedly for children. Group-based trajectory models were applied to fit the different trajectories of BMI and BF. RESULTS: Maternal anxiety in the 2nd (OR = 0.81; 95% CI: 0.68 to 0.98; P < 0.025) and 3rd (OR = 0.80; 95% CI: 0.67 to 0.97; P = 0.020) trimesters was associated with a decreased risk of rapid weight gain (RWG) in the first year of life. Children aged 48 to 72 months of mothers with anxiety in the 3rd trimester had lower BMI (ß = -0.161; 95% CI, -0.293 to -0.029; P = 0.017) and BF (ß = -0.190; 95% CI, -0.334 to -0.046; P = 0.010), and these children were less likely to develop a very high BMI trajectory (OR = 0.54; 95% CI: 0.34 to 0.84; P = 0.006), and a high BF trajectory (OR = 0.72; 95% CI: 0.53 to 0.99; P = 0.043). Similar associations were found between maternal anxiety in both 2nd and 3rd trimesters and children's physical growth. CONCLUSIONS: Offspring of mothers with prenatal anxiety in the 2nd and 3rd trimesters predicts poorer growth in infancy and preschool age. Early improvement and treatment of prenatal anxiety could benefit physical health and development in early childhood.

Non-Linear and Sex-Specific Effect of Maternal Pre-Pregnancy BMI on Emotional and Behavioral Development of Preschool Children: A Population-Based Cohort Study.

(1) Background: The aim was to examine the non-linear and sex-specific outcomes of maternal pre-pregnancy BMI on emotional and behavioral development of preschool children; (2) Methods: This study was based on the China-Anhui Birth Cohort (C-ABCS), including 3648 mother-child pairs. Maternal pre-pregnancy BMI was calculated from the maternal pre-pregnancy height and weight measured at the first antenatal checkup. Main caregivers completed the Strengths and Difficulties Questionnaire (SDQ) to assess children's preschool emotional and behavioral development. A restricted cubic spline model was drawn using Stata version 15.1 to analyze the association between maternal pre-pregnancy BMI and preschoolers' SDQ scores by sex; (3) Results: Among boys, maternal pre-pregnancy underweight was associated with the increased risk of conduct problems and pro-social behaviors, and pre-pregnancy overweight/obesity related with the increased risk of peer problems. Interestingly, when maternal pre-pregnancy BMI was between 18.50 kg/m2 and 18.67 kg/m2, boys had the increased risk of conduct problems. When pre-pregnancy BMI was between 18.50 kg/m2 and 19.57 kg/m2, boys had the increased risk of pro-social problems. No significant associations were observed; (4) Conclusions: A non-linear effect of maternal pre-pregnancy BMI on emotional and behavioral development has been found in preschool boys. In particular, pre-pregnancy normal weight may still affect boys' emotional and behavioral development.

Identification of novel rheumatoid arthritis-associated MiRNA-204-5p from plasma exosomes.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by infiltration of immune cells in the synovium. However, the crosstalk of immune cells and synovial fibroblasts is still largely unknown. Here, global miRNA screening in plasma exosomes was carried out with a custom microarray (RA patients vs. healthy controls = 9:9). A total of 14 exosomal miRNAs were abnormally expressed in the RA patients. Then, downregulated expression of exosomal miR-204-5p was confirmed in both the replication (RA patients vs. healthy controls = 30:30) and validation groups (RA patients vs. healthy controls = 56:60). Similar to the findings obtained in humans, a decreased abundance of exosomal miR-204-5p was observed in mice with collagen-induced arthritis (CIA). Furthermore, Spearman correlation analysis indicated that plasma exosomal miR-204-5p expression was inversely correlated with disease parameters of RA patients, such as rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein. In vitro, our data showed that human T lymphocytes released exosomes containing large amounts of miR-204-5p, which can be transferred into synovial fibroblasts, inhibiting cell proliferation. Overexpression of miR-204-5p in synovial fibroblasts suppressed synovial fibroblast activation by targeting genes related to cell proliferation and invasion. In vivo assays found that administration of lentiviruses expressing miR-204-5p markedly alleviated the disease progression of the mice with CIA. Collectively, this study identified a novel RA-associated plasma exosomal miRNA-204-5p that mediates the communication between immune cells and synovial fibroblasts and can be used as a potential biomarker for RA diagnosis and treatment.

A Nanosized Codelivery System Based on Intracellular Stimuli-Triggered Dual-Drug Release for Multilevel Chemotherapy Amplification in Drug-Resistant Breast Cancer.

Lacking nano-systems for precisely codelivering the chemotherapeutics paclitaxel (PTX) and the natural P-glycoprotein (P-gp) inhibitor, quercetin (QU), into cancer cells and controlling their intracellular release extremely decreased the anticancer effects in multidrug resistant (MDR) tumors. To overcome this hurdle, we constructed hybrid polymeric nanoparticles (PNPs) which consist of redox-sensitive PTX/polyethyleneimine-tocopherol hydrogen succinate-dithioglycollic acid PNPs and pH-sensitive hyaluronic acid-QU conjugates. The obtained hybrid PNPs can be internalized into drug-resistant breast cancer cells by the hyaluronic acid/CD44-mediated endocytosis pathway and escape from the lysosome through the "proton sponge effect". Under the trigger of intracellular stimuli, the nanoplatform used the pH/glutathione dual-sensitive disassembly to release QU and PTX. The PTX diffused into microtubules to induce tumor cell apoptosis, while QU promoted PTX retention by down-regulating P-gp expression. Moreover, tocopherol hydrogen succinate and QU disturbed mitochondrial functions by generating excessive reactive oxygen species, decreasing the mitochondrial membrane potential, and releasing cytochrome c into the cytosol which consequently achieved intracellular multilevel chemotherapy amplification in MDR cancers. Importantly, the PNPs substantially suppressed tumors growth with an average volume 2.54-fold lower than that of the control group in the MCF-7/ADR tumor-bearing nude mice model. These presented PNPs would provide a valuable reference for the coadministration of natural compounds and anticarcinogens for satisfactory combination therapy in MDR cancers.

Phosphorylation of transcription factor bZIP21 by MAP kinase MPK6-3 enhances banana fruit ripening.

Ripening of fleshy fruits involves both diverse post-translational modifications (PTMs) and dynamic transcriptional reprogramming, but the interconnection between PTMs, such as protein phosphorylation and transcriptional regulation, in fruit ripening remains to be deciphered. Here, we conducted a phosphoproteomic analysis during banana (Musa acuminata) ripening and identified 63 unique phosphopeptides corresponding to 49 proteins. Among them, a Musa acuminata basic leucine zipper transcription factor21 (MabZIP21) displayed elevated phosphorylation level in the ripening stage. MabZIP21 transcript and phosphorylation abundance increased during banana ripening. Genome-wide MabZIP21 DNA binding assays revealed MabZIP21-regulated functional genes contributing to banana ripening, and electrophoretic mobility shift assay, chromatin immunoprecipitation coupled with quantitative polymerase chain reaction, and dual-luciferase reporter analyses demonstrated that MabZIP21 stimulates the transcription of a subset of ripening-related genes via directly binding to their promoters. Moreover, MabZIP21 can be phosphorylated by MaMPK6-3, which plays a role in banana ripening, and T318 and S436 are important phosphorylation sites. Protein phosphorylation enhanced MabZIP21-mediated transcriptional activation ability, and transient overexpression of the phosphomimetic form of MabZIP21 accelerated banana fruit ripening. Additionally, MabZIP21 enlarges its role in transcriptional regulation by activating the transcription of both MaMPK6-3 and itself. Taken together, this study reveals an important machinery of protein phosphorylation in banana fruit ripening in which MabZIP21 is a component of the complex phosphorylation pathway linking the upstream signal mediated by MaMPK6-3 with transcriptional controlling of a subset of ripening-associated genes.

Giant axonal neuropathy (GAN) in an 8-year-old girl caused by a homozygous pathogenic splicing variant in GAN gene.

Giant axonal neuropathy (GAN) is a progressive disease that involves the peripheral and central nervous systems. This neurodegenerative disease is caused by variants in the GAN gene encoding gigaxonin, and is inherited in an autosomal recessive manner. Herein, we performed whole-exome sequencing on a 8-year-old child with dense, curly hair, weakness in both lower limbs, and abnormal MRI. The child was born to consanguineous parents. Our results revealed that the child carried the c.1373+1G>A homozygous pathogenic variant of the GAN gene, while both parents were heterozygous carriers. According to the validation at the cDNA levels, the splicing variant led to the skipping of exon 8 and affected the Kelch domain's formation. Unlike the previously reported cases of GAN, the child's clinical manifestations revealed peripheral nervous system involvement, no vertebral signs, cerebellar signs, and spasticity, but only MRI abnormalities. These results suggested that the patient's central nervous system was mildly involved, which may be related to the genotype. In order to further clarify the correlation between GAN genotype and phenotype, combined with this patient, 54 cases of reported homozygous variants of the GAN gene were merged for the analysis of genotype and phenotype. The results revealed a certain correlation between the GAN gene variant domain and the patient's clinical phenotype, such as central nervous system involvement and age of onset.

PhosSNPs-Regulated Gene Network and Pathway Significant for Rheumatoid Arthritis.

OBJECTIVES: Peripheral blood mononuclear cells (PBMCs) are critical for immunity and participate in multiple human diseases, including rheumatoid arthritis (RA). PhosSNPs are nonsynonymous SNPs influencing protein phosphorylation, thus probably modulate cell signaling and gene expression. We aimed to identify phosSNPs-regulated gene network/pathway potentially significant for RA. METHODS: We collected genome-wide phosSNP genotyping data and transcriptome-wide mRNA expression data from PBMCs of a Chinese sample. We discovered and verified with public datasets differentially expressed genes (DEGs) associated with RA, and replicated RA-associated SNPs in our study sample. We performed a targeted expression quantitative trait locus (eQTL) study on significant phosSNPs and DEGs. RESULTS: We identified 29 nominally significant eQTL phosSNPs and 83 target genes, and constructed comprehensive regulatory/interaction networks, highlighting the vital effects of two eQTL phosSNPs (rs371513 and rs4824675, FDR <0.05) and four critical node genes (HSPA4, NDUFA2, MRPL15, and ATP5O). Besides, two node/key genes NDUFA2 and ATP5O, regulated by rs371513, were significantly enriched in mitochondrial oxidative phosphorylation pathway. Besides, four pairs of eQTL effects were replicated independently in whole blood and/or transformed fibroblasts. CONCLUSIONS: The findings delineated a potential role of protein phosphorylation and genetic variations in RA and warranted the significant roles of phosSNPs in regulating RA-associated genes expression in PBMCs. The results pointed out the relevance and significance of oxidative phosphorylation pathway to RA.