Left atrial strain predicts improvement in left atrial functions of severe rheumatic mitral stenoses undergoing successful percutaneous transmitral commissurotomy.

AIMS: Chronic rheumatic heart disease (RHD) is prevalent in India. The mitral valve in isolation or combination with the aortic or tricuspid valve is involved in 31.6% and 52.8% of chronic RHD patients, respectively. The left atrium (LA) functions as a reservoir during the cardiac cycle. Therefore, the LA enlargement leads to longitudinal lengthening, measured as a positive strain, permitting the measurement of the longitudinal strain of LA. This study aimed to assess the LA functions using peak atrial longitudinal strain (PALS) in patients with severe rheumatic mitral stenoses (MS) in sinus rhythm who underwent successful percutaneous transvenous mitral commissurotomy (PTMC). MATERIAL AND METHODS: We recruited 56 patients with severe rheumatic MS for the study, of which 06 PTMC procedures were considered unsuccessful. So, 50 patients of chronic severe rheumatic MS in sinus rhythm undergoing PTMC were enrolled in a tertiary care centre of the Armed Forces from August 2017 to May 2019. Patients included in the study were not consecutive, and patients with atrial fibrillation (AF) were excluded. RESULTS: PALS improved post-PTMC (P < .001) in this study, effectively concluding that PALS is impaired in patients with severe symptomatic MS and is acutely enhanced after treatment. CONCLUSIONS: PALS is a good indicator of LA function and may predict the success of PTMC on the rheumatic mitral valve.

High expression of CD26 accurately identifies human bacteria-reactive MR1-restricted MAIT cells.

Mucosa-associated invariant T (MAIT) cells express the semi-invariant T-cell receptor TRAV1-2 and detect a range of bacteria and fungi through the MHC-like molecule MR1. However, knowledge of the function and phenotype of bacteria-reactive MR1-restricted TRAV1-2(+) MAIT cells from human blood is limited. We broadly characterized the function of MR1-restricted MAIT cells in response to bacteria-infected targets and defined a phenotypic panel to identify these cells in the circulation. We demonstrated that bacteria-reactive MR1-restricted T cells shared effector functions of cytolytic effector CD8(+) T cells. By analysing an extensive panel of phenotypic markers, we determined that CD26 and CD161 were most strongly associated with these T cells. Using FACS to sort phenotypically defined CD8(+) subsets we demonstrated that high expression of CD26 on CD8(+)  TRAV1-2(+) cells identified with high specificity and sensitivity, bacteria-reactive MR1-restricted T cells from human blood. CD161(hi) was also specific for but lacked sensitivity in identifying all bacteria-reactive MR1-restricted T cells, some of which were CD161(dim) . Using cell surface expression of CD8, TRAV1-2, and CD26(hi) in the absence of stimulation we confirm that bacteria-reactive T cells are lacking in the blood of individuals with active tuberculosis and are restored in the blood of individuals undergoing treatment for tuberculosis.

Game-Theoretic Analysis of Fusion Rules Over Molecular Reporting Channels.

This work adopts a game theoretic approach to analyze the behavior of transmitter nanomachines (TNMs) in a diffusive 3-dimensional (3-D) channel. In order to communicate the local observations about the region of interest (RoI) to a common supervisor nanomachine (SNM), TNMs transmit information-carrying molecules to SNM. For the production of information-carrying molecules, all the TNMs share the common food molecular budget (CFMB). The TNMs apply cooperative and greedy strategic efforts to get their share from the CFMB. In the cooperative case, all the TNMs communicate to SNM as a group, therefore they cooperatively consume the CFMB to increase the group outcome, whereas, in the greedy scenario, all TNMs decide to perform alone and thus greedily consume the CFMB to increase their individual outcomes. The performance is evaluated in terms of the average rate of success, the average probability of error, and the receiver operating characteristic (ROC) of RoI detection. The derived results are verified through Monte-Carlo and particle-based simulations (PBS).

Acute Pancreatitis Caused by Pegylated (PEG)-Asparaginase Associated With Severe Hypertriglyceridemia.

Pegylated (PEG)-asparaginase is used during the induction and intensification phases of treatment for B-cell acute lymphoblastic leukemia (B-ALL). It works by depleting the external sources of asparagine, causing the death of lymphoblasts. It has several adverse effects, including pancreatitis and hypertriglyceridemia; however, the simultaneous occurrence of both is uncommon. We present the case of an 18-year-old man with B-ALL who developed acute epigastric pain radiating to the back and non-bloody, non-bilious emesis following treatment with PEG-asparaginase. He was diagnosed with acute interstitial pancreatitis and severe hypertriglyceridemia. Conservative management was used for the pancreatitis, while hypertriglyceridemia was treated with an insulin infusion. Pancreatic toxicity and hypertriglyceridemia can necessitate the discontinuation of PEG-asparaginase, limiting treatment options and potentially increasing the risk of relapse. Therefore, further studies are needed to identify the factors contributing to hypertriglyceridemia and pancreatitis, aiding clinicians in monitoring and prevention.

Aweak phenotype associated with novel ABO*A allele variant c.106delinsGG.

BACKGROUND AND OBJECTIVES: Discrepancy between forward and reverse ABO grouping could be due to several reasons including genetic mutations of the alleles encoding group specific transferase. The healthy donors found with weak A antigen were investigated to ascertain the allele responsible for variation. MATERIALS AND METHODS: Standard serological methods were employed using commercial antisera. The molecular sequencing was performed on DNA with enrichment library prep kit and a custom designed overlapping probe panel. Binary alignment mapping files, generated on board the Illumina MiSeq instrument and aligned to the GRCh37/Hg19 reference genome, were uploaded to the QIAGEN CLC genomics workbench software (version. 20) where variant call files were generated and analyzed. RESULTS: Red blood cells (RBCs) of six healthy donors, showing weak mix-field agglutination by anti-A and anti-A, B and plasma with absence or weakly reacting anti-A, were investigated serologically. The RBCs incubated with anti-A yield positive elution and their saliva lacked A but possessed H antigen thereby classifying as a historical known phenotype Aend. Family study on 4 probands showed inheritance of the trait. Molecular studies revealed presence of ABO*A allele carrying rare novel variant referred to as c.106delinsGG in line with HGVS recommendation that was thought to be responsible for the variant of A. CONCLUSION: Six cases serologically defined as Aweak were found to be associated with novel allele ABO*A (c.106delinsGG). The Aweak phenotype with the novel allele has not been displayed on International Society of Blood Transfusion database, though c.106delinsGG is listed in the UCSC genome browser under rs782544248.

3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity.

The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts. Integrating childhood obesity GWAS summary statistics with our existing 3D genomic datasets for 57 human cell types, consisting of high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, and RNA-seq, we applied stratified LD score regression and calculated the proportion of genome-wide SNP heritability attributable to cell type-specific features, revealing pancreatic alpha cell enrichment as the most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out for genome-wide significant childhood obesity loci and their linkage disequilibrium proxies to implicate effector genes, yielded the most abundant number of candidate variants and target genes at the BDNF, ADCY3, TMEM18 and FTO loci in skeletal muscle myotubes and the pancreatic beta-cell line, EndoC-BH1. One novel implicated effector gene, ALKAL2 - an inflammation-responsive gene in nerve nociceptors - was observed at the key TMEM18 locus across multiple immune cell types. Interestingly, this observation was also supported through colocalization analysis using expression quantitative trait loci (eQTL) derived from the Genotype-Tissue Expression (GTEx) dataset, supporting an inflammatory and neurologic component to the pathogenesis of childhood obesity. Our comprehensive appraisal of 3D genomic datasets generated in a myriad of different cell types provides genomic insights into pediatric obesity pathogenesis.

3D chromatin-based variant-to-gene maps across 57 human cell types reveal the cellular and genetic architecture of autoimmune disease susceptibility.

A portion of the genetic basis for many common autoimmune disorders has been uncovered by genome-wide association studies (GWAS), but GWAS do not reveal causal variants, effector genes, or the cell types impacted by disease-associated variation. We have generated 3D genomic datasets consisting of promoter-focused Capture-C, Hi-C, ATAC-seq, and RNA-seq and integrated these data with GWAS of 16 autoimmune traits to physically map disease-associated variants to the effector genes they likely regulate in 57 human cell types. These 3D maps of gene cis-regulatory architecture are highly powered to identify the cell types most likely impacted by disease-associated genetic variation compared to 1D genomic features, and tend to implicate different effector genes than eQTL approaches in the same cell types. Most of the variants implicated by these cis-regulatory architectures are highly trait-specific, but nearly half of the target genes connected to these variants are shared across multiple autoimmune disorders in multiple cell types, suggesting a high level of genetic diversity and complexity among autoimmune diseases that nonetheless converge at the level of target gene and cell type. Substantial effector gene sharing led to the common enrichment of similar biological networks across disease and cell types. However, trait-specific pathways representing potential areas for disease-specific intervention were identified. To test this, we pharmacologically validated squalene synthase, a cholesterol biosynthetic enzyme encoded by the FDFT1 gene implicated by our approach in MS and SLE, as a novel immunomodulatory drug target controlling inflammatory cytokine production by human T cells. These data represent a comprehensive resource for basic discovery of gene cis-regulatory mechanisms, and the analyses reported reveal mechanisms by which autoimmune-associated variants act to regulate gene expression, function, and pathology across multiple, distinct tissues and cell types.

Recruitment of Th1 effector cells in human tuberculosis: hierarchy of chemokine receptor(s) and their ligands.

Selective recruitment of IFN-γ biased Th1 effector cells at the pathologic site(s) determines the local immunity of tuberculosis (TB). We observed the enrichment of CXCR3, CCR5 and CD11a(high) T cells in the peripheral blood, pleural fluid and bronchoalveolar lavage of TB pleural effusion (TB-PE) and miliary tuberculosis (MTB) patients respectively. CXCR3(+)CCR5(+) T cells were significantly high at the local disease site(s) in both the forms of TB and their frequency was highest among activated lymphocytes in TB-PE. Interestingly, all CCR5(+) cells were invariably positive for CXCR3 but all CXCR3(+) cells did not co-express CCR5 in pleural fluid whereas the situation was reverse in bronchoalveolar lavage. These CXCR3(+)CCR5(+) cells dominantly produced IFN-γ in response to Mycobacterium tuberculosis antigen. In vitro chemotaxis assay indicates dominant role of RANTES and IP-10 in the selective recruitment of CXCR3(+)CCR5(+)cells at the tubercular pathologic sites.

Implications of Pharmacogenetic Testing for Clopidogrel Therapy in a Tertiary Healthcare Hospital in North India.

Background Clopidogrel hyporesponsiveness with decreased antiplatelet activity is prevalent in percutaneous coronary intervention (PCI) patients due to reduced function polymorphism in the CYP2C19 enzyme gene which results in poor conversion of this prodrug to an active metabolite. However, pharmacogenetic testing is not part of routine clinical practice in India. Methodology In this retrospective observational study, we observed the prevalence of loss of function (LOF) gene variants of CYP2C19 (*2, *3) in 60 patients undergoing PCI with complex anatomies in a tertiary healthcare hospital in North India. We do not have follow-up data for a few patients. However, the treatment regimen was recorded, and the occurrence of any clinical event was monitored for the remaining 52 patients for six months. Results The mean age of the patients was 61.76 ± 10.14 years. We found that 52% of patients carried these LOF mutations, of which 37% were intermediate metabolizers, while 15% were poor metabolizers of clopidogrel. However, out of 52 patients for whom follow-up data were available, 22 (42.3%) were intermediate metabolizers, while six (11.54%) showed genotypes associated with poor metabolism of clopidogrel. Clopidogrel (75 mg BD) was the primary replacement drug in place of ticagrelor (90 mg BD) during follow-up after four weeks (based on the clinician's discretion). Conclusions No major ischemic event was reported during the follow-up of these 52 patients. The intermediate metabolizers' LOF in one copy of the CYP2C19 gene seems to overcome genetic deficiency with the clopidogrel 75 mg BD regime, which is comparable to maintenance with ticagrelor 90 mg BD. This study can be extrapolated to a larger cohort to observe statistically significant differences among various groups.

Extremely Elevated Prostate-Specific Antigen in Acute Prostatitis: A Case Report.

Elevated prostate-specific antigen (PSA) levels are mostly suggestive of prostate cancer, but they are elevated in non-cancerous prostatic conditions as well. However, extreme levels of PSA as reported here have not been observed in cases other than prostatic cancer so far. Our patient had a significantly elevated PSA of 1,398 ng/mL in acute prostatitis. The purpose of this case report is to review the patient's atypical and rare presentation of extremely high PSA in acute prostatitis in the background of benign prostatic hyperplasia (BPH) and chronic prostatitis.

Prevalence, Associated Factors, and Impact of Workplace Violence among Physicians.

BACKGROUND: There is a dearth of objective data and studies pertaining to the prevalence and consequences of workplace violence against physicians in Nepal. This study aims to assess the prevalence, associated factors, and implications of workplace violence on Nepalese physicians. METHODS: We conducted a cross-sectional study from March 2021 to August 2021. Nepal Medical Council-certified physicians currently working in Nepal were included in the study. Baseline characteristics, types of violence experienced, patterns, psychosocial impacts, and changes in patient management were collected. RESULTS: Out of 318 responses received, 302 responses met the inclusion criteria and were included in the final analysis. One-hundred and ninety (62.9%) respondents had ever faced workplace violence. Madhesh Province had the highest prevalence (81.5%). Verbal abuse (93.2%) was the most common type of violence encountered. We found a significant association between workplace violence and hours worked each week. We also found an association between workplace violence and years of experience. Our study found a significant increase in stress/depression/anxiety/idea of persecution, sense of defeat, job turnover, and loss of productivity/income with the increase in severity of workplace violence. CONCLUSIONS: Workplace violence is largely prevalent among Nepalese physicians. In the aftermath of workplace violence, a physician can undergo a multitude of adverse psychosocial consequences leading to a further decrease in productivity. More insights through research, formal training, and policy implementation are necessary to overcome this largely ignored problem of the medical fraternity in Nepal.

Implicating effector genes at COVID-19 GWAS loci using promoter-focused Capture-C in disease-relevant immune cell types.

BACKGROUND: SARS-CoV-2 infection results in a broad spectrum of COVID-19 disease, from mild or no symptoms to hospitalization and death. COVID-19 disease severity has been associated with some pre-existing conditions and the magnitude of the adaptive immune response to SARS-CoV-2, and a recent genome-wide association study (GWAS) of the risk of critical illness revealed a significant genetic component. To gain insight into how human genetic variation attenuates or exacerbates disease following SARS-CoV-2 infection, we implicated putatively functional COVID risk variants in the cis-regulatory landscapes of human immune cell types with established roles in disease severity and used high-resolution chromatin conformation capture to map these disease-associated elements to their effector genes. RESULTS: This functional genomic approach implicates 16 genes involved in viral replication, the interferon response, and inflammation. Several of these genes (PAXBP1, IFNAR2, OAS1, OAS3, TNFAIP8L1, GART) were differentially expressed in immune cells from patients with severe versus moderate COVID-19 disease, and we demonstrate a previously unappreciated role for GART in T cell-dependent antibody-producing B cell differentiation in a human tonsillar organoid model. CONCLUSIONS: This study offers immunogenetic insight into the basis of COVID-19 disease severity and implicates new targets for therapeutics that limit SARS-CoV-2 infection and its resultant life-threatening inflammation.

Relationship between xanthophyll cycle and non-photochemical quenching in rice (Oryza sativa L.) plants in response to light stress.

Thirty days old rice plants grown under low and moderate light conditions were transferred to full sunlight to observe the extent of photoinhibitory damage and protective mechanism, and the relationship between xanthophyll cycle and nonphotochemical quenching (qN) under changing light environment. Control plants (low, moderate and sun grown) exhibited similar Fv/Fm ratio, indicating similar photosynthetic efficiency prior to light stress. On exposure to the high light treatment, low light grown plants exhibited faster and higher degree of photoinhibition compared to moderate and high light grown plants. Moderate and high light grown plants showed relatively less photoinhibition and also showed higher qN, indicating better capacity of energy dissipation. Increase in qN in moderate light and sun grown plants was accompanied by conversion of violaxanthin (V) to antheraxanthin (A) and zeaxanthin (Z) indicating operation of Z-dependent thermal dissipation. Rice plants fed with ascorbate (AsA), a stimulator of the de-epoxidation state of V to Z, showed higher Fv/Fm ratio and qN than the plants fed with dithiothreitol (DTT) an inhibitor of xanthophyll cycle. This indicated that an increased amount of energy reached PS II reaction centre, due to absence of A and Z formation, thereby causing greater damage to photosynthesis in DTT fed rice plants. The present data confirmed the relationship between qN and Z in dissipating the excess light energy, thereby protecting plants against photodamage.

Acute Mycophenolate Mofetil Overdose Managed Conservatively.

Mycophenolate mofetil (MMF) is an immunosuppressant drug widely used in post-transplant patients and the treatment of various inflammatory conditions. It is considered a relatively safe drug with minimal adverse effects. We managed an acute overdose of 19 grams (g) of MMF with a suicidal intention in a 17-year-old female with no significant past medical history. Apart from episodes of mild headaches, she did not develop other symptoms, laboratory abnormalities, or complications.

Soluble Guanylate Cyclase Stimulators in Heart Failure.

Heart failure has a high global burden of morbidity and mortality. Despite significant advances in medical management of heart failure, the prognosis remains poor. This justifies the search for newer therapeutic agents. Recently, soluble guanylate stimulators have demonstrated favorable results in clinical trials. This article aims to summarize the guanylate cyclase signaling pathway, the role of soluble guanylate cyclase stimulators in heart failure, and data from recent clinical trials of these drugs. We concluded that soluble guanylate cyclase stimulators have significant benefits in reducing hospitalizations in patients with heart failure with reduced ejection fraction that are at high risk of cardiovascular events. There appears to be no benefit of these drugs in patients with heart failure with preserved ejection fraction.

Serum Metabolic Disturbances Associated with Acute-on-chronic Liver Failure in Patients with Underlying Alcoholic Liver Diseases: An Elaborative NMR-based Metabolomics Study.

OBJECTIVES: Acute-on-chronic liver failure (ACLF), which develops in patients with underlying alcoholic liver disease (ALD), is characterized by acute deterioration of liver function and organ failures are secondary to that. The clear understanding of metabolic pathways perturbed in ALD-ACLF patients can greatly decrease the mortality and morbidity of patients through predicting outcome, guiding treatment, and monitoring response to treatment. The purpose of this study was to investigate the metabolic disturbances associated with ACLF using nuclear magnetic resonance (NMR)-based serum metabolomics approach and further to assess if the serum metabolic alterations are affected by the severity of hepatic impairment. MATERIALS AND METHODS: The serum-metabolic profiles of 40 ALD-ACLF patients were compared to those of 49 age and sex-matched normal-control (NC) subjects making composite use of both multivariate and univariate statistical tests. RESULTS: Compared to NC, the sera of ACLF patients were characterized by significantly decreased serum levels of several amino acids (except methionine and tyrosine), lipid, and membrane metabolites suggesting a kind of nutritional deficiency and disturbed metabolic homeostasis in ACLF. Twelve serum metabolic entities (including BCAA, histidine, alanine, threonine, and glutamine) were found with AUROC (i.e., area under ROC curve) value >0.9 suggesting their potential in clinical diagnosis and surveillance. CONCLUSION: Overall, the study revealed important metabolic changes underlying the pathophysiology of ACLF and those related to disease progression would add value to standard clinical scores of severity to predict outcome and may serve as surrogate endpoints for evaluating treatment response.

FoxP3+ regulatory T cells suppress effector T-cell function at pathologic site in miliary tuberculosis.

RATIONALE: The inadequacy of effector T-cell response in containment of tubercle bacilli is believed to result in the development of disseminated forms of tuberculosis (TB), such as miliary tuberculosis (MTB). Regulatory T cells (Treg) plausibly play a critical role in the immunopathogenesis of disseminated TB by suppression of effector immune response against Mycobacterium tuberculosis at the pathologic site(s). To understand the role of Treg cells in disseminated tuberculosis, we studied the frequency and function of Treg cells derived from the local disease site specimens (LDSS) of patients with TB pleural effusion and MTB as clinical models of contained and disseminated forms of disease, respectively. OBJECTIVES: To (1) enumerate the frequency of Treg cells in bronchoalveolar lavage (BAL) fluid of patients with MTB and compare with that of peripheral blood, (2) study the role of Treg cells in suppression of local T-cell response, and (3) study the selective recruitment of Treg cells at the local disease site(s). METHODS: Flow cytometry, reverse transcriptase polymerase chain reaction, and 3-(4,5-dimethylthythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT)-based cell proliferation assay. MEASUREMENTS AND MAIN RESULTS: Frequency of Treg cells (CD4(+)CD25(+)FoxP3(+)) was significantly higher in LDSS in MTB along with higher levels of FoxP3 mRNA. Importantly, FoxP3(+) Treg cells obtained from the BAL of patients with MTB predominantly produced IL-10 and could suppress the autologous T-cell proliferation in response to M. tuberculosis antigen. CONCLUSIONS: Our results highlight the importance of Treg cells in suppression of effector immune response and their influence on bacillary dissemination, disease manifestation, and severity.

Adaptational changes in the lipids and fatty acid profile of the cell and thylakoid membrane of rice plants exposed to sunlight.

Adaptational changes occurring in the lipids and fatty acids of the cell and the thylakoid membrane in response to high light treatment, was studied in 30 days old rice (Oryza sativa L. cv. Jyothi) plants grown under low (150-200 µmol m(-2) s(-1)) or moderate (600-800 µmol m(-2) s(-1)) light conditions. Results were compared with rice plants grown in high (1200-2200 µmol m(-2) s(-1)) light conditions. Exposure of rice plants and isolated chloroplast to high light, resulted in an increase in the amount of malonaldehyde, indicating oxidation of membrane lipids. Qualitative and quantitative changes in the phosphoglycolipids and quantitative changes in neutral lipids were observed in rice plants grown under the different growth conditions. A few of the phosphoglycolipids and neutral lipids were present exclusively in plants grown at low or moderate or high light, indicating requirement of different type of lipid composition of rice plants in response to their different growth irradiances. However, no significant quantitative changes were observed in the different saturated and unsaturated fatty acid groups of total lipids in low, moderate and high light grown rice plants, as a result of exposure to high light. No qualitative changes in the fatty acid composition due to difference in growth irradiance or high light treatment were seen. The changes observed in the phosphoglycolipids and neutral lipid composition of cell and thylakoid membrane of low, moderate and high light grown rice plants in response to high light, are probably the result of physiological changes in the rice plants, to sustain optimum structure and function of the cell and thylakoid membrane to maintain active physiological functions to endure high light conditions.

On Gradient Descent Optimization in Diffusion-Advection Based 3-D Molecular Cooperative Communication.

This work considers a cooperative communication system in 3-D fluid medium in which the flow of molecules is supported by the drift and the diffusion phenomena. To enhance the system performance, the equal gain combining is used at the destination nanomachine (DN) where the molecular signals arriving from the direct and the cooperative paths are combined together by employing equal weights. Using the gradient descent algorithm, the optimum threshold at DN, and the optimal number of molecules transmitted from source and cooperative nanomachines are obtained. For this purpose, the convex constraints are determined using the closed-form expression for the average probability of error at DN. Finally, the accuracy of the analytical results is validated through the particle/ Monte Carlo-based simulations.

Mapping effector genes at lupus GWAS loci using promoter Capture-C in follicular helper T cells.

Systemic lupus erythematosus (SLE) is mediated by autoreactive antibodies that damage multiple tissues. Genome-wide association studies (GWAS) link >60 loci with SLE risk, but the causal variants and effector genes are largely unknown. We generated high-resolution spatial maps of SLE variant accessibility and gene connectivity in human follicular helper T cells (TFH), a cell type required for anti-nuclear antibodies characteristic of SLE. Of the ~400 potential regulatory variants identified, 90% exhibit spatial proximity to genes distant in the 1D genome sequence, including variants that loop to regulate the canonical TFH genes BCL6 and CXCR5 as confirmed by genome editing. SLE 'variant-to-gene' maps also implicate genes with no known role in TFH/SLE disease biology, including the kinases HIPK1 and MINK1. Targeting these kinases in TFH inhibits production of IL-21, a cytokine crucial for class-switched B cell antibodies. These studies offer mechanistic insight into the SLE-associated regulatory architecture of the human genome.