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Summary: The rhizosphere microbiome is important for plant health, yet their contributions to disease resistance and assembly dynamics remain unclear. This study employed rhizosphere microbiome transplantation (RMT) to delineate the impact of the rhizosphere microbiome and the immune response of eggplant (Solanum melongena) on resistance to bacterial wilt caused by Ralstonia solanacearum. We first identified disease-suppressive and disease-conducive rhizosphere microbiome in a susceptible tomato recipient. Using a non-destructive rhizobox and 16S rRNA amplicon sequencing, we monitored the dynamics of both microbiome types during the eggplant development. Most differences were observed at the early stage and then diminished over time. The suppressive microbiome maintained a higher proportion of initial community members throughout eggplant development and exhibited stronger deterministic processes in the early stage, underscoring the importance of plant selection in recruiting protective microbes for rhizosphere immunity. Our study sheds light on the development of microbiome-based strategies for plant disease management and resistance breeding.

Abstract HLX01 (HanliKang®) is a rituximab biosimilar that showed bioequivalence to reference rituximab in untreated CD20-positive diffuse large B-cell lymphoma (DLBCL) in the phase 3 HLX01-NHL03 study. Here, we report the 5-year follow-up results from the open-label extension part. Patients were randomised to either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or HLX01 plus CHOP (H-CHOP) every 21 days for up to six cycles. The primary efficacy endpoint was overall survival (OS), and secondary efficacy endpoint was progression-free survival (PFS). Of the 407 patients enrolled in HLX01-NHL03, 316 patients (H-CHOP = 157; R-CHOP = 159) were included in the 5-year follow-up for a median duration of 65.1 (range, 2.2–76.5) months. 96.5% of the patients had an International Prognostic Index (IPI) of 1 or 2, and 17.7% had bone marrow involvement. The 5-year OS rates were 81.0% (95% CI: 74.9–87.5%) and 75.4% (95% CI: 68.9–82.6%)( HR: 0.75, 95% CI 0.47–1.20; p = 0.23) while 5-year PFS rates were 77.7% (95% CI: 71.4–84.6%) and 73.0% (95% CI: 66.3–80.3%) (HR: 0.84, 95% CI 0.54–1.30; p = 0.43) in the H-CHOP and R-CHOP groups, respectively. Treatment outcomes did not differ between groups regardless of IPI score and were consistent with the primary analysis. H-CHOP and R-CHOP provided no significant difference in 5-year OS or PFS in previously untreated patients with low or low-intermediate risk DLBCL.

Objective: To analyze the immune parameters of cerebrospinal fluid (CSF) and oligoclonal band (OCB) type in patients with anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated diseases (MOGAD). Methods: Patients who were seropositive for MOG-IgG and diagnosed with MOGAD according to the diagnosis criteria in the Department of Neurology, Huashan Hospital, Fudan University from December 2020 to June 2022 were retrospectively included in this study. Complete clinical data, blood and cerebrospinal fluid samples were collected from all the participants. Paired serum and CSF MOG-IgG and autoimmune encephalitis antibody were assayed by Cell Based Assay (CBA) based on transfected target antigens. Paired serum and CSF albumin and IgG were detected by turbidimetric scattering method, and OCB was detected by standard operation procedure as described. Results: A total of 86 patients (44 males and 42 females) with MOGAD were included in this study, with a median age of 30 years (range: 5–82 years). Among all the patients, 73 patients showed OCB type I, 12 patients showed OCB type II, and one patient showed OCB type III. The overall positive rate of CSF-OCB in MOGAD patients was 15.1 %. The 24-h intrathecal synthesis rate of CSF in the OCB-positive group (n = 13) was higher than that in the OCB-negative group [n = 73, 0.62 (0.26) vs 5.11 (13.67), P = 0.003]. Subgroup analysis revealed that the positive rates of CSF-OCB in the single MOG group (n = 61) and the group combined with other antibodies (n = 25) were 14.8 % and 16.0 %, respectively. The incidence of meningoencephalitis (13/61 vs 13/25, P = 0.011) was significantly different between the two groups. The proportion of patients with high (≥1:32) or low (≤1:10) CSF MOG-IgG also showed significant difference in the group combined with other antibodies (P = 0.032). Optic neuritis was more common in the relapse course group (n = 49) than the monophasic course group (n = 37, P

Background: The determination of serum anti-pertussis toxin (PT) IgG antibodies is recommended for the diagnosis and surveillance of pertussis. However, the diagnostic power of anti-PT IgG can be hampered by possible interference from previous vaccinations. We aim to assess if anti-PT IgA antibodies can be well induced by Bordetella pertussis (B. pertussis) infections in children, and their capacity to improve pertussis serodiagnosis. Methods: Serum samples from 172 hospitalized children younger than 10 years old with confirmed pertussis were tested. Pertussis was confirmed by culture, PCR and/or serology. Anti-PT IgA antibodies were determined with commercial ELISA kits. Results: Sixty-four (37.2 %) subjects had anti-PT IgA antibodies greater than or equal to 15 IU/ml, and 52 (30.2 %) of them had anti-PT IgA antibodies greater than or equal to 20 IU/ml. No children with negative anti-PT IgG (less than 40 IU/ml) were observed to have anti-PT IgA antibodies greater than or equal to 15 IU/ml. Of patients younger than one year of age, about 50 % had an IgA antibody response. Moreover, the proportion of subjects with anti-PT IgA antibodies greater than or equal to 15 IU/ml among PCR negative subjects was significantly higher than that among PCR positive subjects (76.9 % vs 35.5 %). Conclusions: The determination of anti-PT IgA antibodies does not seem to have added value for the serodiagnosis of pertussis in children older than one year of age. However, for infants, determination of serum anti-PT IgA antibodies appears to be useful for the diagnosis of pertussis especially when PCR and culture are negative. The results should be interpreted with caution as the number of subjects included in this study was limited.

Abstract Background As the rate of multiple pregnancies increases, delayed interval delivery (DID) is increasingly being implemented to improve perinatal outcomes. But there are no international guidelines for DID in multiple pregnancies. We report a case of DID in a quadruplet pregnancy and review the relevant literature to summarize the management of DID in multiple pregnancies. Case presentation A 22-year-old woman, 22 2/7 weeks' gestation, with quadruplets, was admitted to the hospital for a first cervical cerclage due to cervical dilation. Twenty-five days later, it was found that the cervix was dilated again, so after removing the cervical cerclage, the first quadruplet was delivered vaginally (25 6/7 weeks), and a second cervical cerclage was performed. Four days later, due to re-dilation of the cervix, after removal of the cervical cerclage, the second quadruplet was delivered vaginally (26 3/7 weeks), followed by a third cervical cerclage. Six days later, the pregnancy was terminated by cesarean section due to fetal distress, and the third and fourth quadruplets were delivered (27 2/7 weeks). The patient had no postoperative complications, and all four infants were treated in the neonatal intensive care unit and discharged successfully. Conclusion This case emphasizes that comprehensive management of delayed interval delivery can improve perinatal outcomes in multiple pregnancies, including anti-infection, tocolytic therapy, practice to promote fetal lung, and cervical cerclage.

BackgroundCerebrospinal fluid oligoclonal band (CSF-OCB) is an established biomarker in diagnosing multiple sclerosis (MS), however, there are no nationwide data on CSF-OCB prevalence and its diagnostic performance in Chinese MS patients, especially in the virtue of common standard operation procedure (SOP).MethodsWith a consensus SOP and the same isoelectric focusing system, we conducted a nationwide multi-center study on OCB status in consecutively, and recruited 483 MS patients and 880 non-MS patients, including neuro-inflammatory diseases (NID, n = 595) and non-inflammatory neurological diseases (NIND, n=285). Using a standardized case report form (CRF) to collect the clinical, radiological, immunological, and CSF data, we explored the association of CSF-OCB positivity with patient characters and the diagnostic performance of CSF-OCB in Chinese MS patients. Prospective source data collection, and retrospective data acquisition and statistical data analysis were used.Findings369 (76.4%) MS patients were OCB-positive, while 109 NID patients (18.3%) and 6 NIND patients (2.1%) were OCB-positive, respectively. Time from symptom onset to diagnosis was significantly shorter in OCB-positive than that in OCB-negative MS patients (13.2 vs 23.7 months, P=0.020). The prevalence of CSF-OCB in Chinese MS patients was significantly higher in high-latitude regions (41°-50°N)(P=0.016), and at high altitudes (>1000m)(P=0.025). The diagnostic performance of CSF-OCB differentiating MS from non-MS patients yielded a sensitivity of 76%, a specificity of 87%.InterpretationThe nationwide prevalence of CSF-OCB was 76.4% in Chinese MS patients, and demonstrated a good diagnostic performance in differentiating MS from other CNS diseases. The CSF-OCB prevalence showed a correlation with high latitude and altitude in Chinese MS patients.

Abstract Background The prognostic value of preoperative systemic inflammatory markers, including the neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and lymphocyte‐to‐monocyte ratio (LMR), remains controversial in patients with intrahepatic cholangiocarcinoma (ICC). Therefore, this meta‐analysis aimed to investigate the prognostic value of preoperative NLR, PLR, and LMR in patients with ICC who underwent hepatic resection. Methods We conducted a comprehensive search of four electronic databases. Two researchers assessed the quality of the available data using the Newcastle–Ottawa Scale. We selected overall survival (OS) as the primary outcome and recurrence‐free survival (RFS) and disease‐free survival (DFS) as secondary outcomes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were merged to evaluate the associations between inflammatory markers and ICC patient prognosis. Results Fifteen studies (18 cohorts) with 4123 cases were included in this meta‐analysis. The results revealed that a high preoperative NLR was associated with short OS and RFS (HR = 1.04, 95% CI: 1.01–1.07, and HR = 1.29, 95% CI: 1.04–1.60, respectively) in patients with ICC. However, the association between PLR or LMR and ICC prognosis was not statistically significant. In addition, the publication bias and sensitivity analyses demonstrated that the results were reliable and stable. Conclusion Our meta‐analysis revealed that preoperative NLR may be a useful prognostic predictor for patients with ICC.

The rapid and sensitive detection of pepsin plays an important role in clinical and medical practice. A label-free and sensitive micro-tapered long-period fiber grating (MTLPFG) sensor that functionalized by graphene oxide (GO) was proposed for pepsin detection. MTLPFG was fabricated with CO2 laser heating and tapered to form a series of periods, and the GO that activated oxygen groups by EDC/NHS was deposited onto MTLPFG surface. On account of large specific surface area and oxygen containing groups of GO, the biomolecules can be adsorbed on the GO surface through amide groups and π-π stacking. The spectrum variation trend during sensing process obeys Langmuir absorption mode, which illustrates biomolecule adsorption on GO layer. The bare MTLPFG and GO-MTLPFG separately demonstrate the limit of detection (LOD) of 104.6 ng/ml and 25.79 ng/ml, which corresponding to the effectively detection range of 1–1000 ng/ml. Combination of GO and optical fibers exhibit great adaptive capacity to the biosensors, and provides inspirations for biochemical sensing applications.

Heterozygous variants in the glucocerebrosidase (GBA) gene are common and potent risk factors for Parkinson's disease (PD). GBA also causes the autosomal recessive lysosomal storage disorder (LSD), Gaucher disease, and emerging evidence from human genetics implicates many other LSD genes in PD susceptibility. We have systemically tested 86 conserved fly homologs of 37 human LSD genes for requirements in the aging adult Drosophila brain and for potential genetic interactions with neurodegeneration caused by α-synuclein (αSyn), which forms Lewy body pathology in PD. Our screen identifies 15 genetic enhancers of αSyn-induced progressive locomotor dysfunction, including knockdown of fly homologs of GBA and other LSD genes with independent support as PD susceptibility factors from human genetics (SCARB2, SMPD1, CTSD, GNPTAB, SLC17A5). For several genes, results from multiple alleles suggest dose-sensitivity and context-dependent pleiotropy in the presence or absence of αSyn. Homologs of two genes causing cholesterol storage disorders, Npc1a / NPC1 and Lip4 / LIPA, were independently confirmed as loss-of-function enhancers of αSyn-induced retinal degeneration. The enzymes encoded by several modifier genes are upregulated in αSyn transgenic flies, based on unbiased proteomics, revealing a possible, albeit ineffective, compensatory response. Overall, our results reinforce the important role of lysosomal genes in brain health and PD pathogenesis, and implicate several metabolic pathways, including cholesterol homeostasis, in αSyn-mediated neurotoxicity.

As plant-specific transcription factors, the TIFY family genes are involved in the responses to a series of biotic and abiotic stresses and the regulation of the development of multiple organs. To explore the potential roles of the TIFY gene family in shoot branching, which can shape plant architecture and finally determine seed yield, we conducted comprehensive genome-wide analyses of the TIFY gene family in Brassica napus. Here, HMMER search and BLASTp were used to identify the TIFY members. A total of 70 TIFY members were identified and divided into four subfamilies based on the conserved domains and motifs. These TIFY genes were distributed across 19 chromosomes. The predicted subcellular localizations revealed that most TIFY proteins were located in the nucleus. The tissue expression profile analyses indicated that TIFY genes were highly expressed in the stem, flower bud, and silique at the transcriptional level. High-proportioned activation of the dormant axillary buds on stems determined the branch numbers of rapeseed plants. Here, transcriptome analyses were conducted on axillary buds in four sequential developing stages, that is, dormant, temporarily dormant, being activated, and elongating (already activated). Surprisingly, the transcription of the majority of TIFY genes (65 of the 70) significantly decreased on the activation of buds. GO enrichment analysis and hormone treatments indicated that the transcription of TIFY family genes can be strongly induced by jasmonic acid, implying that the TIFY family genes may be involved in the regulation of jasmonic acid-mediated branch development. These results shed light on the roles of TIFY family genes in plant architecture.

Propylea japonica (Thunberg) (Coleoptera: Coccinellidae) is a dominant natural enemy of insect pests in farmland ecosystems. It also serves as an important non-target insect for environmental safety evaluations of transgenic crops. Widespread planting of transgenic crops may result in direct or indirect exposure of P. japonica to recombinant Bacillus thuringiensis (Bt) protein, which may in turn affect the biological performance of this natural enemy by affecting the P. japonica microflora. However, the effects of Bt proteins (such as Cry1B) on the P. japonica microbiota are currently unclear. Here, we used a high-throughput sequencing method to investigate differences in the P. japonica microbiota resulting from treatment with Cry1B compared to a sucrose control. The results demonstrated that the P. japonica microbiome was dominated by Firmicutes at the phylum level and by Staphylococcus at the genus level. Within-sample (α) diversity indices demonstrated a high degree of consistency between the microbial communities of P. japonica treated with the sucrose control and those treated with 0.25 or 0.5 mg/mL Cry1B. Furthermore, there were no significant differences in the abundance of any taxa after treatment with 0.25 mg/mL Cry1B for 24 or 48 h, and treatment with 0.5 mg/mL Cry1B for 24 or 48 h led to changes only in Staphylococcus, a member of the phylum Firmicutes. Treatment with a high Cry1B concentration (1.0 mg/mL) for 24 or 48 h caused significant changes in the abundance of specific taxa (e.g., Gemmatimonades, Patescibacteria, Thauera, and Microbacterium). However, compared with the control, most taxa remained unchanged. The statistically significant differences may have been due to the stimulatory effects of treatment with a high concentration of Cry1B. Overall, the results showed that Cry1B protein could alter endophytic bacterial community abundance, but not composition, in P. japonica. The effects of Bt proteins on endophytes and other parameters in non-target insects require further study. This study provides data support for the safety evaluation of transgenic plants.

In recent years, aiming to uncover the neural mechanism of parent-child interaction and link it to the children’s social development, a newly developed index, namely, parent-child inter-brain neural synchronization (INS) has attracted growing interest. Existing studies have mainly focused on three aspects of the INS; these are the specificity of the INS (i.e., stronger INS for parent-child dyads than stranger-child dyads), the situational modulations of the INS (i.e., how the valence of the situation or the types of interaction modulate INS), and the associations between the INS and the state-like behavioral tendencies or trait-like individual features of the parents and children. This review summarizes the existing findings in line with these three topics and provides preliminary suggestions to promote parent-child INS. In the meanwhile, the inconsistent findings and unstudied questions were discussed, opening new avenues for future studies.

The lady beetle Propylea japonica is a dominant natural predator of insect pests in farmland ecosystems and an important non-target indicator insect for the environmental safety assessment of GM crops. The commercial cultivation of GM crops may cause P. japonica to frequently be exposed to the Bt protein environment. In this study, the biological characteristics, enzyme activity, and expression levels of detoxification and metabolism in P. japonica were studied after Cry1B protein treatment. No significant differences were observed in developmental duration, emergence rate, or body weight at different ages after feeding larvae 0.5 mg/mL of Cry1B protein compared with the control. Furthermore, there were no significant differences in the activities of glutathione S-transferase (GST), catalase (CAT), and peroxidase (POD) after feeding 0.25 mg/mL and 0.5 mg/mL Cry1B protein. However, when the concentration of Cry1B protein increased to 1.0 mg/mL, the activities of the GST, CAT, and POD increased significantly. Compared with the control group, there were no significant differences in the expression levels of most detoxification metabolism related genes; only a few genes had changed expression levels at the individual concentrations (CYP345B1, CYP4Q2, CYP9F2, GST, and microsomal GST). Overall, these results suggest that Cry1B protein has little or no effect on the biological characteristics of P. japonica. Genes related to enzyme activity and detoxification are differentially expressed at high concentration stimulation. Therefore, this research suggests that the potential risks of Cry1B for the predator P. japonica are negligible.

Abstract To reduce the uncertainty of cloud feedback, models should prioritize the evaluation of cloud response to surface warming. Using International Satellite Cloud Climatology Project‐H data sets, we quantified the cloud fraction response of different cloud types to surface warming in the Tibetan Plateau (TP) and examined the performance of Coupled Model Intercomparison Project Phase 6 models in reproducing cloud response. Results showed multimodel ensemble mean (MEM) exhibited a similar pattern of total cloud fraction response with the observation but severely underestimated it over the western TP. MEM also obviously underestimated cloud fraction of optically thin cirrus (bias >15%) and had a wrong trend of −0.02% 10a−1 against observed +2.44% 10a−1. Moreover, models failed to reproduce extensive negative response of optically thick clouds and exhibited significant underestimation for the negative response of optically thick but lower‐top clouds. Especially, models even simulated an opposite response with International Satellite Cloud Climatology Project for optically thin but lower‐top cloud (bias hit −0.4% K−1).

Maturity-onset diabetes of the young (MODY) is rare monogenic diabetes. However, MODY is often undiagnosed or misdiagnosed. In this study, we aimed to investigate the pathogenic gene for diabetes and provide precise treatment for diabetes patients in three families. Three families with suspected MODY were enrolled and screened for germline mutations using Whole exome sequencing (WES). Candidate pathogenic variants were validated in other family members and non-related healthy controls. Three heterozygous missense mutations in the ABCC8 gene (NM_001287174), c.1555 C>T (p.R519C), c.3706 A>G (p.I1236V), and c.2885 C>T (p.S962L) were found in families A, B, and C, respectively. All mutation sites cosegregated with diabetes, were predicted to be harmful by bioinformatics and were not found in non-related healthy controls. Two probands (onset ages, 8 and 12 years) were sensitive to glimepiride. However, an insufficient dose (2 mg/day) led to ketoacidosis. When the dosage of glimepiride was increased to 4 mg/day, blood sugar remained under control. A dose of 4 mg glimepiride daily also effectively controlled blood sugar in an adult patient 25-year-old. In addition, all patients were sensitive to liraglutide, which could control blood sugar better. These data suggest that ABCC8 was the pathogenic gene in three families with diabetes. Glimepiride (2 mg/day) was not effective in controlling blood sugar in children with ABCC8 mutations, however, 4 mg/daily glimepiride was effective in both adults and children. Moreover, liraglutide was effective in controlling blood sugar in both adults and children with ABCC8 mutations.

Antibodies against SARS-CoV-2 S protein can provide a treatment strategy for COVID-19. Here, Guo et al. provide the crystal structure of a SARS-CoV2 neutralizing antibody isolated from a convalescent patient and highlight the therapeutic efficacy in a rhesus monkey model of an engineered version with optimized pharmacokinetic and safety profile.

Abstract Background The global prevalent ptxP3 strains varies from about 10% to about 50% of circulating B. pertussis population in different areas of China. Methods To investigate the difference of vaccination status between different genotypes in the circulating B. pertussis after 10 years of acellular pertussis vaccine (aPV) used in China. The nasopharyngeal swabs and isolates of B. pertussis from these patients were used to perform genotyping of antigen genes. We use antibiotic susceptibility test against erythromycin and sequencing methods for site 2047 of 23S rRNA to determine the resistance status. Results The ptxP1 allele with erythromycin resistant (ER) B. pertussis infection (total of 449 subjects) consisted of 84.70 to 96.70% from 2012 to 2016 in this study. Vaccinated with co-purified aPV was found in 133(133/403,33.0%), 1(1/9,11.1%) and 2(2/21,9.5%) in ptxP1/fhaB3-ER, ptxP1/fhaB2-ES and ptxP3/fhaB2-ES B. pertussis infected children each, which showed a significant difference (χ2 = 6.87, P = 0.032). Conclusions The ptxP3-ES B. pertussis was rare while the ptxP1-ER B. pertussis was steadily increased in Xi’an, China from 2012 to 2016, where co-purified aPV was prevalent used. This pose a hypothesis that the co-purified aPV might protect against ptxP3 strains more efficient, which generated a rare chance for ptxP3 strains to be under the antibiotic pressure and further developed to be erythromycin resistance. A further cohort study and the mechanisms of the additional antigen proteins of co-purified aPV protected against B. pertussis should be consideration.

Camellia oil is an edible health oil with high medicinal value. While phospholipids, peroxides, and free fatty acids are present in unrefined camellia virgin oil (CVO), which has a negative impact on the quality characteristics and storage stability. This paper is to investigate the testing effects of transmembrane pressure and temperature on the membrane flux and degumming (the removal of colloidal substances from crude oil and which is mainly phospholipids) to determine the optimum process parameters for the purification of CVO. On this basis, the effects of purification treatments applied by using a membrane system with membranes of different pore sizes (200, 140, 20, 15, and 10 nm) on CVO were tested. The results indicate that the purification treatments of ceramic membrane on CVO reduced the contents of phospholipids (87.0% reduction), peroxides (29.2% reduction), and free fatty acids (16.2% reduction) at a transmembrane pressure of 0.4 MPa and temperature of 60 °C. At the same time, these treatments did not significantly alter the fatty acid composition. Thus, ceramic membranes have the potential for the purification of camellia oil, which could be an effective way to achieve the purification of camellia oil.

BackgroundStudies investigating the correlation between the expression of programmed cell death-ligand 1 (PD-L1) and prognosis in patients with esophageal squamous cell carcinoma (ESCC) not receiving preoperative therapy have increased significantly, but conclusions remain inconclusive. Therefore, this study aimed to determine the association between clinical outcomes and expression of PD-L1 in ESCC patients without preoperative therapy.MethodsWe conducted a comprehensive literature search using four databases up to May 2020. Quality assessment was carried out according to the Newcastle–Ottawa Quality Assessment Scale (NOS). Hazard ratios (HRs) were used to analyze the association between PD-L1 expression with prognosis. Furthermore, we evaluated the correlation between PD-L1 and clinicopathological characteristics using odds ratios (ORs) and 95% confidence intervals (CIs).ResultsTwenty studies (19 publications) comprising 3,677 patients were included in this meta-analysis. We found that the expression of PD-L1 was not related to overall survival (OS, HR: 1.16, 95% CI: 0.94–1.42, p = 0.16) or disease-free survival (DFS, HR: 0.85, 95% CI: 0.66–1.10, p = 0.21) in ESCC. Furthermore, although PD-L1 expression was not significantly associated with sex, degree of differentiation, TNM stage, T stage, lymph node status, smoking, or alcohol use, the merged OR demonstrated that the expression of PD-L1 was higher in older patients compared to younger patients (OR: 1.40, 95% CI: 1.07–1.83, p = 0.01). No obvious publication bias was observed.ConclusionsOur present study illustrated that PD-L1 expression was not related to poor prognosis of ESCC patients not receiving preoperative therapy, albeit the association only showed a tendency for statistical significance. Notably, PD−L1 expression showed a significant association with age. This meta-analysis had several limitations; therefore, our results need to be verified through further large-scale and prospective studies.

ABSTRACTMacrolides such as erythromycin are the empirical treatment of Bordetella pertussis infections. China has experienced an increase in erythromycin-resistant B. pertussis isolates since they were first reported in 2013. Here, we undertook a genomic study on Chinese B. pertussis isolates from 2012 to 2015 to elucidate the origins and phylogenetic relationships of erythromycin-resistant B. pertussis isolates in China. A total of 167 Chinese B. pertussis isolates were used for antibiotic sensitivity testing and multiple locus variable-number tandem repeat (VNTR) analysis (MLVA). All except four isolates were erythromycin-resistant and of the four erythromycin-sensitive isolates, three were non-ptxP1. MLVA types (MT), MT55, MT104 and MT195 were the predominant types. Fifty of those isolates were used for whole genome sequencing and phylogenetic analysis. Genome sequencing and phylogenetic analysis revealed three independent erythromycin-resistant lineages and all resistant isolates carried a mutation in the 23S rRNA gene. A novel fhaB3 allele was found uniquely in Chinese ptxP1 isolates and these Chinese ptxP1-ptxA1-fhaB3 had a 5-fold higher mutation rate than the global ptxP1-ptxA1 B. pertussis population. Our results suggest that the evolution of Chinese B. pertussis is likely to be driven by selection pressure from both vaccination and antibiotics. The emergence of the new non-vaccine fhaB3 allele in Chinese B. pertussis population may be a result of selection from vaccination, whereas the expansion of ptxP1-fhaB3 lineages was most likely to be the result of selection pressure from antibiotics. Further monitoring of B. pertussis in China is required to better understand the evolution of the pathogen.

Lynch syndrome (LS) is an inherited autosomal dominant disorder caused by germline mutations of mismatch repair (MMR) genes, including MSH2, MSH6, PMS2, and MLH1. This study aimed to analyze the molecular defects and clinical manifestations of an affected family and propose appropriate individual prevention strategies for all mutation carriers. A novel splicing mutation (c.1661+2 T>G) was identified in the MSH2 gene, which was found to co-segregate among affected family members by Whole exome sequencing (WES). RT-PCR analysis confirmed that c.1661+2 T>G could produce 3 transcripts, including 1 normal transcript and 2 aberrant transcripts. The 2 aberrant transcripts resulted in premature termination at the 6th nucleotide codon of MSH2 exon 11, so that the predicted products of the mutant MSH2 mRNAs were truncated proteins of 505 amino acids (with all of exon 10 deleted) and 528 amino acids (with a deletion of 82-nucleotides in exon 10), resulting in the loss of the interaction domain, the ATP domain and post-translationally modified residues. Quantitative RT-PCR (qRT-PCR) analysis showed that MSH2 mRNA levels in all patients were reduced to only 1/4 of the control levels. Our study reveals that a novel splicing mutation (c.1661+2 T>G) in the MSH2 gene causes LS and reaffirms the importance of genetic testing for LS.

Retromer, including Vps35, Vps26, and Vps29, is a protein complex responsible for recycling proteins within the endolysosomal pathway. Although implicated in both Parkinson’s and Alzheimer’s disease, our understanding of retromer function in the adult brain remains limited, in part because Vps35 and Vps26 are essential for development. In Drosophila, we find that Vps29 is dispensable for embryogenesis but required for retromer function in aging adults, including for synaptic transmission, survival, and locomotion. Unexpectedly, in Vps29 mutants, Vps35 and Vps26 proteins are normally expressed and associated, but retromer is mislocalized from neuropil to soma with the Rab7 GTPase. Further, Vps29 phenotypes are suppressed by reducing Rab7 or overexpressing the GTPase activating protein, TBC1D5. With aging, retromer insufficiency triggers progressive endolysosomal dysfunction, with ultrastructural evidence of impaired substrate clearance and lysosomal stress. Our results reveal the role of Vps29 in retromer localization and function, highlighting requirements for brain homeostasis in aging.

There could be an overlap of monogenic diabetes and early-onset type 2 diabetes mellitus. Precise diagnosis of early-onset diabetes has proven valuable for understanding the mechanism of diabetes and selecting optimal therapy. The majority of maturity onset diabetes of the young (MODY) pathogenic genes in China is still unknown. In this study, a family with suspected MODY was enrolled. Whole-exome sequencing (WES) was used to analyze the variants of the proband. Variants were filtered according to their frequency, location, functional consequences, and bioinformatics software. Candidate pathogenic variants were validated by Sanger sequencing and tested for cosegregation in other members of the family and nonrelated healthy controls. KEGG (Kyoto Encyclopedia of Genes and Genomes) and PPI (protein-protein interaction) analysis were conducted using the DAVID (Database for Annotation, Visualization, and Integrated Discovery) and the STRING online analysis tools for the candidate pathogenic gene. A total of 123291 variants including 105344 SNPs and 17947 InDels were found in WES. A likely pathogenic rare missense heterozygous mutation in diabetes genes (c.2137C > T, p.His713Tyr in IRS1) was identified, which was a cosegregate in this family and not in nonrelated healthy controls. The position of the mutation in the aminoacid sequence of the gene is highly conserved among the species. 2 significantly enriched KEGG pathways were identified including bta04930, type II diabetes mellitus (GCK, INS, PDX1, ABCC8, and IRS1), and bta04910, insulin signaling pathway (GCK, INS, and IRS1). PPI analysis displayed that IRS1 interacts with 3 known pathogenic proteins including INS, KCNJ11, and GCK. We conclude that WES could be an initial option for genetic testing in patients with early-onset diabetes. IRS1 p.His713Tyr is implicated as a possible pathogenic mutation in monogenic diabetes, which might require further validation, and the precise molecular mechanism underlying the influence of IRS1 p.His713Tyr on the development of diabetes remains to be determined in the further prospective studies.

Summary: In Alzheimer’s disease (AD), spliceosomal proteins with critical roles in RNA processing aberrantly aggregate and mislocalize to Tau neurofibrillary tangles. We test the hypothesis that Tau-spliceosome interactions disrupt pre-mRNA splicing in AD. In human postmortem brain with AD pathology, Tau coimmunoprecipitates with spliceosomal components. In Drosophila, pan-neuronal Tau expression triggers reductions in multiple core and U1-specific spliceosomal proteins, and genetic disruption of these factors, including SmB, U1-70K, and U1A, enhances Tau-mediated neurodegeneration. We further show that loss of function in SmB, encoding a core spliceosomal protein, causes decreased survival, progressive locomotor impairment, and neuronal loss, independent of Tau toxicity. Lastly, RNA sequencing reveals a similar profile of mRNA splicing errors in SmB mutant and Tau transgenic flies, including intron retention and non-annotated cryptic splice junctions. In human brains, we confirm cryptic splicing errors in association with neurofibrillary tangle burden. Our results implicate spliceosome disruption and the resulting transcriptome perturbation in Tau-mediated neurodegeneration in AD. : Integrating studies of human postmortem brain tissue and Drosophila melanogaster models, Hsieh et al. show that Alzheimer’s disease Tau neurofibrillary tangle pathology disrupts spliceosome activity. RNA-splicing errors, including intron retention and non-annotated cryptic junctions, and resulting transcriptome perturbation are implicated in Tau-mediated neurodegenerative mechanisms. Keywords: Alzheimer’s disease, neurodegeneration, Tau, neurofibrillary tangles, spliceosome, RNA splicing, cryptic splicing, intron retention, SmB, U1-70K

Summary: The Alzheimer’s disease (AD) susceptibility gene, CD2-associated protein (CD2AP), encodes an actin binding adaptor protein, but its function in the nervous system is largely unknown. Loss of the Drosophila ortholog cindr enhances neurotoxicity of human Tau, which forms neurofibrillary tangle pathology in AD. We show that Cindr is expressed in neurons and present at synaptic terminals. cindr mutants show impairments in synapse maturation and both synaptic vesicle recycling and release. Cindr associates and genetically interacts with 14-3-3ζ, regulates the ubiquitin-proteasome system, and affects turnover of Synapsin and the plasma membrane calcium ATPase (PMCA). Loss of cindr elevates PMCA levels and reduces cytosolic calcium. Studies of Cd2ap null mice support a conserved role in synaptic proteostasis, and CD2AP protein levels are inversely related to Synapsin abundance in human postmortem brains. Our results reveal CD2AP neuronal requirements with relevance to AD susceptibility, including for proteostasis, calcium handling, and synaptic structure and function. : CD2AP is an Alzheimer’s disease susceptibility gene with uncertain brain function. Ojelade et al. discover that mutation of the Drosophila homolog cindr disrupts ubiquitin-proteasome system activity, causing calcium dyshomeostasis and impaired synaptic vesicle recycling and release. Cd2ap null mice and human brain proteomic studies support a conserved role in synaptic proteostasis. Keywords: PMCA, synapsin, ubiquitin-proteasome system, 14-3-3, GWAS, neurofibrillary tangles, Tau, endocytosis, exocytosis, neuromascular junction

Current passive sensors fail to accurately identify cloud phase, thus largely limiting the quantification of radiative contributions and precipitation of different cloud phases over the Tibet Plateau (TP), especially for the mixed-phase and supercooled water clouds. By combining the 4 years of (January 2007–December 2010) cloud phase (2B-CLDCLASS-LIDAR), radiative fluxes (2B-FLXHR-LIDAR), and precipitation (2C-PRECIP-COLUMN) products from CloudSat, this study systematically quantifies the radiative contribution of cloud phases and precipitation over the TP. Statistical results indicate that the ice cloud frequently occurs during the cold season, while mixed-phase cloud fraction is more frequent during the warm season. In addition, liquid clouds exhibit a weak seasonal variation, and the relative cloud fraction is very low, but supercooled water cloud has a larger cloud distribution (the value reaches about 0.24) than those of warm water clouds in the eastern part of the TP during the warm season. Within the atmosphere, the ice cloud has the largest radiative contribution during the cold season, the mixed-phase cloud is the second most important cloud phase for the cloud radiative contribution during the warm season, and supercooled water clouds’ contribution is particularly important during the cold season. In particular, the precipitation frequency over the TP is mainly dominated by the ice and mixed-phase clouds and is larger over the southeastern part of the TP during the warm season.

Using the space-borne lidar/radar observations, this study identifies deep convection systems (DCS), including deep convection core (DCC) and anvils, over Tibetan Plateau (TP) and tropical oceans (TO), and finds that DCSs over TP are less frequent, exhibiting narrower and thinner DCCs and anvils compared to those over TO. The thinner DCCs over TP exert weaker radiative cooling effects at the top of atmosphere (TOA) compared to the TO. But, the shortwave TOA cloud radiative effect (CRE) of TP anvils is stronger than that of the TO possibly due to more densely packed cloud tops over TP. It results in stronger TOA CRE of DCSs over TP than that of TO. Especially, longwave CRE of DCSs over TP is notable greater at surface and low-level atmosphere due to the distinct lower temperature and less water vapor. The width of DCSs shows a positive correlation with wind shear and atmospheric instability, and the underlying mechanisms are discussed. We also find that the impact of aerosols on cloud top heights and precipitation displays significant discrepancies between the two regions. It is because that the aerosol invigoration effect is less efficient on the TP DCSs, mainly attributed to the significantly colder cloud base. Due to competition between invigoration and radiative effects of aerosols, the correlation between precipitation and aerosols over TP is not significant. However, precipitation in the TO experiences invigoration followed by suppression with increasing aerosols, due to the dominance of aerosol radiative effect and enhancement entrainment under polluted conditions. [ABSTRACT FROM AUTHOR]