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Synthetic biology is a powerful tool to create therapeutics which can be rationally designed to enable unique and combinatorial functionalities. Here we utilize non-pathogenic E coli Nissle as a versatile platform for the development of a living biotherapeutic for the treatment of cancer. The engineered bacterial strain, referred to as SYNB1891, targets STING-activation to phagocytic antigen-presenting cells (APCs) in the tumor and activates complementary innate immune pathways. SYNB1891 treatment results in efficacious antitumor immunity with the formation of immunological memory in murine tumor models and robust activation of human APCs. SYNB1891 is designed to meet manufacturability and regulatory requirements with built in biocontainment features which do not compromise its efficacy. This work provides a roadmap for the development of future therapeutics and demonstrates the transformative potential of synthetic biology for the treatment of human disease when drug development criteria are incorporated into the design process for a living medicine. Synthetic biology can be used to create rationally designed living therapeutics. Here the authors engineer E. coli Nissle to target STING activation in antigen presenting cells for the treatment of solid tumors and demonstrate preclinical activity in murine models.

The availability of l -arginine in tumours is a key determinant of an efficient anti-tumour T cell response 1 – 4 . Consequently, increases of typically low l -arginine concentrations within the tumour may greatly potentiate the anti-tumour responses of immune checkpoint inhibitors, such as programmed death-ligand 1 (PD-L1)-blocking antibodies 5 . However, currently no means are available to locally increase intratumoural l -arginine levels. Here we used a synthetic biology approach to develop an engineered probiotic Escherichia coli Nissle 1917 strain that colonizes tumours and continuously converts ammonia, a metabolic waste product that accumulates in tumours 6 , to l -arginine. Colonization of tumours with these bacteria increased intratumoural l -arginine concentrations, increased the number of tumour-infiltrating T cells and had marked synergistic effects with PD-L1 blocking antibodies in the clearance of tumours. The anti-tumour effect of these bacteria was mediated by l -arginine and was dependent on T cells. These results show that engineered microbial therapies enable metabolic modulation of the tumour microenvironment leading to enhanced efficacy of immunotherapies. Injection of engineered bacteria that convert ammonia to l -arginine into tumours enhance the anti-tumour response in a mouse model and synergize with anti-PD-L1 treatment to clear tumours.

Despite considerable interest in the modulation of tumor-associated Foxp3 + regulatory T cells (T regs ) for therapeutic benefit, little is known about the developmental origins of these cells and the nature of the antigens that they recognize. We identified an endogenous population of antigen-specific T regs (termed MJ23 T regs ) found recurrently enriched in the tumors of mice with oncogene-driven prostate cancer. MJ23 T regs were not reactive to a tumor-specific antigen but instead recognized a prostate-associated antigen that was present in tumor-free mice. MJ23 T regs underwent autoimmune regulator (Aire)—dependent thymic development in both male and female mice. Thus, Aire-mediated expression of peripheral tissue antigens drives the thymic development of a subset of organ-specific T regs , which are likely coopted by tumors developing within the associated organ.

Bacterial living therapeutics (BLTs) hold promise for treating cancer and other human diseases because they can be engineered and transported into the microbiota (e.g., of tumors, gastrointestinal tract) to deliver therapeutic payloads. Current approaches rely on the natural tropism of the bacterial chassis used and trigger the local release of protein cargoes, typically through active extracellular secretion or bacterial lysis. BLTs capable of targeting specific cellular subsets and delivering payloads intracellularly might provide new therapeutic opportunities and improve efficacy while reducing off-target effects. We used synthetic biology to develop BLTs that can deliver defined cargo proteins into the cytoplasm of target cells. We designed a modular synthetic bacterium with programmed adhesion to cells by targeting defined cell surface antigen and armed with an inducible type III secretion system (T3SS) for injection of a protein cargo of interest. As a proof of principle, we programmed synthetic bacteria to recognize the epidermal growth factor receptor (EGFR) and inject the catalytic fragments of the potent adenosine diphosphate-ribosyltransferase toxins ExoA and TccC3. These BLTs demonstrated the ability to trigger robust tumor cell death in vitro. Intratumoral administration of these synthetic bacteria suppressed tumor growth in vivo and prolonged the survival of treated animals when the tumor cells were recognized by the engineered bacteria. These results demonstrate the potential of programming cell targeting and controlled protein injection for the development of effective and specific BLTs.

Rapid action suppression is often modeled as a race between 'Go' and 'Stop' processes, but how this corresponds to brain mechanisms has been unclear. The authors recorded simultaneously from multiple rat basal ganglia structures during a Stop-signal task and found Go-related activity in striatum and stop-related activity in the subthalamic nucleus. These distinct signals provide convergent, competing influences over individual cells in the substanti anigra pars reticulata, whose activity reflects whether stopping is successful or not. The results tie together neurophysiology and psychological theory to provide a mechanistic account of how we can or cannot cancel forthcoming actions. Salient cues can prompt the rapid interruption of planned actions. It has been proposed that fast, reactive behavioral inhibition involves specific basal ganglia pathways, and we tested this by comparing activity in multiple rat basal ganglia structures during performance of a stop-signal task. Subthalamic nucleus (STN) neurons exhibited low-latency responses to 'Stop' cues, irrespective of whether actions were canceled or not. By contrast, neurons downstream in the substantia nigra pars reticulata (SNr) only responded to Stop cues in trials with successful cancellation. Recordings and simulations together indicate that this sensorimotor gating arises from the relative timing of two distinct inputs to neurons in the SNr dorsolateral 'core' subregion: cue-related excitation from STN and movement-related inhibition from striatum. Our results support race models of action cancellation, with stopping requiring Stop-cue information to be transmitted from STN to SNr before increased striatal input creates a point of no return.

Brain dopamine is critical for normal motor control, as evidenced by its importance in Parkinson Disease and related disorders. Current hypotheses are that dopamine influences motor control by ‘invigorating’ movements and regulating motor learning. Most evidence for these aspects of dopamine function comes from simple tasks (e.g. lever pressing). Therefore, the influence of dopamine on motor skills requiring multi-joint coordination is unknown. To determine the effects of precisely timed dopamine manipulations on the performance of a complex, finely coordinated dexterous skill, we optogenetically stimulated or inhibited midbrain dopamine neurons as rats performed a skilled reaching task. We found that reach kinematics and coordination between gross and fine movements progressively changed with repeated manipulations. However, once established, rats transitioned abruptly between aberrant and baseline reach kinematics in a dopamine-dependent manner. These results suggest that precisely timed dopamine signals have immediate and long-term influences on motor skill performance, distinct from simply ‘invigorating’ movement.

The second iteration of the Autism Brain Imaging Data Exchange (ABIDE II) aims to enhance the scope of brain connectomics research in Autism Spectrum Disorder (ASD). Consistent with the initial ABIDE effort (ABIDE I), that released 1112 datasets in 2012, this new multisite open-data resource is an aggregate of resting state functional magnetic resonance imaging (MRI) and corresponding structural MRI and phenotypic datasets. ABIDE II includes datasets from an additional 487 individuals with ASD and 557 controls previously collected across 16 international institutions. The combination of ABIDE I and ABIDE II provides investigators with 2156 unique cross-sectional datasets allowing selection of samples for discovery and/or replication. This sample size can also facilitate the identification of neurobiological subgroups, as well as preliminary examinations of sex differences in ASD. Additionally, ABIDE II includes a range of psychiatric variables to inform our understanding of the neural correlates of co-occurring psychopathology; 284 diffusion imaging datasets are also included. It is anticipated that these enhancements will contribute to unraveling key sources of ASD heterogeneity. Design Type(s) data integration objective • observation design Measurement Type(s) nuclear magnetic resonance assay Technology Type(s) digital curation Factor Type(s) research institute • study design • Autism Sample Characteristic(s) Homo sapiens • brain Machine-accessible metadata file describing the reported data (ISA-Tab format)

The COVID-19 pandemic has exceeded 6 million known disease-related deaths and there is evidence of an increase in maternal deaths, especially in low- and middle-income countries. We aimed to estimate excess maternal deaths in Brazil and its macroregions as well as their trajectories in the first 15 months of the COVID-19 epidemic. This study evaluated maternal deaths from the Mortality Information System of the Ministry of Health, with excess deaths being assessed between March 2020 and May 2021 by quasi-Poisson generalized additive models adjusted for overdispersion. Observed deaths were compared to deaths expected without the pandemic, accompanied by 95% confidence intervals according to region, age group, and trimester of occurrence. Analyses were conducted in R version 3.6.1 and RStudio version 1.2.1335. There were 3,291 notified maternal deaths during the study period, resulting in a 70% excess of deaths regardless of region, while in the North, Northeast, South and Southeast regions, excess deaths occurred regardless of age group. Excess deaths occurred in the March-May 2021 trimester regardless of region and age group. Excess deaths were observed in the Southeast region for the 25-36-year-old age group regardless of the trimester assessed, and in the North, Central-West and South regions, the only period in which excess deaths were not observed was September-November 2020. Excess deaths regardless of trimester were observed in the 37-49-year-old age group in the North region, and the South region displayed explosive behavior from March-May 2021, with a 375% excess of deaths. Excess maternal deaths, with geographically heterogenous trajectories and consistently high patterns at the time of the epidemic's greatest impact, reflect not only the previous effect of socioeconomic inequalities and of limited access to maternal health services, but most of all the precarious management of Brazil's health crisis.

Calcineurin inhibitors (CNI), the cornerstone of immunosuppression after transplantation are implicated in nephrotoxicity and allograft dysfunction. We hypothesized that combined low doses of CNI and Everolimus (EVR) may result in better graft outcomes and greater tolerogenic milieu. Forty adult renal transplant recipients were prospectively randomized to (steroid free) low dose Tacrolimus (TAC) and EVR or standard dose TAC and Mycophenolate (MMF) after Alemtuzumab induction. Baseline characteristics were statistically similar. EVR levels were maintained at 3-8 ng/ml. TAC levels were 4.5±1.9 and 6.4±1.5 ng/ml in the TAC+EVR and TAC+MMF group respectively. Follow up was 14±4 and 17±5 months respectively and included protocol kidney biopsies at 3 and 12 months post-transplantation. Rejection-rate was lower in the TAC+EVR group. However patient and overall graft survival, eGFR and incidence of adverse events were similar. TAC+EVR induced expansion of CD4+CD25hiFoxp3+ regulatory T cells as early as 3 months and expansion of IFN-γ+CD4+CD25hiFoxp3+ regulatory T cells at 12 months post-transplant. Gene expression profile showed a trend toward decreased inflammation, angiogenesis and connective tissue growth in the TAC+EVR Group. Thus, greater tolerogenic mechanisms were found to be operating in patients with low dose TAC+EVR and this might be responsible for the lower rejection-rate than in patients on standard dose TAC+MMF. However, further studies with longer follow up and evaluating impact on T regulatory cells are warranted.

Methamphetamine (MA) use disorder is a serious psychiatric condition for which there are no FDA-approved medications. Naltrexone (NTX) is an opioid receptor antagonist with demonstrated efficacy, albeit moderate, for the treatment of alcoholism and opioid dependence. Preclinical and clinical studies suggest that NTX may be useful for the treatment of MA use disorder. To inform treatment development, we conducted a double-blind, randomized, crossover, placebo-controlled human laboratory study of NTX. Non-treatment-seeking individuals meeting DSM-IV criteria for MA abuse or dependence (n=30) completed two separate 5-day inpatient stays. During each admission, participants completed testing sessions comprised of MA cue-reactivity and intravenous MA administration (30 mg) after receiving oral NTX (50 mg) or placebo for 4 days. This study tested the hypotheses that NTX would (a) attenuate cue-induced MA craving, and (b) reduce subjective responses to MA administration. Results largely supported the study hypotheses such that (a) NTX significantly blunted cue-induced craving for MA and (b) attenuated several of the hedonic subjective effects of MA, including craving, during controlled MA administration and as compared with placebo. NTX decreased overall subjective ratings of 'crave drug,' 'stimulated,' and 'would like drug access,' decreased the the post-MA administration timecourse of 'anxious' and increased ratings of 'bad drug effects,' as compared with placebo. These findings support a potential mechanism of action by showing that NTX reduced cue-induced craving and subjective responses to MA. This is consistent with positive treatment studies of NTX for amphetamine dependence, as well as ongoing clinical trials for MA.