Fast-Response Micro-Phototransistor Based on MoS2/Organic Molecule Heterojunction.

Over the past years, molybdenum disulfide (MoS2) has been the most extensively studied two-dimensional (2D) semiconductormaterial. With unique electrical and optical properties, 2DMoS2 is considered to be a promising candidate for future nanoscale electronic and optoelectronic devices. However, charge trapping leads to a persistent photoconductance (PPC), hindering its use for optoelectronic applications. To overcome these drawbacks and improve the optoelectronic performance, organic semiconductors (OSCs) are selected to passivate surface defects, tune the optical characteristics, and modify the doping polarity of 2D MoS2. Here, we demonstrate a fast photoresponse in multilayer (ML) MoS2 by addressing a heterojunction interface with vanadylphthalocyanine (VOPc) molecules. The MoS2/VOPc van der Waals interaction that has been established encourages the PPC effect in MoS2 by rapidly segregating photo-generated holes, which move away from the traps of MoS2 toward the VOPc molecules. The MoS2/VOPc phototransistor exhibits a fast photo response of less than 15 ms for decay and rise, which is enhanced by 3ordersof magnitude in comparison to that of a pristine MoS2-based phototransistor (seconds to tens of seconds). This work offers a means to realize high-performance transition metal dichalcogenide (TMD)-based photodetection with a fast response speed.

Population genomic analysis reveals distinct demographics and recent adaptation in the black flying fox (Pteropus alecto).

As the only mammalian group capable of powered flight, bats have many unique biological traits. Previous comparative genomic studies in bats have focused on long-term evolution, the micro-evolutionary processes driving recent evolution are largely under-explored. Using resequencing data from 50 black flying foxes (Pteropus alecto), one of the model species for bats, we find that black flying fox has much higher genetic diversity and lower levels of linkage disequilibrium than most of the mammalian species. Demographic inference reveals strong population fluctuations (>100 fold) coinciding with multiple historical events including last glacial change and Toba super eruption, suggesting that the black flying fox is a very resilient species with strong recovery abilities. While long-term adaptation in the black flying fox is enriched in metabolic genes, recent adaptation in the black flying fox has a unique landscape where recently selected genes are not strongly enriched in any functional category. The demographic history and mode of adaptation suggest that black flying fox might be a well-adapted species with strong evolutionary resilience. Taken together, this study unravels a vibrant landscape of recent evolution for the black flying fox and sheds light on several unique evolutionary processes for bats comparing to other mammalian groups.

Bat ASC2 suppresses inflammasomes and ameliorates inflammatory diseases.

Bats are special in their ability to live long and host many emerging viruses. Our previous studies showed that bats have altered inflammasomes, which are central players in aging and infection. However, the role of inflammasome signaling in combating inflammatory diseases remains poorly understood. Here, we report bat ASC2 as a potent negative regulator of inflammasomes. Bat ASC2 is highly expressed at both the mRNA and protein levels and is highly potent in inhibiting human and mouse inflammasomes. Transgenic expression of bat ASC2 in mice reduced the severity of peritonitis induced by gout crystals and ASC particles. Bat ASC2 also dampened inflammation induced by multiple viruses and reduced mortality of influenza A virus infection. Importantly, it also suppressed SARS-CoV-2-immune-complex-induced inflammasome activation. Four key residues were identified for the gain of function of bat ASC2. Our results demonstrate that bat ASC2 is an important negative regulator of inflammasomes with therapeutic potential in inflammatory diseases.

Incontinentia Pigmenti: A Case Report of Early Clinical Symptoms in a Lack of Family Inheritance Positive Result.

Background: Incontinentia pigmenti (IP), also known as Bloch-Sulzberger syndrome, is an X-linked dominant genetic disease involving multiple systems. Previous literature has not reported the case of parents with negative genetic test results, and typical early clinical symptoms and auxiliary inspection results were also lacking. Case Report: A female child was found to have broken skin immediately after birth with no family inheritance disease, and the area of the broken skin increased. Immediately afterward, Head magnetic resonance imaging (MRI) showed multiple blood lesions in the brain. Then, the wide-angle digital retinal imaging system suggesting that fundus fluorescein angiography showed fundus vascular loop-like changes. And blood genetic testing showed that exons 4-10 of the NEMO gene located in Xq28 were deleted. The patient was eventually diagnosed with IP. However, her parents were a non-consanguineous healthy couple, with no specific skin, oral, or perineal diseases. And her parents' blood genetic testing showed that the parents and sisters of the patient did not have the NEMO gene exon deletion of Xq28. Conclusion: This case demonstrates the process from suspected neonatal IP cases without familial inheritance to diagnosis, which showed the typical early clinical symptoms and auxiliary inspection results. This case showed that the parents of patients with IP do not necessarily have clinical symptoms and positive symptoms of genetic testing results.

Environmental impact assessment for the use of an orally aerosolised adenovirus type-5 vector-based COVID-19 vaccine in randomised clinical trials.

BACKGROUND: An orally aerosolised adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) has recently been authorized for boosting immunization in China. Our study aims to assess the environmental impact of the use of aerosolised Ad5-nCoV. METHODS: We collected air samples from rooms, swabs from the setting desks of the vaccine nebuliser, mask samples from participants and blood samples of nurses who administered the inoculation in the clinical trials. The viral load of adenovirus type-5 vector in the samples and the antibody levels against the wild-type SARS-CoV-2 strain in serum were detected. RESULTS: Only one (4.00%) air samples collected before the initiation of vaccination was positive, which were almost positive during and after the vaccination (97.96%, 100%, respectively). All nurses in the trial A showed at least four-fold increase of the neutralizing antibody against the SARS-CoV-2 after the initiation of the study. In trial B, the positive proportion of the mask samples was 72.97% at 30 minutes after vaccination, 8.11% at day 1, and 0% at days 3, 5, and 7, respectively. CONCLUSION: The vaccination with the orally aerosolised Ad5-nCoV could have some spillage of the vaccine vector viral particles in the environment and cause human exposure.

A combination of pre-infusion serum ferritin, CRP and IL-6 predicts outcome in relapsed/refractory multiple myeloma patients treated with CAR-T cells.

Background: Chimeric antigen receptor - T (CAR-T) cell therapy has shown remarkable efficacy in patients with relapsed/refractory multiple myeloma (R/R MM). However, a subset of patients still experienced progression or relapse, and the predictors of prognosis are little known. We analyzed the inflammatory markers before CAR-T cell infusion, to clarify their correlation with survival and toxicity. Methods: This study involved 109 R/R MM patients who received CAR-T therapy between June 2017 and July 2021. Inflammatory markers, including ferritin, c-reactive protein (CRP), and interleukin-6 (IL-6) before CAR-T cell infusion were detected and then categorized by quartiles. Adverse events and clinical outcomes were compared between patients with upper quartile of inflammatory markers and patients with lower three quartiles of inflammatory markers. An inflammatory prognostic index (InPI) based on these three inflammatory markers was developed in this study. Patients were divided into 3 groups according to the InPI score, progression-free survival (PFS) and overall survival (OS) were compared among the groups. In addition, we explored the correlation between cytokine release syndrome (CRS) and pre-infusion inflammatory markers. Results: We found that the pre-infusion high ferritin (hazard ratio [HR], 3.382; 95% confidence interval [CI], 1.667 to 6.863; P = .0007), high CRP (HR, 2.043; 95% CI, 1.019 to 4.097; P = .044), and high IL-6 (HR, 3.298; 95% CI, 1.598 to 6.808; P = .0013) were significantly associated with inferior OS. The formula of the InPI score was based on the HR value of these 3 variables. Three risk groups were formed: (good, 0 to 0.5 point; intermediate, 1 to 1.5 points; poor, 2 to 2.5 points). Median OS for patients with good, intermediate, and poor InPI was not reached, 24 months, and 4 months, respectively, and median PFS was 19.1 months, 12.3 months, and 2.9 months, respectively. In the cox proportional hazards model, poor InPI remained an independent prognostic factor for PFS and OS. Pre-infusion ferritin was negatively associated with CAR T-cell expansion normalized to baseline tumor burden. Spearman correlation analysis showed that pre-infusion ferritin and IL-6 levels positively correlated with the grade of CRS (P = .0369 and P = .0117, respectively). The incidence of severe CRS was higher in patients with high IL-6 compared with patients with low IL-6 (26% vs. 9%, P = .0405). Pre-infusion ferritin, CRP and IL-6 were positively correlated with each peak values within the first month after infusion. Conclusions: Our results suggest that patients with elevated inflammation markers before CAR-T cell infusion are more likely to have poor prognosis.

C-Phycocyanin Ameliorates the Senescence of Mesenchymal Stem Cells through ZDHHC5-Mediated Autophagy via PI3K/AKT/mTOR Pathway.

The senescence of mesenchymal stem cells (MSCs) impairs their regenerative capacity to maintain tissue homeostasis. Numerous studies are focusing on the interventions and mechanisms to attenuate the senescence of MSCs. C-phycocyanin (C-PC) is reported to have multiple functions such as antitumor, antioxidation, anti-inflammation and anti-aging roles, but there is little research about the effects of C-PC on the senescence of MSCs. Here we investigated the roles and mechanism of C-PC on MSCs senescence. In vitro results showed that C-PC could reduce senescence, enhance proliferation, promote the adipogenic and osteogenic differentiation in senescent MSCs induced by oxidative stress. In vivo D-Galactose (D-Gal) induced rats aging models showed C-PC also increased the viability and differentiation of intrinsic senescent bone marrow derived MSCs (BMSCs). Furthermore, C-PC also decreased the levels of oxidative stress markers ROS or MDA, elevated the SOD activity, and increased the anti-inflammatory factors. Proteomic chip analysis showed that C-PC interacted with ZDHHC5, and their interaction was verified by pull down assay. Overexpression of ZDHHC5 aggravated the senescence of MSCs and greatly lessened the beneficial effects of C-PC on senescence. In addition, we found ZDHHC5 regulated autophagy by altering LC3, Beclin1 and PI3K/AKT/mTOR pathway. In summary, our data indicated that C-PC ameliorates the senescence of MSCs through zinc finger Asp-His-His-Cys (DHHC) domain-containing protein 5 (ZDHHC5) mediated autophagy via PI3K/AKT/mTOR pathway. The present study uncovered the key role of autophagy in MSCs senescence and PI3K/AKT/mTOR pathway may be a potential target for anti-senescence studies of MSCs.

RNAincoder: a deep learning-based encoder for RNA and RNA-associated interaction.

Ribonucleic acids (RNAs) involve in various physiological/pathological processes by interacting with proteins, compounds, and other RNAs. A variety of powerful computational methods have been developed to predict such valuable interactions. However, all these methods rely heavily on the 'digitalization' (also known as 'encoding') of RNA-associated interacting pairs into a computer-recognizable descriptor. In other words, it is urgently needed to have a powerful tool that can not only represent each interacting partner but also integrate both partners into a computer-recognizable interaction. Herein, RNAincoder (deep learning-based encoder for RNA-associated interactions) was therefore proposed to (a) provide a comprehensive collection of RNA encoding features, (b) realize the representation of any RNA-associated interaction based on a well-established deep learning-based embedding strategy and (c) enable large-scale scanning of all possible feature combinations to identify the one of optimal performance in RNA-associated interaction prediction. The effectiveness of RNAincoder was extensively validated by case studies on benchmark datasets. All in all, RNAincoder is distinguished for its capability in providing a more accurate representation of RNA-associated interactions, which makes it an indispensable complement to other available tools. RNAincoder can be accessed at https://idrblab.org/rnaincoder/.

Plant biochemical genetics in the multiomics era.

Modern genetics and biochemistry have revolutionized our understanding of plant biology. However, biochemical genetics can be traced to the foundation of Mendelian genetics indeed one of the milestone discoveries of Mendels seven characteristics of pea plants could later be ascribed to be due to mutation in starch branching enzyme. Here we review both current and historical strategies for the elucidation of plant metabolic pathways and the genes which encode their component enzymes and regulators. We utilize this historical review to discuss a range of classical genetic phenomena including, epistasis, canalization and heterosis as viewed through the lens of contemporary high-throughput data obtained via the array of approaches currently adopted in multi-omics studies.

Caspase-3 in glioma indicates an unfavorable prognosis by involving surrounding angiogenesis and tumor cell repopulation.

AIM: Effective biomarkers for estimating glioma prognosis are deficient. Canonically, caspase-3 acts as an "apoptosis executioner". However, its prognostic role in glioma and mechanistic effects on prognosis remain unclear. METHODS: With glioma tissue microarrays, the prognostic roles of cleaved caspase-3 and its association with angiogenesis were explored. Next, by analyzing the mRNA microarray data from the CGGA, the prognostic role of CASP3 expression and correlations between CASP3 and markers of glioma angiogenesis and proliferation were investigated. To biologically interpret the prognostic role of caspase-3 in glioma, the influence of caspase-3 on surrounding angiogenesis and glioma cell repopulation was investigated with an in vitro cell co-culture model, which comprises irradiated U87 cells and un-irradiated firefly luciferase (Fluc)-labeled HUVEC (HUVEC-Fluc) or U87 (U87-Fluc) cells. The over-expressed dominant-negative caspase-3 was used to suppress normal caspase-3 activity. RESULTS: High levels of cleaved caspase-3 expression were associated with poor survival outcomes in glioma patients. Higher microvessel density was observed in patients with high levels of cleaved caspase-3 expression. By mining the microarray data in CGGA, it was revealed that higher CASP3 expression was found in glioma patients with lower Karnofsky Performance score, higher WHO grade, malignant histological subtype, wild-type IDH. Higher CASP3 expression indicated a worse survival rate in glioma patients. Patients with high CASP3 expression and negative IDH mutation showed the worst survival rate. Positive correlations were found between CASP3 and markers of tumor angiogenesis and proliferation. Subsequent data based on an in vitro cell co-culture model revealed that caspase-3 in irradiated glioma cells mediated pro-angiogenic and repopulation-promoting effects via regulating COX-2 signaling. With glioma tissue microarrays, high levels of COX-2 expression showed inferior survival outcomes in glioma patients. Glioma patients with high levels of cleaved caspase-3 and COX-2 expression showed the worst survival outcomes. CONCLUSION: This study innovatively identified an unfavorable prognostic role of caspase-3 in glioma. The pro-angiogenic and repopulation-prompting effects of caspase-3/COX-2 signaling may explain its unfavorable prognostic role and offer novel insights into therapy sensitization and curative effect prediction of glioma.

Association between methylation in the promoter region of the GAD2 gene and opioid use disorder.

DNA methylation is one of the epigenetic mechanisms involved in opioid use disorder. GAD2 is a key catalyticase in gamma amino butyric acid (GABA) synthesis from glutamate, that is implicated in opioid-induced rewarding effect. To reveal the relationship and the underlying mechanism between GAD2 gene methylation and opioid use disorder, we first examined and compared the methylation levels in the promoter region of the GAD2 gene in peripheral blood between 120 patients with opioid use disorder and 110 healthy controls by using a targeted approach. A diagnostic model with methylation biomarkers was established to distinguish opioid use disorder and healthy control groups. Correlations between methylation levels in the promoter region of the GAD2 gene and the duration and dosage of opioid use were then determined. Finally, the transcription factors that potentially bind to the target sequences including the detected CpG sites were predicted with the JASPAR database. Our results demonstrated that hypermethylation in the promoter region of the GAD2 gene was associated with opioid use disorder. A diagnostic model based on 10 methylation biomarkers could distinguish the opioid use disorder and healthy control groups. Several correlations between methylation levels in the GAD2 gene promoter and the duration and dosage of opioid use were observed. Transcription factors TFAP2A, Arnt and Runx1 were predicted to bind to the target sequences including several CpG sites detected in the present study in the GAD2 gene promoter. Our findings highlight and extend the role of DNA methylation in the GAD2 gene in opioid use disorder.

Predicting the negative conversion time of nonsevere COVID-19 patients using machine learning methods.

Based on the patient's clinical characteristics and laboratory indicators, different machine-learning methods were used to develop models for predicting the negative conversion time of nonsevere coronavirus disease 2019 (COVID-19) patients. A retrospective analysis was performed on 376 nonsevere COVID-19 patients admitted to Wuxi Fifth People's Hospital from May 2, 2022, to May 14, 2022. The patients were divided into training set (n = 309) and test set (n = 67). The clinical features and laboratory parameters of the patients were collected. In the training set, the least absolute shrinkage and selection operator (LASSO) was used to select predictive features and train six machine learning models: multiple linear regression (MLR), K-Nearest Neighbors Regression (KNNR), random forest regression (RFR), support vector machine regression (SVR), XGBoost regression (XGBR), and multilayer perceptron regression (MLPR). Seven best predictive features selected by LASSO included: age, gender, vaccination status, IgG, lymphocyte ratio, monocyte ratio, and lymphocyte count. The predictive performance of the models in the test set was MLPR > SVR > MLR > KNNR > XGBR > RFR, and MLPR had the strongest generalization performance, which is significantly better than SVR and MLR. In the MLPR model, vaccination status, IgG, lymphocyte count, and lymphocyte ratio were protective factors for negative conversion time; male gender, age, and monocyte ratio were risk factors. The top three features with the highest weights were vaccination status, gender, and IgG. Machine learning methods (especially MLPR) can effectively predict the negative conversion time of non-severe COVID-19 patients. It can help to rationally allocate limited medical resources and prevent disease transmission, especially during the Omicron pandemic.

Investigating the impact of tumor location and size on the risk of recurrence for papillary thyroid carcinoma in the isthmus.

BACKGROUND: The purpose of the study was to investigate the ability of new parameters in distinguishing high-risk patients of recurrence from isthmic papillary thyroid carcinomas (iPTCs). METHODS: One hundred sixteen iPTC patients who underwent total thyroidectomy were identified from 3461 PTC patients from 2014 to 2019. Tumor margin to trachea midline distance (TTD), maximum tumor size (TS), and transverse diameter of trachea (TD) were measured on CT images. Cox proportional hazard models served to identify risk factors associated with recurrence-free survival (RFS). The iPTC prognostic formula (IPF = TD/(TTD - TS) - TD/TTD) was evaluated to assess the prognosis. RFS was conducted between the different groups using the Kaplan-Meier analysis. The receiver operating characteristic (ROC) curve of each parameter was drawn to predict recurrence. RESULTS: Central lymph node metastasis (CLNM) and extrathyroidal invasion in iPTC were 58.6% and 31.0%, respectively. Regional recurrence occurred in 16 (13.8%) patients, and no patient died or had distant metastasis. The 3- and 5-year RFS of iPTC were 87.5% and 84.5%, respectively. Gender (p = 0.001) and PLNM (prelaryngeal lymph node metastasis) (p = 0.010) in cPTC (center of iPTC located between two imaginary lines perpendicular to the surface of the skin from the most lateral points of the trachea) and non-cPTC (iPTC patients enrolled in this study excluding cPTC) groups differed significantly. A cut-off point of tumor size >1.1 cm and IPF ≤5.57 were established to have significant differences in prognosis (p = 0.032 and p = 0.005, respectively). Multivariate analysis showed that IPF ≤5.57 was independent prognostic factor for RFS (HR: 4.415, 95%CI: 1.118-17.431, p = 0.034). CONCLUSION: This study indicated the association between IPF and RFS in iPTC patients and established new models to assess risk factors for recurrence pre-operation. IPF ≤5.57 was significantly associated with poor RFS and might be promising parameters for predicting prognosis and surgical decision-making pre-operation.

Prognostic value of prelymphodepletion absolute lymphocyte counts in relapsed/refractory diffuse large B-cell lymphoma patients treated with chimeric antigen receptor T cells.

Introduction: Chimeric antigen receptor (CAR) T cell therapy has achieved unprecedented efficacy recently. However, the factors related to responses and durable remission are elusive. This study was to investigate the impact of pre-lymphodepletion (pre-LD) absolute lymphocyte count (ALC) on CAR T cell therapy outcomes. Methods: We conducted a retrospective study of 84 patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) who underwent CAR T cell treatment at the Affiliated Hospital of Xuzhou Medical University between March 1,2016 and December 31, 2021. The enrolled patients were divided into high group and low group according to the optimal cutoff value of pre-LD ALC. The Kaplan-Meier analyses was used to calculate survival curves. The Cox proportional hazards model was used for univariate and multivariate analysis to assess the prognostic factors. Results: The ROC showed that the optimal cutoff value of pre-LD ALC was 1.05 x 109/L. The overall response (defined as partial response or complete response) rate was significantly higher in patients with a high pre-LD ALC (75% versus 52.08%; P=0.032). Patients with a low pre-LD ALC had significantly inferior overall survival (OS) and progression-free survival (PFS) compared with those having a high pre-LD ALC (median OS, 9.6 months versus 45.17 months [P=0.008]; median PFS, 4.07 months versus 45.17 months [P= 0.030]). Meanwhile, low pre-LD ALC is an independent risk factor for PFS and OS. Discussion: The data suggested that pre-LD ALC may serve as a helpful indicator to predict the outcomes of CAR T cell therapy in patients with R/R DLBCL.

Dysregulation of miR-146a: a causative factor in epilepsy pathogenesis, diagnosis, and prognosis.

miR-146a is an NF-κB-dependent miRNA that acts as an anti-inflammatory miRNA via the Toll-like receptor (TLR) pathway. miR-146a targets multiple genes and has been identified to directly or indirectly regulate processes other than inflammation, including intracellular Ca changes, apoptosis, oxidative stress, and neurodegeneration. miR-146a is an important regulator of gene expression in epilepsy development and progression. Furthermore, miR-146a-related single nucleotide polymorphisms (SNPs) and single nucleotide variants (SNVs) contribute to the genetic susceptibility to drug resistance and seizure severity in epilepsy patients. This study summarizes the abnormal expression patterns of miR-146a in different types and stages of epilepsy and its potential molecular regulation mechanism, indicating that miR-146a can be used as a novel biomarker for epilepsy diagnosis, prognosis, and treatment.

Safety, immunogenicity, and efficacy of the mRNA vaccine CS-2034 as a heterologous booster versus homologous booster with BBIBP-CorV in adults aged ≥18 years: a randomised, double-blind, phase 2b trial.

BACKGROUND: Heterologous boosting is suggested to be of use in populations who have received inactivated COVID-19 vaccines. We aimed to assess the safety and immunogenicity of a heterologous vaccination with the mRNA vaccine CS-2034 versus the inactivated BBIBP-CorV as a fourth dose, as well as the efficacy against the SARS-CoV-2 omicron (BA.5) variant. METHODS: This trial contains a randomised, double-blind, parallel-controlled study in healthy participants aged 18 years or older (group A) and an open-label cohort in participants 60 years and older (group B), who had received three doses of inactivated whole-virion vaccines at least 6 months before enrolment. Pregnant women and people with major chronic illnesses or a history of allergies were excluded. Eligible participants in group A were stratified by age (18-59 years and ≥60 years) and then randomised by SAS 9.4 in a ratio of 3:1 to receive a dose of the mRNA vaccine (CS-2034, CanSino, Shanghai, China) or inactivated vaccine (BBIBP-CorV, Sinopharm, Beijing, China). Safety and immunogenicity against omicron variants of the fourth dose were evaluated in group A. Participants 60 years and older were involved in group B for safety observations. The primary outcome was geometric mean titres (GMTs) of the neutralising antibodies against omicron and seroconversion rates against BA.5 variant 28 days after the boosting, and incidence of adverse reactions within 28 days. The intention-to-treat group was involved in the safety analysis, while all patients in group A who had blood samples taken before and after the booster were involved in the immunogenicity analysis. This trial was registered at the Chinese Clinical Trial Registry Centre (ChiCTR2200064575). FINDINGS: Between Oct 13, and Nov 22, 2022, 320 participants were enrolled in group A (240 in the CS-2034 group and 80 in the BBIBP-CorV group) and 113 in group B. Adverse reactions after vaccination were more frequent in CS-2034 recipients (158 [44·8%]) than BBIBP-CorV recipients (17 [21·3%], p<0·0001). However, most adverse reactions were mild or moderate, with grade 3 adverse reactions only reported by eight (2%) of 353 participants receiving CS-2034. Heterologous boosting with CS-2034 elicited 14·4-fold (GMT 229·3, 95% CI 202·7-259·4 vs 15·9, 13·1-19·4) higher concentration of neutralising antibodies to SARS-CoV-2 omicron variant BA.5 than did homologous boosting with BBIBP-CorV. The seroconversion rates of SARS-CoV-2-specific neutralising antibody responses were much higher in the mRNA heterologous booster regimen compared with BBIBP-CorV homologous booster regimen (original strain 47 [100%] of 47 vs three [18·8%] of 16; BA.1 45 [95·8%] of 48 vs two [12·5%] 16; and BA.5 233 [98·3%] of 240 vs 15 [18·8%] of 80 by day 28). INTERPRETATION: Both the administration of mRNA vaccine CS-2034 and inactivated vaccine BBIBP-CorV as a fourth dose were well tolerated. Heterologous boosting with mRNA vaccine CS-2034 induced higher immune responses and protection against symptomatic SARS-CoV-2 omicron infections compared with homologous boosting, which could support the emergency use authorisation of CS-2034 in adults. FUNDING: Science and Technology Commission of Shanghai, National Natural Science Foundation of China, Jiangsu Provincial Science Fund for Distinguished Young Scholars, and Jiangsu Provincial Key Project of Science and Technology Plan. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Integrating multiomics data accelerates elucidation of plant primary and secondary metabolic pathways.

Plants are the most important sources of food for humans, as well as supplying many ingredients that are of great importance for human health. Developing an understanding of the functional components of plant metabolism has attracted considerable attention. The rapid development of liquid chromatography and gas chromatography, coupled with mass spectrometry, has allowed the detection and characterization of many thousands of metabolites of plant origin. Nowadays, elucidating the detailed biosynthesis and degradation pathways of these metabolites represents a major bottleneck in our understanding. Recently, the decreased cost of genome and transcriptome sequencing rendered it possible to identify the genes involving in metabolic pathways. Here, we review the recent research which integrates metabolomic with different omics methods, to comprehensively identify structural and regulatory genes of the primary and secondary metabolic pathways. Finally, we discuss other novel methods that can accelerate the process of identification of metabolic pathways and, ultimately, identify metabolite function(s).

KRASG12C mutation-induced TOPK overexpression contributes to tumour progression in non-small cell lung cancer.

KRAS mutation is the most frequent type of genetic mutation in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma. However, KRAS mutation can affect many biological processes and the mechanisms underlying KRAS mutation-mediate carcinogenesis in NSCLC have not been fully understood. In this research, we found that KRASG12C mutation was associated with the upregulation of T-LAK cell-originated protein kinase (TOPK), which is a well-known serine/threonine MAPK-like protein kinase implicated in tumorigenesis. The overexpression of TOPK significantly promoted the malignant phenotype of A549 cells, and TOPK silencing impaired the malignant phenotype with KRASG12C mutation. Moreover, we demonstrated that TOPK level was regulated by MAPK/ERK signalling and the transcription factor Elk1. TOPK was also found to promote the activation of NF-κB signalling in A549 cells with KRASG12C mutation via facilitating the phosphorylation of TAK1. In the in vivo tumorigenesis model, the administration of TOPK inhibitor OTS514 enhanced the anticancer effect of 5-FU, and the combinatory use of OTS514 and KRASG12C inhibitor AMG510 showed synergistic anti-tumour effect. These results suggest that KRAS-TOPK axis contributes to the progression of NSCLC and targeting this axis could synergize with anticancer effect of the existing chemotherapeutics.

State-of-the-art Application of Artificial Intelligence to Transporter-centered Functional and Pharmaceutical Research.

Protein transporters not only have essential functions in regulating the transport of endogenous substrates and remote communication between organs and organisms, but they also play a vital role in drug absorption, distribution, and excretion and are recognized as major determinants of drug safety and efficacy. Understanding transporter function is important for drug development and clarifying disease mechanisms. However, the experimental-based functional research on transporters has been challenged and hinged by the expensive cost of time and resources. With the increasing volume of relevant omics datasets and the rapid evolution of artificial intelligence (AI) techniques, next-generation AI is becoming increasingly prevalent in the functional and pharmaceutical research of transporters. Thus, a comprehensive discussion on the state-of-the-art application of AI in three cutting-edge directions was provided in this review, which included (a) transporter classification and function annotation, (b) structure discovery of membrane transporters, and (c) drug-transporter interaction prediction. This study provides a panoramic view of AI algorithms and tools applied to the field of transporters. It is expected to guide a better understanding and utilization of AI techniques for in-depth studies of transporter-centered functional and pharmaceutical research.