The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3'-UTR and promoting Rag1 mRNA expression.

The regulation of thymocyte development by RNA-binding proteins (RBPs) is largely unexplored. We identify 642 RBPs in the thymus and focus on Arpp21, which shows selective and dynamic expression in early thymocytes. Arpp21 is downregulated in response to T cell receptor (TCR) and Ca2+ signals. Downregulation requires Stim1/Stim2 and CaMK4 expression and involves Arpp21 protein phosphorylation, polyubiquitination and proteasomal degradation. Arpp21 directly binds RNA through its R3H domain, with a preference for uridine-rich motifs, promoting the expression of target mRNAs. Analysis of the Arpp21-bound transcriptome reveals strong interactions with the Rag1 3'-UTR. Arpp21-deficient thymocytes show reduced Rag1 expression, delayed TCR rearrangement and a less diverse TCR repertoire. This phenotype is recapitulated in Rag1 3'-UTR mutant mice harboring a deletion of the Arpp21 response region. These findings show how thymocyte-specific Arpp21 promotes Rag1 expression to enable TCR repertoire diversity until signals from the TCR terminate Arpp21 and Rag1 activities.

FPLS-DC: functional partial least squares through distance covariance for imaging genetics.

MOTIVATION: Imaging genetics integrates imaging and genetic techniques to examine how genetic variations influence the function and structure of organs like the brain or heart, providing insights into their impact on behavior and disease phenotypes. The use of organ-wide imaging endophenotypes has increasingly been used to identify potential genes associated with complex disorders. However, analyzing organ-wide imaging data alongside genetic data presents two significant challenges: high dimensionality and complex relationships. To address these challenges, we propose a novel, nonlinear inference framework designed to partially mitigate these issues. RESULTS: We propose a functional partial least squares through distance covariance (FPLS-DC) framework for efficient genome wide analyses of imaging phenotypes. It consists of two components. The first component utilizes the FPLS-derived base functions to reduce image dimensionality while screening genetic markers. The second component maximizes the distance correlation between genetic markers and projected imaging data, which is a linear combination of the FPLS-basis functions, using simulated annealing algorithm. In addition, we proposed an iterative FPLS-DC method based on FPLS-DC framework, which effectively overcomes the influence of inter-gene correlation on inference analysis. We efficiently approximate the null distribution of test statistics using a gamma approximation. Compared to existing methods, FPLS-DC offers computational and statistical efficiency for handling large-scale imaging genetics. In real-world applications, our method successfully detected genetic variants associated with the hippocampus, demonstrating its value as a statistical toolbox for imaging genetic studies. AVAILABILITY AND IMPLEMENTATION: The FPLS-DC method we propose opens up new research avenues and offers valuable insights for analyzing functional and high-dimensional data. In addition, it serves as a useful tool for scientific analysis in practical applications within the field of imaging genetics research. The R package FPLS-DC is available in Github: https://github.com/BIG-S2/FPLSDC.

CaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responses.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated B cell compartment responsible for the production of autoantibodies. Here, we show that T cell-specific expression of calcium/calmodulin-dependent protein kinase IV (CaMK4) leads to T follicular helper (Tfh) cells expansion in models of T-dependent immunization and autoimmunity. Mechanistically, CaMK4 controls the Tfh-specific transcription factor B cell lymphoma 6 (Bcl6) at the transcriptional level through the cAMP responsive element modulator α (CREMα). In the absence of CaMK4 in T cells, germinal center formation and humoral immunity is impaired in immunized mice, resulting in reduced anti-dsDNA titres, as well as IgG and complement kidney deposition in the lupus-prone B6.lpr mouse. In human Tfh cells, CaMK4 inhibition reduced BCL6 expression and IL-21 secretion ex vivo, resulting in impaired plasmablast formation and IgG production. In patients with SLE, CAMK4 mRNA levels in Tfh cells correlated with those of BCL6. In conclusion, we identify CaMK4/CREMα as a driver of T cell-dependent B cell dysregulation in autoimmunity.

Ultra-high dimensional variable selection for doubly robust causal inference.

Causal inference has been increasingly reliant on observational studies with rich covariate information. To build tractable causal procedures, such as the doubly robust estimators, it is imperative to first extract important features from high or even ultra-high dimensional data. In this paper, we propose causal ball screening for confounder selection from modern ultra-high dimensional data sets. Unlike the familiar task of variable selection for prediction modeling, our confounder selection procedure aims to control for confounding while improving efficiency in the resulting causal effect estimate. Previous empirical and theoretical studies suggest excluding causes of the treatment that are not confounders. Motivated by these results, our goal is to keep all the predictors of the outcome in both the propensity score and outcome regression models. A distinctive feature of our proposal is that we use an outcome model-free procedure for propensity score model selection, thereby maintaining double robustness in the resulting causal effect estimator. Our theoretical analyses show that the proposed procedure enjoys a number of properties, including model selection consistency and pointwise normality. Synthetic and real data analysis show that our proposal performs favorably with existing methods in a range of realistic settings. Data used in preparation of this paper were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database.

Phosphofructokinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic autoimmunity.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by defective regulatory T (Treg) cells. Here, we demonstrate that a T cell-specific deletion of calcium/calmodulin-dependent protein kinase 4 (CaMK4) improves disease in B6.lpr lupus-prone mice and expands Treg cells. Mechanistically, CaMK4 phosphorylates the glycolysis rate-limiting enzyme 6-phosphofructokinase, platelet type (PFKP) and promotes aerobic glycolysis, while its end product fructose-1,6-biphosphate suppresses oxidative metabolism. In Treg cells, a CRISPR-Cas9-enabled Pfkp deletion recapitulated the metabolism of Camk4-/- Treg cells and improved their function and stability in vitro and in vivo. In SLE CD4+ T cells, PFKP enzymatic activity correlated with SLE disease activity and pharmacologic inhibition of CaMK4-normalized PFKP activity, leading to enhanced Treg cell function. In conclusion, we provide molecular insights in the defective metabolism and function of Treg cells in SLE and identify PFKP as a target to fine-tune Treg cell metabolism and thereby restore their function.

Influence Factors and Predictive Models for the Outcome of Patients with Ischemic Stroke after Intravenous Thrombolysis: A Multicenter Retrospective Cohort Study.

Objective: Intravenous thrombolysis (IVT) is currently the main effective treatment for patients with ischemic stroke. This study aimed to analyze the factors affecting the early neurological recovery and prognosis of thrombolytic therapy after surgery and to construct predictive models. Materials and Methods: A total of 849 patients with ischemic stroke who received IVT treatment at six centers from June 2017 to March 2021 were included. Patients were divided into the training cohort and the validation cohort. Based on the independent factors that influence the early recovery of neurological function and the prognosis, the respective predictive nomograms were established. The predictive accuracy and discrimination ability of the nomograms were evaluated by ROC and calibration curve, while the decision curve and clinical impact curve were adopted to evaluate the clinical applicability of the nomograms. Results: The nomogram constructed based on the factors affecting the prognosis in 3 months had ideal accuracy as the AUC (95% CI) was 0.901 (0.874~0.927) in the training cohort and 0.877 (0.826~0.929) in the validation cohort. The accuracy of the nomogram is required to be improved, since the AUC (95% CI) of the training cohort and the validation cohort was 0.641 (0.597~0.685) and 0.627 (0.559~0.696), respectively. Conclusions: Based on this ideal and practical prediction model, we can early identify and actively intervene in patients with ischemic stroke after IVT to improve their prognosis. Nevertheless, the accuracy of predicting nomograms for the recovery of early neurological function after IVT still needs improvement.

PPP2R2D Suppresses Effector T Cell Exhaustion and Regulatory T Cell Expansion and Inhibits Tumor Growth in Melanoma.

We had shown previously that the protein phosphatase 2A regulatory subunit PPP2R2D suppresses IL-2 production, and PPP2R2D deficiency in T cells potentiates the suppressive function of regulatory T (Treg) cells and alleviates imiquimod-induced lupus-like pathology. In this study, in a melanoma xenograft model, we noted that the tumor grew in larger sizes in mice lacking PPP2R2D in T cells (LckCreR2Dfl/fl) compared with wild type (R2Dfl/fl) mice. The numbers of intratumoral T cells in LckCreR2Dfl/fl mice were reduced compared with R2Dfl/fl mice, and they expressed a PD-1+CD3+CD44+ exhaustion phenotype. In vitro experiments confirmed that the chromatin of exhaustion markers PD-1, LAG3, TIM3, and CTLA4 remained open in LckCreR2Dfl/fl CD4 T conventional compared with R2Dfl/fl T conventional cells. Moreover, the percentage of Treg cells (CD3+CD4+Foxp3+CD25hi) was significantly increased in the xenografted tumor of LckCreR2Dfl/fl mice compared with R2Dfl/fl mice probably because of the increase in the percentage of IL-2-producing LckCreR2Dfl/fl T cells. Moreover, using adoptive T cell transfer in mice xenografted with melanoma, we demonstrated that PPP2R2D deficiency in T cells enhanced the inhibitory effect of Treg cells in antitumor immunity. At the translational level, analysis of publicly available data from 418 patients with melanoma revealed that PPP2R2D expression levels correlated positively with tumor-infiltration level of CD4 and CD8 T cells. The data demonstrate that PPP2R2D is a negative regulator of immune checkpoint receptors, and its absence exacerbates effector T cell exhaustion and promotes Treg cell expansion. We conclude that PPP2R2D protects against melanoma growth, and PPP2R2D-promoting regimens can have therapeutic value in patients with melanoma.

Seed dressing with mefenpyr-diethyl as a safener for mesosulfuron-methyl application in wheat: The evaluation and mechanisms.

Mesosulfuron-methyl is always applied by foliar spraying in combination with the safener mefenpyr-diethyl to avoid phytotoxicity on wheat (Triticum aestivum L.) cultivars. However, it was observed that the tolerance of Tausch's goatgrass (Aegilops tauschii Coss.) to mesosulfuron-methyl significantly increased in the presence of mefenpyr-diethyl by performing bioassay. This confirmed phenomenon may lead to overuse of mesosulfuron-methyl and weed resistance evolution in field conditions. Therefore, we tested the effect of wheat seed dressing with mefenpyr-diethyl as a possible alternative and disclosed the underlying mechanisms by herbicide dissipation study, enzymatic analysis and transcriptome profiling. The results suggest that increase of ALS activity, enhancement of metabolic processes, and other stress responses are crucial for the regulation of herbicide detoxification induced by mefenpyr-diethyl. Additionally, transcription factors such as AP2/ERF-ERF, bHLH, NAC, and MYB, and protein kinase such as RLK-Pelle_DLSV might play vital regulatory roles. The current study has important implications for mesosulfuron-methyl application in wheat field to control Tausch's goatgrass and provides a comprehensive understanding of the protective effect of mefenpyr-diethyl.

The Regulatory Subunit PPP2R2A of PP2A Enhances Th1 and Th17 Differentiation through Activation of the GEF-H1/RhoA/ROCK Signaling Pathway.

Protein phosphatase 2A (PP2A) composed of a scaffold subunit, a catalytic subunit, and multiple regulatory subunits is a ubiquitously expressed serine/threonine phosphatase. We have previously shown that the PP2A catalytic subunit is increased in T cells from patients with systemic lupus erythematosus and promotes IL-17 production by enhancing the activity of Rho-associated kinase (ROCK) in T cells. However, the molecular mechanism whereby PP2A regulates ROCK activity is unknown. In this study, we show that the PP2A regulatory subunit PPP2R2A is increased in T cells from people with systemic lupus erythematosus and binds to, dephosphorylates, and activates the guanine nucleotide exchange factor GEF-H1 at Ser885, which in turn increases the levels of RhoA-GTP and the activity of ROCK in T cells. Genetic PPP2R2A deficiency in murine T cells reduced Th1 and Th17, but not regulatory T cell differentiation and mice with T cell-specific PPP2R2A deficiency displayed less autoimmunity when immunized with myelin oligodendrocyte glycoprotein peptide. Our studies indicate that PPP2R2A is the regulatory subunit that dictates the PP2A-directed enhanced Th1 and Th17 differentiation, and therefore, it represents a therapeutic target for pathologies linked to Th1 and Th17 cell expansion.

Protein Tyrosine Phosphatase SHP2 Suppresses Host Innate Immunity against Influenza A Virus by Regulating EGFR-Mediated Signaling.

Influenza A virus (IAV) is a highly contagious pathogen, causing acute respiratory illnesses in human beings and animals and frequently giving rise to epidemic outbreaks. Evasion by IAV of host immunity facilitates viral replication and spread, which can be initiated through various mechanisms, including epidermal growth factor receptor (EGFR) activation. However, how EGFR mediates the suppression of antiviral systems remains unclear. Here, we examined host innate immune responses and their relevant signaling to EGFR upon IAV infection. IAV was found to induce the phosphorylation of EGFR and extracellular signal-regulated kinase (ERK) at an early stage of infection. Inhibition of EGFR or ERK suppressed the viral replication but increased the expression of type I and type III interferons (IFNs) and interferon-stimulated genes (ISGs), supporting the idea that IAV escapes from antiviral innate immunity by activating EGFR/ERK signaling. Meanwhile, IAV infection also induced the activation of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2). Pharmacological inhibition or small interfering RNA (siRNA)-based silencing of SHP2 enhanced the IFN-dependent antiviral activity and reduced virion production. Furthermore, knockdown of SHP2 attenuated the EGFR-mediated ERK phosphorylation triggered by viral infection or EGF stimulation. Conversely, ectopic expression of constitutively active SHP2 noticeably promoted ERK activation and viral replication, concomitant with diminished immune function. Altogether, the results indicate that SHP2 is crucial for IAV-induced activation of the EGFR/ERK pathway to suppress host antiviral responses.IMPORTANCE Viral immune evasion is the most important strategy whereby viruses evolve for their survival. This work shows that influenza A virus (IAV) suppressed the antiviral innate immunity through downregulation of IFNs and ISGs by activating EGFR/ERK signaling. Meanwhile, IAV also induced the activation of protein tyrosine phosphatase SHP2, which was found to be responsible for modulating the EGFR-mediated ERK activity and subsequent antiviral effectiveness both in vitro and in vivo The results suggest that SHP2 is a key signal transducer between EGFR and ERK and plays a crucial role in suppressing host innate immunity during IAV infection. The finding enhances our understanding of influenza immune evasion and provides a new therapeutic approach to viral infection.

Co-sparse reduced-rank regression for association analysis between imaging phenotypes and genetic variants.

MOTIVATION: The association analysis between genetic variants and imaging phenotypes must be carried out to understand the inherited neuropsychiatric disorders via imaging genetic studies. Given the high dimensionality in imaging and genetic data, traditional methods based on massive univariate regression entail large computational cost and disregard many-to-many correlations between phenotypes and genetic variants. Several multivariate imaging genetic methods have been proposed to alleviate the above problems. However, most of these methods are based on the l1 penalty, which might cause the over-selection of variables and thus mislead scientists in analyzing data from the field of neuroimaging genetics. RESULTS: To address these challenges in both statistics and computation, we propose a novel co-sparse reduced-rank regression model that identifies complex correlations in a dimensional reduction manner. We developed an iterative algorithm based on a group primal dual-active set formulation to detect simultaneously important genetic variants and imaging phenotypes efficiently and precisely via non-convex penalty. The simulation studies showed that our method achieved accurate and stable performance in parameter estimation and variable selection. In real application, the proposed approach successfully detected several novel Alzheimer's disease-related genetic variants and regions of interest, which indicate that our method may be a valuable statistical toolbox for imaging genetic studies. AVAILABILITY AND IMPLEMENTATION: The R package csrrr, and the code for experiments in this article is available in Github: https://github.com/hailongba/csrrr. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Ball Covariance: A Generic Measure of Dependence in Banach Space.

Technological advances in science and engineering have led to the routine collection of large and complex data objects, where the dependence structure among those objects is often of great interest. Those complex objects (e.g, different brain subcortical structures) often reside in some Banach spaces, and hence their relationship cannot be well characterized by most of the existing measures of dependence such as correlation coefficients developed in Hilbert spaces. To overcome the limitations of the existing measures, we propose Ball Covariance as a generic measure of dependence between two random objects in two possibly different Banach spaces. Our Ball Covariance possesses the following attractive properties: (i) It is nonparametric and model-free, which make the proposed measure robust to model mis-specification; (ii) It is nonnegative and equal to zero if and only if two random objects in two separable Banach spaces are independent; (iii) Empirical Ball Covariance is easy to compute and can be used as a test statistic of independence. We present both theoretical and numerical results to reveal the potential power of the Ball Covariance in detecting dependence. Also importantly, we analyze two real datasets to demonstrate the usefulness of Ball Covariance in the complex dependence detection.

PPP2R2D suppresses IL-2 production and Treg function.

Protein phosphatase 2A is a ubiquitously expressed serine/threonine phosphatase that comprises a scaffold, a catalytic, and multiple regulatory subunits and has been shown to be important in the expression of autoimmunity. We considered that a distinct subunit may account for the decreased production of IL-2 in people and mice with systemic autoimmunity. We show that the regulatory subunit PPP2R2D is increased in T cells from people with systemic lupus erythematosus and regulates IL-2 production. Mice lacking PPP2R2D only in T cells produce more IL-2 because the IL-2 gene and genes coding for IL-2-enhancing transcription factors remain open, while the levels of the enhancer phosphorylated CREB are high. Mice with T cell-specific PPP2R2D deficiency display less systemic autoimmunity when exposed to a TLR7 stimulator. While genes related to Treg function do not change in the absence of PPP2R2D, Tregs exhibit high suppressive function in vitro and in vivo. Because the ubiquitous expression of protein phosphatase 2A cannot permit systemic therapeutic manipulation, the identification of regulatory subunits able to control specific T cell functions opens the way for the development of novel, function-specific drugs.

Genome-wide association studies of brain imaging data via weighted distance correlation.

MOTIVATION: Imaging genetics is mainly used to reveal the pathogenesis of neuropsychiatric risk genes and understand the relationship between human brain structure, functional and individual differences. Increasingly, the brain-wide imaging phenotypes in voxels are available to test the association with genetic markers. A challenge with analyzing such data is their high dimensionality and complex relationships. RESULTS: To tackle this challenge, we introduce a weighed distance correlation (wdCor) that can assess the association between genetic markers and voxel-based imaging data. Importantly, the wdCor test takes the voxel-based data as a whole multivariate phenotype, which preserves the spatial continuity and might enhance the power. Besides, an adaptive permutation procedure is introduced to determine the P-values of the wdCor test and also alleviate the computational burden in GWAS. In extensive simulation studies, wdCor achieves much better performances compared to the original distance correlation. We also successfully apply wdCor to conduct a large-scale analysis on data from the Alzheimer's disease neuroimaging project (ADNI). AVAILABILITY AND IMPLEMENTATION: Our wdCor method provides new research directions and ideas for multivariate analysis of high-dimensional data, it can also be used as a tool for scientific analysis of imaging genetics research in practical applications. The R package wdcor, and the code for reproducing all results in this article is available in Github: https://github.com/yangyuhui0129/wdcor. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Temperature-dependent variations in toxicity of diamide insecticides against three lepidopteran insects.

The effect of temperature on the toxicities of four diamide insecticides (chlorantraniliprole, cyantraniliprole, flubendiamide, tetraniliprole) against three lepidopteran insects (Helicoverpa armigera, Plutella xylostella, Athetis lepigone) were determined from 15 to 35 °C by exposing third-instar larvae to dip-treated cabbage leaf. The results indicated that increase in temperature led to an increase significantly and regularly in the toxicities of the four diamide insecticides against P. xylostella and H. armigera, but not for A. lepigone. The temperature coefficients (TCs) of the four diamide insecticides increased from 15 to 35 °C. Tetraniliprole for H. armigera (+825.83), chlorantraniliprole for P. xylostella (+315.65) and cyantraniliprole for H. armigera (+225.77) exhibited high positive TCs. For A. lepigone, temperature had a positively weak or no effect on the toxicities of most of the diamide insecticides from 20 to 30 °C, but a higher effect from 30 to 35 °C. In addition, the toxicities of chlorantraniliprole, cyantraniliprole and tetraniliprole all decreased from 15 to 20 °C. This study can guide pest managers in choosing suitable ambient field temperature when spraying diamide insecticides against lepidopteran insects.

Serine/threonine phosphatase PP2A is essential for optimal B cell function.

Protein phosphatase 2A (PP2A), a serine/threonine phosphatase, has been shown to control T cell function. We found that in vitro-activated B cells and B cells from various lupus-prone mice and patients with systemic lupus erythematosus display increased PP2A activity. To understand the contribution of PP2A to B cell function, we generated a Cd19CrePpp2r1afl/fl (flox/flox) mouse which lacks functional PP2A only in B cells. Flox/flox mice displayed reduced spontaneous germinal center formation and decreased responses to T cell-dependent and T-independent antigens, while their B cells responded poorly in vitro to stimulation with an anti-CD40 antibody or CpG in the presence of IL-4. Transcriptome and metabolome studies revealed altered nicotinamide adenine dinucleotide (NAD) and purine/pyrimidine metabolism and increased expression of purine nucleoside phosphorylase in PP2A-deficient B cells. Our results demonstrate that PP2A is required for optimal B cell function and may contribute to increased B cell activity in systemic autoimmunity.

Analysis of Differentially Expressed Transcripts in Apolygus lucorum (Meyer-Dür) Exposed to Different Temperature Coefficient Insecticides.

The existence of a temperature effect of insecticides frustrated the control of the green plant bug Apolygus lucorum (Meyer-Dür). Previous studies mostly focused on the application of insecticides, but the underlying mechanism remains incompletely understood. Here, we report a transcriptome profiling of A. lucorum treated by three kinds of temperature coefficient insecticides (TCIs) (positive TCI: imidacloprid, negative TCI: b-cypermethrin and non-effect TCI: phoxim) at 15 °C, 25 °C and 35 °C by using next- and third-generation RNA-Seq methods. A total of 34,739 transcripts were annotated from 277.74 Gb of clean data. There were more up-regulated transcripts than down-regulated transcripts in all three kinds of TCI treatments. Further Venn diagrams indicate the regulatory transcripts and regulatory modes were different at the three temperatures. The responses to imidacloprid involved more detox and stress response transcripts such as cytochrome P450 (CYP450), carboxylesterase (CarE) and catalase (CAT) at 35 °C, which was the case for beta-cypermethrin at 15 °C. UDP-glucuronyltransferase (UGT) and heat shock protein (HSP) transcripts were heavily involved, and thus deserve particular note in the temperature effect of insecticides. This high-confidence transcriptome atlas provides improved gene information for further study on the insecticide temperature effect related physiological and biochemical processes of A. lucorum.

CSMD: a computational subtraction-based microbiome discovery pipeline for species-level characterization of clinical metagenomic samples.

MOTIVATION: Microbiome analyses of clinical samples with low microbial biomass are challenging because of the very small quantities of microbial DNA relative to the human host, ubiquitous contaminating DNA in sequencing experiments and the large and rapidly growing microbial reference databases. RESULTS: We present computational subtraction-based microbiome discovery (CSMD), a bioinformatics pipeline specifically developed to generate accurate species-level microbiome profiles for clinical samples with low microbial loads. CSMD applies strategies for the maximal elimination of host sequences with minimal loss of microbial signal and effectively detects microorganisms present in the sample with minimal false positives using a stepwise convergent solution. CSMD was benchmarked in a comparative evaluation with other classic tools on previously published well-characterized datasets. It showed higher sensitivity and specificity in host sequence removal and higher specificity in microbial identification, which led to more accurate abundance estimation. All these features are integrated into a free and easy-to-use tool. Additionally, CSMD applied to cell-free plasma DNA showed that microbial diversity within these samples is substantially broader than previously believed. AVAILABILITY AND IMPLEMENTATION: CSMD is freely available at https://github.com/liuyu8721/csmd. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A Generic Sure Independence Screening Procedure.

Extracting important features from ultra-high dimensional data is one of the primary tasks in statistical learning, information theory, precision medicine and biological discovery. Many of the sure independent screening methods developed to meet these needs are suitable for special models under some assumptions. With the availability of more data types and possible models, a model-free generic screening procedure with fewer and less restrictive assumptions is desirable. In this paper, we propose a generic nonparametric sure independence screening procedure, called BCor-SIS, on the basis of a recently developed universal dependence measure: Ball correlation. We show that the proposed procedure has strong screening consistency even when the dimensionality is an exponential order of the sample size without imposing sub-exponential moment assumptions on the data. We investigate the flexibility of this procedure by considering three commonly encountered challenging settings in biological discovery or precision medicine: iterative BCor-SIS, interaction pursuit, and survival outcomes. We use simulation studies and real data analyses to illustrate the versatility and practicability of our BCor-SIS method.

Pyruvate kinase M2 is requisite for Th1 and Th17 differentiation.

Th1 and Th17 are important in the pathogenesis of autoimmune diseases and they depend on glycolysis as a source of energy. T cell antigen receptor signaling phosphorylates a serine/threonine kinase, calcium/calmodulin-dependent protein kinase IV (CaMK4), and promotes glycolysis. Based on these findings we hypothesized that CaMK4 promotes glycolysis. Camk4-deficient CD4+ T cells and cells treated with a CaMK4 inhibitor had less glycolysis compared with their counterparts. Pull-down of CaMK4 and mass spectrometry identified pyruvate kinase muscle isozyme (PKM), the final rate-limiting enzyme in glycolysis, as a binding partner. Coimmunoprecipitation and Western blotting showed that CaMK4 interacts directly with PKM2. Camk4-deficient CD4+ T cells displayed decreased pyruvate kinase activity. Silencing or pharmacological inhibition of PKM2 reduced glycolysis and in vitro differentiation to Th1 and Th17 cells, while PKM2 overexpression restored Th17 cell differentiation. Treatment with a PKM2 inhibitor ameliorated experimental autoimmune encephalomyelitis and CD4+ T cells treated with PKM2 inhibitor or Pkm2-shRNA caused limited disease activity in an adoptive cell transfer model of experimental autoimmune encephalomyelitis. Our data demonstrate that CaMK4 binds to PKM2 and promotes its activity, which is requisite for Th1 and Th17 differentiation in vitro and in vivo. PKM2 represents a therapeutic target for T cell-dependent autoimmune diseases.