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Background High throughput RNA sequencing is a powerful approach to study gene expression. Due to the complex multiple-steps protocols in data acquisition, extreme deviation of a sample from samples of the same treatment group may occur due to technical variation or true biological differences. The high-dimensionality of the data with few biological replicates make it challenging to accurately detect those samples, and this issue is not well studied in the literature currently. Robust statistics is a family of theories and techniques aim to detect the outliers by first fitting the majority of the data and then flagging data points that deviate from it. Robust statistics have been widely used in multivariate data analysis for outlier detection in chemometrics and engineering. Here we apply robust statistics on RNA-seq data analysis. Results We report the use of two robust principal component analysis (rPCA) methods, PcaHubert and PcaGrid , to detect outlier samples in multiple simulated and real biological RNA-seq data sets with positive control outlier samples. PcaGrid achieved 100% sensitivity and 100% specificity in all the tests using positive control outliers with varying degrees of divergence. We applied rPCA methods and classical principal component analysis (cPCA) on an RNA-Seq data set profiling gene expression of the external granule layer in the cerebellum of control and conditional SnoN knockout mice. Both rPCA methods detected the same two outlier samples but cPCA failed to detect any. We performed differentially expressed gene detection before and after outlier removal as well as with and without batch effect modeling. We validated gene expression changes using quantitative reverse transcription PCR and used the result as reference to compare the performance of eight different data analysis strategies. Removing outliers without batch effect modeling performed the best in term of detecting biologically relevant differentially expressed genes. Conclusions rPCA implemented in the PcaGrid function is an accurate and objective method to detect outlier samples. It is well suited for high-dimensional data with small sample sizes like RNA-seq data. Outlier removal can significantly improve the performance of differential gene detection and downstream functional analysis.

T cell immunity is central to contemporary cancer and autoimmune therapies, encompassing immune checkpoint blockade and adoptive T cell therapies. Their diverse characteristics can be reprogrammed by different immune challenges dependent on antigen stimulation levels, metabolic conditions, and the degree of inflammation. T cell-based therapeutic strategies are gaining widespread adoption in oncology and treating inflammatory conditions. Emerging researches reveal that clustered regularly interspaced palindromic repeats–associated protein 9 (CRISPR–Cas9) genome editing has enabled T cells to be more adaptable to specific microenvironments, opening the door to advanced T cell therapies in preclinical and clinical trials. CRISPR–Cas9 can edit both primary T cells and engineered T cells, including CAR-T and TCR-T, in vivo and in vitro to regulate T cell differentiation and activation states. This review first provides a comprehensive summary of the role of CRISPR–Cas9 in T cells and its applications in preclinical and clinical studies for T cell-based therapies. We also explore the application of CRISPR screen high-throughput technology in editing T cells and anticipate the current limitations of CRISPR–Cas9, including off-target effects and delivery challenges, and envisioned improvements in related technologies for disease screening, diagnosis, and treatment.

Agarwood is a resin produced by wounded Aquilaria plants. Aquilaria sinensis (Lour.) Gilg  is the original plant source of agarwood in China. Formic acid combined with Botryosphaeria rhodina A13 (FAA13) induces the formation of artificial agarwood as an effective integrated induction method. However, its formation mechanism is still unclear, and the harvesting time of agarwood has not been elucidated. In this work, we analyzed FAA13-induced artificial agarwood and leaves at different time points within one year based on endophytic fungal community, expression of related genes, and secondary metabolites. The induction process by FAA13 was divided into two stages. In agarwood, we found that fungal diversity and relative abundance decreased in stage 1 but increased in stage 2. Additionally, genes related to 2-(2-phenylethyl) chromones synthesis were mainly expressed in stage 1, while those related to sesquiterpene synthesis were mainly expressed in stage 2. The primary differential metabolites between the two stages were the content of ethanol-soluble extractives (EEC%) in the agarwood and epi-friedelinol and friedelin in the leaves. EEC% in agarwood stabilized and was at a high level in stage 2. At the same time, we observed friedelin rose rapidly from a plateau or after a slight decline, and epi-friedelinol continued to rise. We found similar results in artificial agarwood induced by combining formic acid with Fusarium sp. A2 (FAA2). The content of epi-friedelinol and friedelin in leaves can be used as an index to judge agarwood’s harvesting period during the integrated method’s induction process. The appropriate harvesting period for agarwood should be determined by collecting leaves in stage 2 (8 months later) without damaging the tree and assessing whether friedelin enters a rapid rise from the plateau stage by rapidly determining epi- friedlinol and friedelin content.

Molluscum contagiosum virus is an important human skin pathogen: it can cause disfigurement and suffering in children, in adults it is less common and often sexually transmitted. Extensive and persistent skin infection with the virus can indicate underlying immunodeficiency. Traditional ablative therapies have not been compared directly with newer immune-modulating and specific antiviral therapies. Advances in research raise the prospect of new approaches to treatment informed by the biology of the virus; in human skin, the infection is localised in the epidermal layers, where it induces a typical, complex hyperproliferative lesion with an abundance of virus particles but a conspicuous absence of immune effectors. Functional studies of the viral genome have revealed effects on cellular pathways involved in the cell cycle, innate immunity, inflammation, and cell death. Extensive lesions caused by molluscum contagiosum can occur in patients with DOCK8 deficiency—a genetic disorder affecting migration of dendritic and specialised T cells in skin. Sudden disappearance of lesions is the consequence of a vigorous immune response in healthy people. Further study of the unique features of infection with molluscum contagiosum virus could give fundamental insight into the nature of skin immunity.

Teacher innovative behavior is one of the vital factors, affecting student engagement, addresses diverse needs, promotes critical thinking, fosters lifelong learning, and contributes to educational research and development. By encouraging and supporting teacher innovation, we may can ensure that education remains relevant, effective, and impactful in preparing students for the future. Teacher innovative behavior is also needed to improve the mathematics skills of elementary school students, and it is important to determine the predictors that significantly affecting Teacher innovative behavior. Therefore, this study aimed to develop a model that predicted possible factors affecting mathematics teachers' innovative behavior based on Social Cognitive Theory (SCT). Data were collected from 132 elementary school teachers in China to verify the model, and the analysis was conducted using a structural equation modelling approach. Theoretically, 10 of the 15 hypotheses were found to be significant. The results showed that facilitating conditions and self-efficacy significantly affect mathematics teachers' innovative behavior. Meanwhile, Technological, Pedagogical and Content Knowledge (TPACK) knowledge, Social Influences, Rewards, Work engagement and anxiety did not show any effect. The contribution developed a model and provided new knowledge about the factors affecting elementary school teachers' innovative behavior. Practically, this could be used to improve teachers' innovative behavior.

To adapt to habitat temperature, vertebrates have developed sophisticated physiological and ecological mechanisms through evolution. Transient receptor potential melastatin 8 (TRPM8) serves as the primary sensor for cold. However, how cold activates TRPM8 and how this sensor is tuned for thermal adaptation remain largely unknown. Here we established a molecular framework of how cold is sensed in TRPM8 with a combination of patch-clamp recording, unnatural amino acid imaging, and structural modeling. We first observed that the maximum cold activation of TRPM8 in eight different vertebrates (i.e., African elephant and emperor penguin) with distinct side-chain hydrophobicity (SCH) in the pore domain (PD) is tuned to match their habitat temperature. We further showed that altering SCH for residues in the PD with solventaccessibility changes leads to specific tuning of the cold response in TRPM8. We also observed that knockin mice expressing the penguin’s TRPM8 exhibited remarkable tolerance to cold. Together, our findings suggest a paradigm of thermal adaptation in vertebrates, where the evolutionary tuning of the cold activation in the TRPM8 ion channel through altering SCH and solvent accessibility in its PD largely contributes to the setting of the cold-sensitive/ tolerant phenotype.

Background Chemotherapy-induced premature ovarian failure (POF) is a severe complication affecting tumor patients at a childbearing age. Mesenchymal stem cells (MSCs) can partially restore the ovarian structure and function damaged by chemotherapy. miR-21 is a microRNA that can regulate cell apoptosis. This study discusses the repair effect and mechanism of MSCs overexpressing miR-21 on chemotherapy-induced POF. Methods Rat MSCs and granulosa cells (GCs) were isolated in vitro. MSCs were transfected with miR-21 lentiviral vector (LV-miR-21) to obtain MSCs stably expressing miR-21 (miR-21-MSCs). The microenvironment of an ovary receiving chemotherapy was mimicked by adding phosphamide mustard (PM) into the cellular culture medium. The apoptosis rate and the mRNA and protein expression of target genes PTEN and PDCD4 were detected in MSCs. Apoptosis was induced by adding PM into the culture medium for GCs, which were cocultured with miR-21-MSCs. The apoptosis rate and the mRNA and protein expression of PTEN and PDCD4 were detected. The chemotherapy-induced POF model was built into rats by intraperitoneal cyclophosphamide injection. miR-21-MSCs were transplanted into the bilateral ovary. The rats were sacrificed at 15, 30, 45, and 60 days after the last injection. The ovarian weights, follicle count, estrous cycle, and sex hormone levels (estradiol (E2) and follicle-stimulating hormone (FSH)) were detected. Apoptosis of GCs was determined by TUNEL assay. The miR-21 and mRNA and protein expression of PTEN and PDCD4 were determined. Results The apoptosis decreased in MSCs transfected with miR-21. The mRNA and protein expression of target genes PTEN and PDCD4 was downregulated. GCs cocultured with miR-21-MSCs showed a decreased apoptosis, an upregulation of miR-21, and a downregulation of PTEN and PDCD4. Following the injection of miR-21-MSCs, the ovarian weight and follicle counts increased; E 2 levels increased while FSH levels decreased, with less severe apoptosis of GCs. The miR-21 expression in the ovaries was upregulated, while the mRNA expression and protein expression of PTEN and PDCD4 were downregulated. Conclusions Overexpression of miR-21 in MSCs promoted efficacy against chemotherapy-induced POF and its improvement of the repair effect was related to the inhibition of GC apoptosis by targeting PTEN and PDCD4.

Although the link of white matter to pathophysiology of schizophrenia is documented, loss of myelin is not detected in patients at the early stages of the disease, suggesting that pathological evolution of schizophrenia may occur before significant myelin loss. Disrupted-in-schizophrenia-1 (DISC1) protein is highly expressed in oligodendrocyte precursor cells (OPCs) and regulates their maturation. Recently, DISC1-Δ3, a major DISC1 variant that lacks exon 3, has been identified in schizophrenia patients, although its pathological significance remains unknown. In this study, we detected in schizophrenia patients a previously unidentified pathological phenotype of OPCs exhibiting excessive branching. We replicated this phenotype by generating a mouse strain expressing DISC1-Δ3 gene in OPCs. We further demonstrated that pathological OPCs, rather than myelin defects, drive the onset of schizophrenic phenotype by hyperactivating OPCs’ Wnt/β-catenin pathway, which consequently upregulates Wnt Inhibitory Factor 1 (Wif1), leading to the aberrant synaptic formation and neuronal activity. Suppressing Wif1 in OPCs rescues synaptic loss and behavioral disorders in DISC1-Δ3 mice. Our findings reveal the pathogenetic role of OPC-specific DISC1-Δ3 variant in the onset of schizophrenia and highlight the therapeutic potential of Wif1 as an alternative target for the treatment of this disease.

This study proposes a novel approach to suppress noise jamming and smart jamming. The traditional method of using auxiliary channels to cancel interference requires pure interference samples to calculate weights, which is almost impossible for pulsed interference signals. In this work, to avoid the difficulty of choosing suitable interference samples, we construct the parameterized expected signal according to the time-delay relation between target reflecting echo and transmitted signal. The objective function is established in the form of the minimum mean square error between the recovered signal and the expected signal. The optimization problem is solved by an alternating iteration method. Simulation results demonstrate that the proposed method achieves excellent performance for suppressing noise jamming and smart jamming and is not sensitive to signal-to-noise ratio and jamming-to-noise ratio. The processing results of the measured data show that the method has a certain practical application value.

Rice (Oryza sativa), the staple food for almost half of the world's population, prefers ammonium (NH4 +) as the major nitrogen resource, and while NH4 + has profound effects on rice growth and yields, the underlying regulatory mechanisms remain largely unknown. Brassinosteroids (BRs) are a class of steroidal hormones playing key roles in plant growth and development. In this study, we show that NH4 + promotes BR biosynthesis through miR444 to regulate rice root growth. miR444 targeted five homologous MADS-box transcription repressors potentially forming homologous or heterogeneous complexes in rice. miR444 positively regulated BR biosynthesis through its MADS-box targets, which directly repress the transcription of BR-deficient dwarf 1 (OsBRD1), a key BR biosynthetic gene. NH4 + induced the miR444-OsBRD1 signaling cascade in roots, thereby increasing the amount of BRs, whose biosynthesis and signaling were required for NH4 +-dependent root elongation inhibition. Consistently, miR444-overexpressing rice roots were hypersensitive to NH4 + depending on BR biosynthesis, and overexpression of miR444's target, OsMADS57, resulted in rice hyposensitivity to NH4 + in root elongation, which was associated with a reduction of BR content. In summary, our findings reveal a cross talk mechanism between NH4 + and BR in which NH4 + activates miR444-OsBRD1, an undescribed BR biosynthesis-promoting signaling cascade, to increase BR content, inhibiting root elongation in rice.