Search

Individuals within the criminal justice system are at greater risk of substance use–related morbidity and mortality and have substantial healthcare needs. In this quasi-experimental study, we assessed utilization patterns of Massachusetts Medicaid Program (MassHealth) services and associated expenditures among drug court probationers compared to a propensity score–matched sample of traditional court probationers. Risk of reoffending, employment status, age, and living arrangement data were used to calculate propensity scores and match probationers between the two court types, producing a final sample of 271 in each court (N=542). Utilization of services and associated expenditures were analyzed using a two-part model to address the skewed distribution of the data and to control for residual differences after matching from the perspective of the payer (i.e., MassHealth). The largest categories of MassHealth spending were prescription pharmaceuticals, hospital inpatient visits, and physician visits. In the unadjusted analysis, drug court probationers exhibited greater MassHealth services utilization and expenditures than traditional court probationers. However, drug courts enrolled more females, more people at higher risk of reoffending, and more people with opioid use disorders. After controlling for differences between the two court types, the difference in MassHealth services utilization and associated expenditures did not reach statistical significance. Drug court probationers were more likely to engage with healthcare services but did not incur significantly greater expenditures than traditional court probationers after controlling for differences between the samples.

Abstract Background In humans, two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2, catalyze myristate transfer to proteins to facilitate membrane targeting and signaling. We investigated the expression of NMTs in numerous cancers and found that NMT2 levels are dysregulated by epigenetic suppression, particularly so in hematologic malignancies. This suggests that pharmacological inhibition of the remaining NMT1 could allow for the selective killing of these cells, sparing normal cells with both NMTs. Methods and results Transcriptomic analysis of 1200 NMT inhibitor (NMTI)-treated cancer cell lines revealed that NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non-myristoylated proteins are degraded by a glycine-specific N-degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first-in-class NMTI PCLX-001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phosphorylation and respiration, which impacted metabolomes. Conclusions Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zelenirstat in select cancer types. While the prognostic value of the sensitivity score MISS-54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment.

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. The standard treatment achieves a median overall survival for GBM patients of only 15 months. Hence, novel therapies based on an increased understanding of the mechanistic underpinnings of GBM are desperately needed. In this study, we show that elevated expression of 28S rRNA (cytosine‐C(5))‐methyltransferase NSUN5, which methylates cytosine 3782 of 28S rRNA in GBM cells, is strongly associated with the poor survival of GBM patients. Moreover, we demonstrate that overexpression of NSUN5 increases protein synthesis in GBM cells. NSUN5 knockdown decreased protein synthesis, cell proliferation, sphere formation, migration, and resistance to temozolomide in GBM cell lines. NSUN5 knockdown also decreased the number and size of GBM neurospheres in vitro. As a corollary, mice harboring U251 tumors wherein NSUN5 was knocked down survived longer than mice harboring control tumors. Taken together, our results suggest that NSUN5 plays a protumorigenic role in GBM by enabling the enhanced protein synthesis requisite for tumor progression. Accordingly, NSUN5 may be a hitherto unappreciated target for the treatment of GBM.

Abstract Background For more than 20 years, and despite the development of new social networks, health forums have remained a privileged place for people to discuss health issues. This study investigates the motivations of participants to post a message on a French online health forum (called 'Doctissimo') (Forum Santé - Doctissimo, 2022). Method Between January 1, 2017 and December 31, 2019, all the first messages recorded on the health forum doctissimo ( www.forum.doctissimo.fr ) were selected in their initial format by a crawler. The transcripts were imported into the qualitative analysis software Nvivo. Two researchers coded the data until a theoretical saturation was obtained. Results We identified four categories of motivation: 1) 'Questioning' allows the exchange of mainly medical information, or sharing of feedback on experiences with the disease: 1722 codes, 44.8%, 2) Worry, need for reassurance: 1066 codes, 27.7% about symptoms or anticipatory anxiety, 3) 'Expressing oneself' mainly allows a catharsis and thus an emotional release, especially negative, but also to share a personal experience: 764 codes 19.9%, 4) Community spirit is a central element to create an emotional support group for psychological support, exchange ideas, meet people in similar situations: 291 codes, 7.6%. The relationship with a health professional when mentioned is generally marked by doubts 39.5%, confusion, or lack of information and the need for additional elements 64.6% or reassurance 60%. The relationship and the obstacles to a medical consultation are described in relation to the use of the forum: immediate availability, anonymity, absence of taboo and community spirit. Conclusion The use of information sources offered by the Internet is a way to ask questions, to be reassured, to express oneself or to be confirmed by the community in the hypothesis emitted by a health professional. Patients are looking for an immediate answer, they come to the community for reassurance, they feel free and legitimate.

Summary: The central circadian regulator within the suprachiasmatic nucleus transmits time of day information by a diurnal spiking rhythm driven by molecular clock genes controlling membrane excitability. Most brain regions, including the hippocampus, harbor similar intrinsic circadian transcriptional machinery, but whether these molecular programs generate oscillations of membrane properties is unclear. Here, we show that intrinsic excitability of mouse dentate granule neurons exhibits a 24-h oscillation that controls spiking probability. Diurnal changes in excitability are mediated by antiphase G-protein regulation of potassium and sodium currents that reduce excitability during the Light phase. Disruption of the circadian transcriptional machinery by conditional deletion of Bmal1 enhances excitability selectively during the Light phase by removing G-protein regulation. These results reveal that circadian transcriptional machinery regulates intrinsic excitability by coordinated regulation of ion channels by G-protein signaling, highlighting a potential novel mechanism of cell-autonomous oscillations.

ABSTRACT Worldwide, extended-spectrum β-lactamase (ESBL) rates are increasing at an alarming level with increasing rates of health care exposures, international travel, and antibiotic usage. In this study, we investigated whether enhanced social isolation, travel restrictions, and the reduced use of antibiotics in Ontario, Canada during coronavirus disease 2019 (COVID-19) pandemic had an impact on ESBL rates in urine cultures collected from the community and long-term-care (LTC) facilities across the province. Data from a total of 8.6 million urine cultures performed at LifeLabs Ontario from 2016 to 2021 were utilized for analysis. ESBL-producing Escherichia coli (ESBL Escherichia coli) and ESBL Klebsiella pneumoniae were identified using standard operating procedures. Data trends were estimated by interrupted time series (ITS) regression analysis. Among 2.3 million positive urine cultures, 48.9% and 7.2% grew E. coli and K. pneumoniae, of which 5.8% and 3.3% produced ESBLs, respectively. While the overall rate of ESBL isolation was higher in the pandemic period than in the prepandemic period, by ITS regression analysis of the monthly rates of ESBL isolation, decreasing trends were noted for ESBL E. coli in both the community and LTC facilities and for ESBL K. pneumoniae in the community. The ESBL K. pneumoniae rates in LTC facilities continued to increase throughout the COVID-19 period. By subgroup analysis for different genders, age groups, and local health integration network (LHIN) units, similar trends were seen in most cases (P

Host behavioural changes are among the most apparent effects of infection. 'Sickness behaviour' can involve a variety of symptoms, including anorexia, depression, and changed activity levels. Here, using a real-time tracking and behavioural profiling platform, we show that in Drosophila melanogaster, several systemic bacterial infections cause significant increases in physical activity, and that the extent of this activity increase is a predictor of survival time in some lethal infections. Using multiple bacteria and D. melanogaster immune and activity mutants, we show that increased activity is driven by at least two different mechanisms. Increased activity after infection with Micrococcus luteus, a Gram-positive bacterium rapidly cleared by the immune response, strictly requires the Toll ligand spätzle. In contrast, increased activity after infection with Francisella novicida, a Gram-negative bacterium that cannot be cleared by the immune response, is entirely independent of both Toll and the parallel IMD pathway. The existence of multiple signalling mechanisms by which bacterial infections drive increases in physical activity implies that this effect may be an important aspect of the host response.

Abstract Magnetic resonance imaging systems rely on signal detection via radiofrequency coil arrays which, ideally, need to provide both bendability and form-fitting stretchability to conform to the imaging volume. However, most commercial coils are rigid and of fixed size with a substantial mean offset distance of the coil from the anatomy, which compromises the spatial resolution and diagnostic image quality as well as patient comfort. Here, we propose a soft and stretchable receive coil concept based on liquid metal and ultra-stretchable polymer that conforms closely to a desired anatomy. Moreover, its smart geometry provides a self-tuning mechanism to maintain a stable resonance frequency over a wide range of elongation levels. Theoretical analysis and numerical simulations were experimentally confirmed and demonstrated that the proposed coil withstood the unwanted frequency detuning typically observed with other stretchable coils (0.4% for the proposed coil as compared to 4% for a comparable control coil). Moreover, the signal-to-noise ratio of the proposed coil increased by more than 60% as compared to a typical, rigid, commercial coil.

Abstract Background Desoxycorticosterone pivalate (DOCP) is a commonly used mineralocorticoid replacement for dogs with primary hypoadrenocorticism (HA), but manufacturer‐recommended dosing protocols can be cost‐prohibitive. Recent reports also have raised concerns that label dose protocols could be excessive. Objective To investigate the relative efficacy and adverse effects of 2 DOCP dosages in dogs with primary glucocorticoid and mineralocorticoid deficient HA. Animals Thirty‐seven dogs, including 19 test population dogs and 18 controls. Methods Randomized controlled double‐blinded clinical trial. Dogs with newly diagnosed primary HA were assigned to standard (2.2 mg/kg q30d, control population) or low‐dose (1.1 mg/kg q30d, test population) DOCP treatment. Clinical and laboratory variables were assessed 10 to 14 days and approximately 30 days after each DOCP treatment for 90 days. Results Mean serum sodium to potassium ratios at reevaluations were ≥32 in both populations throughout the study. No dog developed electrolyte abnormalities warranting medical treatment, although hypokalemia occurred on at least 1 occasion in 9 controls and 6 test population dogs. Urine specific gravities (median, interquartile range) were lower in control dogs (1.022, 1.016‐1.029) as compared to test population dogs (1.033, 1.023‐1.039; P = .006). Plasma renin activity was overly suppressed on 84 of 104 (80.8%) assessments in control dogs whereas increased renin activity occurred on 23 of 112 (20.5%) assessments in test population dogs. Conclusions and Clinical Importance Low‐dose DOCP protocols appear to be safe and effective for treatment of HA in most dogs. Standard‐dose protocols are more likely to result in biochemical evidence of overtreatment.

N-myristoyltransferases (NMTs) target many signaling proteins to membranes. Here the authors show an NMT inhibitor named PCLX-001 selectively kills lymphoma cells by shutting down their main survival signaling pathway and offers an additional treatment strategy for lymphoma patients.

Protein synthesis suppression protects breast cancer cells from clinically relevant stresses like hypoxia. Here, the authors show that unique mRNA isoforms that govern stem cell-like phenotypes escape translational repression to drive tumor progression and chemoresistance.

Abstract Background Autosomal‐recessive renal tubular dysgenesis (AR‐RTD) is a rare genetic disorder caused by defects in the renin‐angiotensin system that manifests as fetal anuria leading to oligohydramnios and Potter sequence. Although the most common outcome is neonatal death from renal failure, pulmonary hypoplasia, and/or refractory arterial hypotension; several cases have been reported that describe survival past the neonatal period. Methods Herein, we report the first family with biallelic ACE variants and more than one affected child surviving past the neonatal period, as well as provide a review of the previously reported 18 cases with better outcomes. Results While both siblings with identical compound heterozygous ACE variants have received different treatments, neither required renal replacement therapy. We show that both vasopressin and fludrocortisone in the neonatal period may provide survival advantages, though outcomes may also be dependent on the type of gene variant, as well as other factors. Conclusion While AR‐RTD is most often a lethal disease in the neonatal period, it is not universally so. A better understanding of the factors affecting survival will help to guide prognostication and medical decision‐making.

The current study examines COVID-19 prevention behaviors and vaccine intentions among 83 youth at high risk for HIV. Most youth self-identified as Latinx (52%), cisgender men (84%), and homosexual (66%). Youth self-reported COVID-19 prevention behaviors and intentions to vaccinate. Participants reported wearing face masks, washing hands, and staying six feet apart, but fewer reported leaving home only for essential needs. About one-third reported that they would not get a vaccine, and lack of trust in their doctors and the government were significantly associated with non-intention. To improve efforts towards herd immunity, interventions to improve health messaging from trusted sources for at-risk youth may be necessary to achieve higher vaccine uptake.

In the United States, approximately 292,000 adults (>18 years old) per year suffer an in-hospital cardiac arrest (IHCA). Survival rates have increased over the last decade and many survivors return to their communities. IHCA has been recognized as a unique disease entity because the arrest happens in a medical care setting and survivors often have more medical co-morbidities. Although more individuals are surviving IHCA, very little is known about their long-term recovery experiences. Semi-structured interviews with 19 IHCA survivors were conducted to better understand their recovery experiences and identify strategies of adaptation that they felt aided their recovery. Thematic analysis indicated that IHCA survivors experience ongoing challenges to recovery. Reconceptualization of independence was necessary for some participants to re-engage in social and physical activities and a few were able to engage in new activities. Our findings suggest that IHCA survivors often develop their own strategies for adaptation in order to continue participation in their social lives and that their recovery experiences are ongoing. Intervention programs and follow-up care should continuously ask survivors what is important to them and identify resources that will support their goals. Questions should include physical, cognitive, psychological and social goals that extend beyond those specifically related to IHCA since our findings indicate that the effects of IHCA are long-lasting and encompass all aspects of survivors’ lives.

Subspecies of the protozoan parasite Trypanosoma brucei are the causative agents of Human African Trypanosomiasis (HAT), a debilitating neglected tropical disease prevalent across sub-Saharan Africa. HAT case numbers have steadily decreased since the start of the century, and sustainable elimination of one form of the disease is in sight. However, key to this is the development of novel drugs to combat the disease. Acoziborole is a recently developed benzoxaborole, currently in advanced clinical trials, for treatment of stage 1 and stage 2 HAT. Importantly, acoziborole is orally bioavailable, and curative with one dose. Recent studies have made significant progress in determining the molecular mode of action of acoziborole. However, less is known about the potential mechanisms leading to acoziborole resistance in trypanosomes. In this study, an in vitro-derived acoziborole-resistant cell line was generated and characterised. The AcoR line exhibited significant cross-resistance with the methyltransferase inhibitor sinefungin as well as hypersensitisation to known trypanocides. Interestingly, transcriptomics analysis of AcoR cells indicated the parasites had obtained a procyclic- or stumpy-like transcriptome profile, with upregulation of procyclin surface proteins as well as differential regulation of key metabolic genes known to be expressed in a life cycle-specific manner, even in the absence of major morphological changes. However, no changes were observed in transcripts encoding CPSF3, the recently identified protein target of acoziborole. The results suggest that generation of resistance to this novel compound in vitro can be accompanied by transcriptomic switches resembling a procyclic- or stumpy-type phenotype.

A water table mapping method that accounts for surface-water–groundwater (SW-GW) connectivity and human pressure, such as pumping and underground structures occurrence, has been elaborated and tested in the heavily urbanized Parisian area. The method developed here consists of two steps. First, hard data (hydraulic head) and soft data (dry wells) are used as conditioning points for the estimation of the SW-GW connection status. A disconnection criteria of 0.75 m is adjusted on observed unsaturated zone depth (UZD). It is a default value in areas where such data are missing. The second step consists of the final mapping of the water table. Given the knowledge of the disconnection criteria, the final map is achieved with an ordinary kriging of the UZD that integrates the surface water elevation without unsaturated zone where it is relevant. The methodology is demonstrated on two datasets of UZD observations that were collected under low- and high-flow conditions.

The role of climate change (CC) contrarians is neglected in climate change communication studies. Here the authors used a data-driven approach to identify CC contrarians and CC scientists and found that CC scientists have much higher citation impact than those for contrarians but lower media visibility.

Abstract Background To study patient physiology throughout a period of acute hospitalization, we sought to create accessible, standardized nationwide data at the level of the individual patient-facility-day. This methodology paper summarizes the development, organization, and characteristics of the Veterans Affairs Patient Database 2014–2017 (VAPD 2014–2017). The VAPD 2014–2017 contains acute hospitalizations from all parts of the nationwide VA healthcare system with daily physiology including clinical data (labs, vitals, medications, risk scores, etc.), intensive care unit (ICU) indicators, facility, patient, and hospitalization characteristics. Methods The VA data structure and database organization represents a complex multi-hospital system. We define a single-site hospitalization as one or more consecutive stays with an acute treating specialty at a single facility. The VAPD 2014–2017 is structured at the patient-facility-day level, where every patient-day in a hospital is a row with separate identification variables for facility, patient, and hospitalization. The VAPD 2014–2017 includes daily laboratory, vital signs, and inpatient medication. Such data were validated and verified through lab value range and comparison with patient charts. Sepsis, risk scores, and organ dysfunction definitions were standardized and calculated. Results We identified 565,242 single-site hospitalizations (SSHs) in 2014; 558,060 SSHs in 2015; 553,961 SSHs in 2016; and 550,236 SSHs in 2017 at 141 VA hospitals. The average length of stay was four days for all study years. In-hospital mortality decreased from 2014 to 2017 (1.7 to 1.4%), 30-day readmission rates increased from 15.3% in 2014 to 15.6% in 2017; 30-day mortality also decreased from 4.4% in 2014 to 4.1% in 2017. From 2014 to 2017, there were 107,512 (4.8%) of SSHs that met the Center for Disease Control and Prevention’s Electronic Health Record-based retrospective definition of sepsis. Conclusion The VAPD 2014–2017 represents a large, standardized collection of granular data from a heterogeneous nationwide healthcare system. It is also a direct resource for studying the evolution of inpatient physiology during both acute and critical illness.

Livestock diseases caused by Trypanosoma congolense, T. vivax and T. brucei, collectively known as nagana, are responsible for billions of dollars in lost food production annually. There is an urgent need for novel therapeutics. Encouragingly, promising antitrypanosomal benzoxaboroles are under veterinary development. Here, we show that the most efficacious subclass of these compounds are prodrugs activated by trypanosome serine carboxypeptidases (CBPs). Drug-resistance to a development candidate, AN11736, emerged readily in T. brucei, due to partial deletion within the locus containing three tandem copies of the CBP genes. T. congolense parasites, which possess a larger array of related CBPs, also developed resistance to AN11736 through deletion within the locus. A genome-scale screen in T. brucei confirmed CBP loss-of-function as the primary mechanism of resistance and CRISPR-Cas9 editing proved that partial deletion within the locus was sufficient to confer resistance. CBP re-expression in either T. brucei or T. congolense AN11736-resistant lines restored drug-susceptibility. CBPs act by cleaving the benzoxaborole AN11736 to a carboxylic acid derivative, revealing a prodrug activation mechanism. Loss of CBP activity results in massive reduction in net uptake of AN11736, indicating that entry is facilitated by the concentration gradient created by prodrug metabolism.

The origins and causes of infection pathologies are often not understood. Despite this, the study of infection and immunity relies heavily on the ability to discern between potential sources of pathology. Work in the fruit fly has supported the assumption that mortality resulting from bacterial invasion is largely due to direct host-pathogen interactions, as lower pathogen loads are often associated with reduced pathology, and bacterial load upon death is predictable. However, the mechanisms through which these interactions bring about host death are complex. Here we show that infection with the bacterium Francisella novicida leads to metabolic dysregulation and, using treatment with a bacteriostatic antibiotic, we show that this pathology is the result of direct interaction between host and pathogen. We show that mutants of the immune deficiency immune pathway fail to exhibit similar metabolic dysregulation, supporting the idea that the reallocation of resources for immune-related activities contributes to metabolic dysregulation. Targeted investigation into the cross-talk between immune and metabolic pathways has the potential to illuminate some of this interaction.

California is midway through one of the grandest public infrastructure projects ever attempted. Over the coming decade school officials will complete an $82 billion effort, building new schools and renovating old facilities, supported by taxpayers and private investors. But are state officials and local planners building schools mindfully to advance educational quality and lift local communities?After committing one-third of these revenues, students and teachers are feeling robust benefits across the state: fewer pupils are crammed into overcrowded schools; smaller high schools are nurturing stronger relationships between teachers and students; and energy efficient green schools are sprouting, yielding savings for taxpayers. But state policies governing school construction are contributing to some unintended side effects.California can target its $82 billion investment more mindfully to build and renovate schools in ways that raise educational quality and the sustainability of regional economies. Or, the state can squander this historic opportunity, stifling inventive forms of schooling and reinforcing the state’s centrifugal, unsustainable sprawl. That would be one of California’s greatest missed opportunities.Schools are centers of social activity in many communities. They can attract new middle-class families, or convince them to leave for suburban outreaches. This report contributes to a new conversation around how careful school construction can enrich metropolitan areas and sustainable forms of regional development.

Abstract Bladder cancer has a recurrence rate of up to 80% and many patients require multiple treatments that often fail, eventually leading to disease progression. In particular, standard of care for high‐grade disease, Bacillus Calmette–Guérin (BCG), fails in 30% of patients. We have generated a novel oncolytic vaccinia virus (VACV) by mutating the F4L gene that encodes the virus homolog of the cell‐cycle‐regulated small subunit of ribonucleotide reductase (RRM2). The F4L‐deleted VACVs are highly attenuated in normal tissues, and since cancer cells commonly express elevated RRM2 levels, have tumor‐selective replication and cell killing. These F4L‐deleted VACVs replicated selectively in immune‐competent rat AY‐27 and xenografted human RT112‐luc orthotopic bladder cancer models, causing significant tumor regression or complete ablation with no toxicity. It was also observed that rats cured of AY‐27 tumors by VACV treatment developed anti‐tumor immunity as evidenced by tumor rejection upon challenge and by ex vivo cytotoxic T‐lymphocyte assays. Finally, F4L‐deleted VACVs replicated in primary human bladder cancer explants. Our findings demonstrate the enhanced safety and selectivity of F4L‐deleted VACVs, with application as a promising therapy for patients with BCG‐refractory cancers and immune dysregulation.

INTRODUCTION:Patients are at risk for medication problems after hospital admissions, particularly those with critical illness. Medication problems include continuation of acute medications and discontinuation of chronic medications after discharge. Little is known across a national integrated health care system about the extent of these two medication problems. OBJECTIVE:To examine the extent of statin medication discontinuation and new antipsychotic medication use after hospital discharge. DESIGN:Retrospective cohort study. SETTING:Veterans Affairs healthcare system. PARTICIPANTS:Veterans with an inpatient hospitalization from January 1, 2014-December 31, 2016, survived at least 180 days post-discharge, and received at least one medication through the VA outpatient pharmacy within one year around admission were included. Hospitalizations were grouped into: 1) direct admission to the intensive care unit (ICU) and a diagnosis of sepsis, 2) direct admission to the ICU without sepsis diagnosis, and 3) no ICU stay during the hospitalization. MAIN OUTCOME MEASURES:Statin medication discontinuation and new antipsychotic use at six months post-hospital discharge. RESULTS:A total of 520,187 participants were included in the statin medication and 910,629 in the antipsychotic medication cohorts. Statin discontinuation ranged from 10-15% and new antipsychotic prescription fills from 2-4% across the three hospitalization groups, with highest rates in the ICU admission and sepsis diagnosis group. Statin discontinuation and new antipsychotic use after a hospitalization varied by hospital, with worse performing hospitals having 11% higher odds of discontinuing a statin (median odds ratio at hospital-level, adjusted for patient differences, aMOR: 1.11 (95% CI: 1.09, 1.13)) and 29% higher odds of new antipsychotic use (aMOR, 1.29 (95% CI: 1.24, 1.34)). Risk-adjusted hospital rates of these two medication changes were not correlated (p = 0.49). CONCLUSIONS:Systemic variation in the rates of statin medication continuation and new antipsychotic use were found.

Unpaired ligands are secreted signals that act via a GP130-like receptor, domeless, to activate JAK/STAT signalling in Drosophila. Like many mammalian cytokines, unpaireds can be activated by infection and other stresses and can promote insulin resistance in target tissues. However, the importance of this effect in non-inflammatory physiology is unknown. Here, we identify a requirement for unpaired-JAK signalling as a metabolic regulator in healthy adult Drosophila muscle. Adult muscles show basal JAK-STAT signalling activity in the absence of any immune challenge. Plasmatocytes (Drosophila macrophages) are an important source of this tonic signal. Loss of the dome receptor on adult muscles significantly reduces lifespan and causes local and systemic metabolic pathology. These pathologies result from hyperactivation of AKT and consequent deregulation of metabolism. Thus, we identify a cytokine signal that must be received in muscle to control AKT activity and metabolic homeostasis.