Antibiotic Prophylaxis in Patients On Extracorporeal Membrane Oxygenation: A Systematic Review.

Despite the frequent use of prophylactic antibiotics in hospitals for extracorporeal membrane oxygenation (ECMO) patients, the Extracorporeal Life Support Organization (ELSO) Infectious Disease Task Force does not recommend routine antibiotic prophylaxis due to a lack of compelling evidence. We assessed the effectiveness of prophylactic antibiotics in ECMO patients. We conducted a comprehensive search of multiple databases from their inception up to September 6, 2023, on various databases using keywords like "antibiotics," "prophylaxis," "extracorporeal membrane oxygenation," and "ECMO." Newcastle-Ottawa Scale (NOS) was used to assess the quality of the included research. We collected data using Microsoft Excel version 2016, mean and standard deviations were calculated for continuous data, while frequencies and percentages were calculated for binomial data. A total of three studies was included in the review with a total of 8,954 participants, of which 4,483 (50.06%) received antibiotic prophylaxis, and 1,131 (25.22%) were female. The administration of antibiotics prophylactically was associated with reduction in rate of mortality, the risk of infections, and complications like acute kidney injury and diarrhea. Although there have been some benefits on antibiotic prophylaxis, prospective research, and possibly the creation of tailored, ECMO-specific bundles will be needed to identify efficient ways to prevent ECMO infection.

Does Caplacizumab for the management of thrombotic thrombocytopenic purpura increase the risk of relapse, exacerbation, and bleeding? An updated systematic review and meta-analysis based on revised criteria by the International Working Group for thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening condition marked by abnormal blood clotting and organ damage. Caplacizumab is a potential treatment for the TTP management. This systematic review and meta-analysis aimed to assess Caplacizumab's effectiveness and safety in the TTP management. A comprehensive database search identified nine studies, including randomized controlled trials and observational studies. Primary outcomes included TTP exacerbation, relapse, and major bleeding. Major bleeding risk was evaluated using updated definitions recommended by the International TTP Working Group in 2021. Revised criteria proposed by the IWG for TTP recurrence were employed for a comprehensive assessment of Caplacizumab's impact on relapse and exacerbation. Analysis revealed Caplacizumab significantly reduced all-cause mortality in TTP patients. Some studies raised concerns about bleeding risk, but overall, it did not significantly differ from standard treatment. Likewise, there was no significant difference in TTP relapse rates between Caplacizumab and standard care. This study supports Caplacizumab as a potential adjunct therapy for TTP. However, careful consideration of its advantages and risks is crucial in clinical practice. Further research is needed to address concerns related to adverse effects like bleeding risk and relapse rates associated with Caplacizumab in the TTP management. The findings emphasize the importance of weighing potential benefits and risks when considering Caplacizumab as an adjunct therapy for TTP.

Safety and Efficacy of an Implantable Cardioverter Defibrillator (ICD) in the Detection and Prevention of Cardiac Arrhythmia - A Systematic Review.

Implantable cardioverter defibrillators (ICD) have been recommended as an effective therapy in treating sudden cardiac deaths. This study evaluates the safety and efficacies of ICDs in detecting arrhythmias. Different ICDs, such as the transvenous cardioverter defibrillator (TV-ICD) and the subcutaneous implantable cardioverter defibrillator (S-ICD), are used. This systematic review identified Embase, PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), and Web of Science as the primary electronic databases for research. Supplementation of the available articles for the review was done using Google Scholar. The population, exposure, control, outcome, and studies (PECOS) criteria were used in this study. The quality of the included studies was assessed using the Critical Appraisal Skills Program (CASP) standard checklist. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used in this systematic review. Two researchers conducted the extraction of data. A pre-designed Excel worksheet (Microsoft, Redmond, Washington) was used in the recording of extracted data. Eight studies were identified for use in this systematic review. Safety of the ICDs was observed with the minimum number of reported inappropriate shocks. Studies conducted identified that women had a lower number of incidences when a long detection setting by sex was conducted. Strategic programming of ICDs was noted as effective in lowering the levels of mortality. Studies claimed that the reduction of inappropriate shocks were important in the reduction of myocardial damage, which resulted in the mortality rate among the patients decreasing. Having high cutoff rates and long intervals for detection in ICD programming was noted to help in reducing ICD therapy intervention among patients. Differences among the male and female populations were inconsequential in the efficacy and safety of ICDs. Their effectiveness in sensitivity, pacing success, and defibrillation success were high and very significant. ICDs were safe in their use in the detection of arrhythmias.

Single-cell CRISPR screens in vivo map T cell fate regulomes in cancer.

CD8+ cytotoxic T cells (CTLs) orchestrate antitumour immunity and exhibit inherent heterogeneity1,2, with precursor exhausted T (Tpex) cells but not terminally exhausted T (Tex) cells capable of responding to existing immunotherapies3-7. The gene regulatory network that underlies CTL differentiation and whether Tex cell responses can be functionally reinvigorated are incompletely understood. Here we systematically mapped causal gene regulatory networks using single-cell CRISPR screens in vivo and discovered checkpoints for CTL differentiation. First, the exit from quiescence of Tpex cells initiated successive differentiation into intermediate Tex cells. This process is differentially regulated by IKAROS and ETS1, the deficiencies of which dampened and increased mTORC1-associated metabolic activities, respectively. IKAROS-deficient cells accumulated as a metabolically quiescent Tpex cell population with limited differentiation potential following immune checkpoint blockade (ICB). Conversely, targeting ETS1 improved antitumour immunity and ICB efficacy by boosting differentiation of Tpex to intermediate Tex cells and metabolic rewiring. Mechanistically, TCF-1 and BATF are the targets for IKAROS and ETS1, respectively. Second, the RBPJ-IRF1 axis promoted differentiation of intermediate Tex to terminal Tex cells. Accordingly, targeting RBPJ enhanced functional and epigenetic reprogramming of Tex cells towards the proliferative state and improved therapeutic effects and ICB efficacy. Collectively, our study reveals that promoting the exit from quiescence of Tpex cells and enriching the proliferative Tex cell state act as key modalities for antitumour effects and provides a systemic framework to integrate cell fate regulomes and reprogrammable functional determinants for cancer immunity.

Modular chimeric cytokine receptors with leucine zippers enhance the antitumour activity of CAR T cells via JAK/STAT signalling.

The limited availability of cytokines in solid tumours hinders maintenance of the antitumour activity of chimeric antigen receptor (CAR) T cells. Cytokine receptor signalling pathways in CAR T cells can be activated by transgenic expression or injection of cytokines in the tumour, or by engineering the activation of cognate cytokine receptors. However, these strategies are constrained by toxicity arising from the activation of bystander cells, by the suboptimal biodistribution of the cytokines and by downregulation of the cognate receptor. Here we show that replacement of the extracellular domains of heterodimeric cytokine receptors in T cells with two leucine zipper motifs provides optimal Janus kinase/signal transducer and activator of transcription signalling. Such chimeric cytokine receptors, which can be generated for common γ-chain receptors, interleukin-10 and -12 receptors, enabled T cells to survive cytokine starvation without induction of autonomous cell growth, and augmented the effector function of CAR T cells in vitro in the setting of chronic antigen exposure and in human tumour xenografts in mice. As a modular design, leucine zippers can be used to generate constitutively active cytokine receptors in effector immune cells.

The Hidden Threat: Endocrine Disruptors and Their Impact on Insulin Resistance.

The association between Insulin resistance, a global health issue, and endocrine disruptors (EDCs), chemicals interfering with the endocrine system, has sparked concern in the scientific community. This article provides a comprehensive review of the existing literature regarding the intricate relationship between EDCs and insulin resistance. Phthalates, commonly found in consumer products, are well-established EDCs with documented effects on insulin-signaling pathways and metabolic processes. Epidemiological studies have connected phthalate exposure to an increased risk of type 2 diabetes mellitus (T2DM). Perfluoroalkyl substances (PFAS), persistent synthetic compounds, have shown inconsistent associations with T2DM in epidemiological research. However, studies suggest that PFAS may influence insulin resistance and overall metabolic health, with varying effects depending on specific PFAS molecules and study populations. Bisphenol A (BPA), found in plastics and resins, has emerged as a concern for glucose regulation and insulin resistance. Research has linked BPA exposure to T2DM, altered insulin release, obesity, and changes in the mass and function of insulin-secreting ß-cells. Triclosan, an antibacterial agent in personal care products, exhibits gender-specific associations with T2DM risk. It may impact gut microbiota, thyroid hormones, obesity, and inflammation, raising concerns about its effects on metabolic health. Furthermore, environmental EDCs like polycyclic aromatic hydrocarbons, pesticides, and heavy metals have demonstrated associations with T2DM, insulin resistance, hypertension, and obesity. Occupational exposure to specific pesticides and heavy metals has been linked to metabolic abnormalities.

CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer's disease pathology.

Neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by innate immune-mediated inflammation, but functional and mechanistic effects of the adaptive immune system remain unclear. Here we identify brain-resident CD8+ T cells that coexpress CXCR6 and PD-1 and are in proximity to plaque-associated microglia in human and mouse AD brains. We also establish that CD8+ T cells restrict AD pathologies, including ß-amyloid deposition and cognitive decline. Ligand-receptor interaction analysis identifies CXCL16-CXCR6 intercellular communication between microglia and CD8+ T cells. Further, Cxcr6 deficiency impairs accumulation, tissue residency programming and clonal expansion of brain PD-1+CD8+ T cells. Ablation of Cxcr6 or CD8+ T cells ultimately increases proinflammatory cytokine production from microglia, with CXCR6 orchestrating brain CD8+ T cell-microglia colocalization. Collectively, our study reveals protective roles for brain CD8+ T cells and CXCR6 in mouse AD pathogenesis and highlights that microenvironment-specific, intercellular communication orchestrates tissue homeostasis and protection from neuroinflammation.

The Key Role of Glutathione Compared to Curcumin in the Management of Systemic Lupus Erythematosus: A Systematic Review.

In recent years, many documented cases of systemic lupus erythematosus (SLE) have been on the rise. The complicated pathophysiology of the disease makes it challenging to manage. Two databases, PubMed and Google Scholar, have a detailed screening using keywords and Medical Subject Heading (MeSH) combinations. The words are "Systemic Lupus Erythematosus OR SLE OR Lupus," "Glutathione," and "Curcumin." Articles had a detailed process of screening and quality appraisal. Using the English language as a primary filtering parameter, papers over the last 20 years, dating from 2002 to 2022, are the basis of this review. We reviewed all possible human studies documenting the use of curcumin and glutathione for treating SLE. A total of 15 articles are part of this systematic review. Curcumin and glutathione can act as potent drugs for treating lupus. Curcumin can be a more promising alternative since it operates on various pathways and is a more easily accessible source.

PTEN directs developmental and metabolic signaling for innate-like T cell fate and tissue homeostasis.

Phosphatase and tensin homologue (PTEN) is frequently mutated in human cancer, but its roles in lymphopoiesis and tissue homeostasis remain poorly defined. Here we show that PTEN orchestrates a two-step developmental process linking antigen receptor and IL-23-Stat3 signalling to type-17 innate-like T cell generation. Loss of PTEN leads to pronounced accumulation of mature IL-17-producing innate-like T cells in the thymus. IL-23 is essential for their accumulation, and ablation of IL-23 or IL-17 signalling rectifies the reduced survival of female PTEN-haploinsufficient mice that model human patients with PTEN mutations. Single-cell transcriptome and network analyses revealed the dynamic regulation of PTEN, mTOR and metabolic activities that accompanied type-17 cell programming. Furthermore, deletion of mTORC1 or mTORC2 blocks PTEN loss-driven type-17 cell accumulation, and this is further shaped by the Foxo1 and Stat3 pathways. Collectively, our study establishes developmental and metabolic signalling networks underpinning type-17 cell fate decisions and their functional effects at coordinating PTEN-dependent tissue homeostasis.

Prevalence and factors associated with symptoms of depression, anxiety and stress among traffic police officers in Kathmandu, Nepal: a cross-sectional survey.

OBJECTIVE: This study aimed to assess the prevalence of depression, anxiety and stress, associated factors and stress-coping strategies among traffic police officers in Kathmandu, Nepal. DESIGN: Cross-sectional survey. SETTING: Kathmandu Valley, Nepal. PARTICIPANTS: A total of 300 traffic police officers working under the different traffic units of Kathmandu Valley for at least 6 months were recruited via a simple random sampling procedure. PRIMARY OUTCOME MEASURES: State of depression, anxiety and stress among traffic police officers based on the Depression, Anxiety and Stress Scale. SECONDARY OUTCOME MEASURES: Coping strategies under stressful conditions based on the Coping Orientation to Problems Experienced Inventory (Brief-COPE) tool. RESULTS: Altogether 124 (41.3%) traffic police officers had symptoms of depression, 141 (47%) had anxiety symptoms and 132 (44%) had symptoms of stress. Smoking was significantly associated with an increased likelihood of experiencing symptoms of depression (adjusted OR (AOR): 10.7, 95% CI: 4.8 to 23.6), anxiety (AOR: 7.1, 95% CI: 3.4 to 14.9) and stress (AOR: 6.8, 95% CI: 3.3 to 14.1). Similarly, longer working hours was significantly associated with higher odds of experiencing symptoms of depression (AOR: 3.4, 95% CI: 1.8 to 6.4), anxiety (AOR: 2.3, 95% CI: 1.3 to 3.9) and stress (AOR: 1.9, 95% CI: 1.1 to 3.4), and lack of physical exercise was associated with an increased likelihood of exhibiting depressive symptoms (AOR: 2.3, 95% CI: 1.1 to 4.7). Participants in this study used positive coping strategies more than negative coping strategies. CONCLUSION: Our study found a high prevalence of depression, anxiety and stress symptoms among traffic police officers in Kathmandu Valley, Nepal. Smoking and longer working hours were associated with an increased likelihood of experiencing symptoms of depression, anxiety and stress, and lack of physical exercise was associated with an increased likelihood of depressive symptoms.

Emergency Caesarean Section in a COVID-19 Infected Mother in a Primary Health Care Centre.

People from rural areas of Nepal struggle to have access to adequate medical care on time. Most of the tertiary centres are overburdened by patients, while the peripheral health facilities have been unable to function efficiently due to a lack of infrastructures and skilled manpower needed to run hospitals smoothly. We present a case of a 21-year-old primigravida at 41 weeks and 3 days of gestation with mild COVID-19 symptoms who underwent a Caesarean section for non-progression of labour and foetal distress at a primary health care centre in Nepal; however, both maternal and foetal outcomes were favourable. Therefore, upgrading the quality of care in peripheral health facilities can help in the achievement of accessibility, equity, and quality in health care service in Nepal. Keywords: caesarean section; COVID-19; health equity; Nepal; primary health care.

An unconventional presentation of Hip Joint Trevor disease with the involvement of the whole capital femoral epiphysis: A case report and literature review.

Dysplasia epiphysealis hemimelica (DEH) or Trevor's disease is a rare, nonhereditary developmental disorder of skeleton affecting epiphysis and short bones of limbs and characterized by a benign overgrowth of the medial half of the epiphysis resembling osteochondroma. We herein report an unconventional presentation of Trevor's disease of the hip with the involvement of the whole epiphysis. Only a few cases of DEH with such unusual features were found in the literature. The aim of this case report is to spread the awareness among the doctors about an unusual case of DEH with the involvement of the whole capital femoral epiphysis which has been neglected for 10 years. We also discuss the natural history of the development of disease, challenges faced during the course of treatment, clinical results, and complications.

Efficacy and Safety of Medical Marijuana in Migraine Headache: A Systematic Review.

Medical marijuana treatment for migraine is becoming more common, although the legality and societal acceptance of marijuana for medical purposes in the United States have been challenged by the stigma attached to it as a recreational drug. These substances function to reduce nociception and decrease the frequency of migraine by having an impact on the endocannabinoid system. Our study reviewed the clinical response, dosing, and side effects of marijuana in migraine management. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a literature search in PubMed, Google Scholar, and Science Direct, and nine studies were included in the systematic review. The studies demonstrated that medical marijuana has a significant clinical response by reducing the length and frequency of migraines. No severe adverse effects were noted. Due to its effectiveness and convenience, medical marijuana therapy may be helpful for patients suffering from migraines. However, additional clinical trials and observational studies with longer follow-ups are required to study the efficacy and safety of the drug.

CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity.

Nutrients are emerging regulators of adaptive immunity1. Selective nutrients interplay with immunological signals to activate mechanistic target of rapamycin complex 1 (mTORC1), a key driver of cell metabolism2-4, but how these environmental signals are integrated for immune regulation remains unclear. Here we use genome-wide CRISPR screening combined with protein-protein interaction networks to identify regulatory modules that mediate immune receptor- and nutrient-dependent signalling to mTORC1 in mouse regulatory T (Treg) cells. SEC31A is identified to promote mTORC1 activation by interacting with the GATOR2 component SEC13 to protect it from SKP1-dependent proteasomal degradation. Accordingly, loss of SEC31A impairs T cell priming and Treg suppressive function in mice. In addition, the SWI/SNF complex restricts expression of the amino acid sensor CASTOR1, thereby enhancing mTORC1 activation. Moreover, we reveal that the CCDC101-associated SAGA complex is a potent inhibitor of mTORC1, which limits the expression of glucose and amino acid transporters and maintains T cell quiescence in vivo. Specific deletion of Ccdc101 in mouse Treg cells results in uncontrolled inflammation but improved antitumour immunity. Collectively, our results establish epigenetic and post-translational mechanisms that underpin how nutrient transporters, sensors and transducers interplay with immune signals for three-tiered regulation of mTORC1 activity and identify their pivotal roles in licensing T cell immunity and immune tolerance.

Retroversion of the hemipelvis rather than hypoplastic posterior wall decreases acetabular anteversion in hips affected by Perthes disease.

The acetabular retroversion has a moderate incidence of 31-60% in all patients of the Perthes disease. It might be caused by posterior wall dysplasia based on recent animal researches. However, some studies support that hemipelvic retroversion is the main factor for the acetabular retroversion. The primary pathological factor of increasing retroversion angle is still controversial anatomically. This study aimed to identify whether there is acetabular retroversion in children with Perthes disease,and to find a method to distinguish version types. Forty children with unilateral Perthes disease who were admitted to our hospital from January 1, 2012 to December 31, 2018 were enrolled, and 40 controls were matched based on sex and age. The acetabular anteversion angle (AAA), internal wall anteversion angle (IWAA), anterior wall height of the acetabulum (A), acetabular posterior wall height (P), and acetabular width (W) were assessed on computed tomography (CT) at the level of the femoral head center. The acetabular wall difference index (AWDI; AWDI = P-A)/W*100) was calculated. The mean AAA was significantly lower in Perthes disease hips (10.59 (8.05-12.46)) than in contralateral hips (12.04 (9.02-13.33)) (p = 0.002) but did not differ from control hips (9.68 ± 3.76) (p = 0.465). The mean IWAA was significantly lower in Perthes hips (9.16 ± 3.89) than in contralateral hips (11.31 ± 4.04) (p = 0.000) but did not differ from control hips (9.43 ± 3.82) (p = 0.753). The mean AWDI did not differ between Perthes hips (0.41 ± 4.94) and contralateral hips (- 1.12 (- 4.50, 2.17)) (p = 0.06) or control hips (- 0.49 ± 5.46) (p = 0.437). The mean W was significantly higher in Perthes hips (44.61 ± 5.06) than in contralateral hips (43.36 ± 4.38) (p = 0.000) but did not differ from control hips (45.02 ± 5.01) (p = 0.719). The mean A and P did not differ between Perthes hips and contralateral hips or control hips. Correlation analysis of all hip joints revealed a significant correlation between AAAs and IWAAs (r = 0.772; r = 0.643; r = 0.608; and r = 0.540). Linear regression analysis revealed that AAAs increased with IWAAs. Multiple linear regression showed that IWAAs and AWDIs have good predictive value for AAAs in both Perthes and control hips (R2 = 0.842, R2 = 0.869). In patients with unilateral Perthes disease, the affected acetabulum is more retroverted than that on the contralateral side, which may be caused by hemipelvic retroversion. The measurements in this study could distinguish the form of acetabular retroversion. IWAAs and AWDIs can be used as new observations in future studies of acetabular version.

Metabolic control of TFH cells and humoral immunity by phosphatidylethanolamine.

T follicular helper (TFH) cells are crucial for B cell-mediated humoral immunity1. Although transcription factors such as BCL6 drive the differentiation of TFH cells2,3, it is unclear whether and how post-transcriptional and metabolic programs enforce TFH cell programming. Here we show that the cytidine diphosphate (CDP)-ethanolamine pathway co-ordinates the expression and localization of CXCR5 with the responses of TFH cells and humoral immunity. Using in vivo CRISPR-Cas9 screening and functional validation in mice, we identify ETNK1, PCYT2, and SELENOI-enzymes in the CDP-ethanolamine pathway for de novo synthesis of phosphatidylethanolamine (PE)-as selective post-transcriptional regulators of TFH cell differentiation that act by promoting the surface expression and functional effects of CXCR5. TFH cells exhibit unique lipid metabolic programs and PE is distributed to the outer layer of the plasma membrane, where it colocalizes with CXCR5. De novo synthesis of PE through the CDP-ethanolamine pathway co-ordinates these events to prevent the internalization and degradation of CXCR5. Genetic deletion of Pcyt2, but not of Pcyt1a (which mediates the CDP-choline pathway), in activated T cells impairs the differentiation of TFH cells, and this is associated with reduced humoral immune responses. Surface levels of PE and CXCR5 expression on B cells also depend on Pcyt2. Our results reveal that phospholipid metabolism orchestrates post-transcriptional mechanisms for TFH cell differentiation and humoral immunity, highlighting the metabolic control of context-dependent immune signalling and effector programs.

Inhibitory effects of biochanin A on titanium particle-induced osteoclast activation and inflammatory bone resorption via NF-κB and MAPK pathways.

Revision operations have become a new issue after successful artificial joint replacements, and periprosthetic osteolysis leading to prosthetic loosening is the main cause of why the overactivation of osteoclasts (OCs) plays an important role. The effect of biochanin A (BCA) has been examined in osteoporosis, but no study on the role of BCA in prosthetic loosening osteolysis has been conducted yet. In this study, we utilised enzyme-linked immunosorbent assay, computed tomography imaging, and histological analysis. Results showed that BCA downregulated the secretion levels of tumor necrosis factor-α, interleukin-1α (IL-1α), and IL-1ß to suppress inflammatory responses. The secretion levels of receptor-activated nuclear factor-κB ligand, CTX-1, and osteoclast-associated receptor as well as Ti-induced osteolysis were also reduced. BCA effectively inhibited osteoclastogenesis and suppressed hydroxyapatite resorption by downregulating OC-related genes in vitro. Analysis of mechanisms indicated that BCA inhibited the signalling pathways of mitogen-activated protein kinase (P38, extracellular signal-regulated kinase, and c-JUN N-terminal kinase) and nuclear factor-κB (inhibitor κB-α and P65), thereby downregulating the expression of nuclear factor of activated T cell 1 and c-Fos. In conclusion, BCA may be an alternative choice for the prevention of prosthetic loosening caused by OCs.

Protein Prenylation Drives Discrete Signaling Programs for the Differentiation and Maintenance of Effector Treg Cells.

Effector regulatory T (eTreg) cells are essential for immune tolerance and depend upon T cell receptor (TCR) signals for generation. The immunometabolic signaling mechanisms that promote the differentiation and maintenance of eTreg cells remain unclear. Here, we show that isoprenoid-dependent posttranslational lipid modifications dictate eTreg cell accumulation and function by intersecting with TCR-induced intracellular signaling. We find that isoprenoids are essential for activated Treg cell suppressive activity, and Treg cell-specific deletion of the respective farnesylation- and geranylgeranylation-promoting enzymes Fntb or Pggt1b leads to the development of fatal autoimmunity, associated with reduced eTreg cell accumulation. Mechanistically, Fntb promotes eTreg cell maintenance by regulating mTORC1 activity and ICOS expression. In contrast, Pggt1b acts as a rheostat of TCR-dependent transcriptional programming and Rac-mediated signaling for establishment of eTreg cell differentiation and immune tolerance. Therefore, our results identify bidirectional metabolic signaling, specifically between immunoreceptor signaling and metabolism-mediated posttranslational lipid modifications, for the differentiation and maintenance of eTreg cells.

Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy.

Adoptive cell therapy represents a new paradigm in cancer immunotherapy, but it can be limited by the poor persistence and function of transferred T cells1. Here we use an in vivo pooled CRISPR-Cas9 mutagenesis screening approach to demonstrate that, by targeting REGNASE-1, CD8+ T cells are reprogrammed to long-lived effector cells with extensive accumulation, better persistence and robust effector function in tumours. REGNASE-1-deficient CD8+ T cells show markedly improved therapeutic efficacy against mouse models of melanoma and leukaemia. By using a secondary genome-scale CRISPR-Cas9 screening, we identify BATF as the key target of REGNASE-1 and as a rheostat that shapes antitumour responses. Loss of BATF suppresses the increased accumulation and mitochondrial fitness of REGNASE-1-deficient CD8+ T cells. By contrast, the targeting of additional signalling factors-including PTPN2 and SOCS1-improves the therapeutic efficacy of REGNASE-1-deficient CD8+ T cells. Our findings suggest that T cell persistence and effector function can be coordinated in tumour immunity and point to avenues for improving the efficacy of adoptive cell therapy for cancer.

Metabolic signaling directs the reciprocal lineage decisions of αß and γδ T cells.

The interaction between extrinsic factors and intrinsic signal strength governs thymocyte development, but the mechanisms linking them remain elusive. We report that mechanistic target of rapamycin complex 1 (mTORC1) couples microenvironmental cues with metabolic programs to orchestrate the reciprocal development of two fundamentally distinct T cell lineages, the αß and γδ T cells. Developing thymocytes dynamically engage metabolic programs including glycolysis and oxidative phosphorylation, as well as mTORC1 signaling. Loss of RAPTOR-mediated mTORC1 activity impairs the development of αß T cells but promotes γδ T cell generation, associated with disrupted metabolic remodeling of oxidative and glycolytic metabolism. Mechanistically, we identify mTORC1-dependent control of reactive oxygen species production as a key metabolic signal in mediating αß and γδ T cell development, and perturbation of redox homeostasis impinges upon thymocyte fate decisions and mTORC1-associated phenotypes. Furthermore, single-cell RNA sequencing and genetic dissection reveal that mTORC1 links developmental signals from T cell receptors and NOTCH to coordinate metabolic activity and signal strength. Our results establish mTORC1-driven metabolic signaling as a decisive factor for reciprocal αß and γδ T cell development and provide insight into metabolic control of cell signaling and fate decisions.