Proteome profiling identifies a link between the mitochondrial pathways and host-microbial sensor ELMO1 following Salmonella infection.

The host EnguLfment and cell MOtility protein 1 (ELMO1) is a cytosolic microbial sensor that facilitates bacterial sensing, internalization, clearance, and inflammatory responses. We have shown previously that ELMO1 binds bacterial effector proteins, including pathogenic effectors from Salmonella and controls host innate immune signaling. To understand the ELMO1-regulated host pathways, we have performed liquid chromatography Multinotch MS3-Tandem Mass Tag (TMT) multiplexed proteomics to determine the global quantification of proteins regulated by ELMO1 in macrophages during Salmonella infection. Comparative proteome analysis of control and ELMO1-depleted murine J774 macrophages after Salmonella infection quantified more than 7000 proteins with a notable enrichment in mitochondrial-related proteins. Gene ontology enrichment analysis revealed 19 upregulated and 11 downregulated proteins exclusive to ELMO1-depleted cells during infection, belonging to mitochondrial functions, metabolism, vesicle transport, and the immune system. By assessing the cellular energetics via Seahorse analysis, we found that Salmonella infection alters mitochondrial metabolism, shifting it from oxidative phosphorylation to glycolysis. Importantly, these metabolic changes are significantly influenced by the depletion of ELMO1. Furthermore, ELMO1 depletion resulted in a decreased ATP rate index following Salmonella infection, indicating its importance in counteracting the effects of Salmonella on immunometabolism. Among the proteins involved in mitochondrial pathways, mitochondrial fission protein DRP1 was significantly upregulated in ELMO1-depleted cells and in ELMO1-KO mice intestine following Salmonella infection. Pharmacological Inhibition of DRP1 revealed the link of the ELMO1-DRP1 pathway in regulating the pro-inflammatory cytokine TNF-α following infection. The role of ELMO1 has been further characterized by a proteome profile of ELMO1-depleted macrophage infected with SifA mutant and showed the involvement of ELMO1-SifA on mitochondrial function, metabolism and host immune/defense responses. Collectively, these findings unveil a novel role for ELMO1 in modulating mitochondrial functions, potentially pivotal in modulating inflammatory responses. Significance Statement: Host microbial sensing is critical in infection and inflammation. Among these sensors, ELMO1 has emerged as a key regulator, finely tuning innate immune signaling and discriminating between pathogenic and non-pathogenic bacteria through interactions with microbial effectors like SifA of Salmonella . In this study, we employed Multinotch MS3-Tandem Mass Tag (TMT) multiplexed proteomics to determine the proteome alterations mediated by ELMO1 in macrophages following WT and SifA mutant Salmonella infection. Our findings highlight a substantial enrichment of host proteins associated with metabolic pathways and mitochondrial functions. Notably, we validated the mitochondrial fission protein DRP1 that is upregulated in ELMO1-depleted macrophages and in ELMO1 knockout mice intestine after infection. Furthermore, we demonstrated that Salmonella -induced changes in cellular energetics are influenced by the presence of ELMO1. This work shed light on a possible novel link between mitochondrial dynamics and microbial sensing in modulating immune responses.

Ambient Environment and the Epidemiology of Preterm Birth.

Preterm birth (PTB) is associated with substantial mortality and morbidity. We describe environmental factors that may influence PTB risks. We focus on exposures associated with an individual's ambient environment, such as air pollutants, water contaminants, extreme heat, and proximities to point sources (oil/gas development or waste sites) and greenspace. These exposures may further vary by other PTB risk factors such as social constructs and stress. Future examinations of risks associated with ambient environment exposures would benefit from consideration toward multiple exposures - the exposome - and factors that modify risk including variations associated with the structural genome, epigenome, social stressors, and diet.

Intrinsic disorder in the human vitreous proteome.

The vitreous is a vital component of the eye, occupying a substantial portion of its volume and maintaining its structure. This study delves into the presence and significance of intrinsically disordered proteins (IDPs) within the vitreous, utilizing a dataset of 1240 vitreous proteins previously discovered in the vitreous proteome by Murthy et al.in five healthy subjects. The results indicate that 26.9 % of vitreous proteins are highly disordered, 68.8 % possess moderate disorder, and only 4.3 % are highly ordered. A complex interaction network among these proteins suggests their biological importance, and approximately 25 % may undergo liquid-liquid phase separation (LLPS). These findings offer new perspectives on the vitreous' molecular composition and behavior, potentially impacting our understanding of eye-related diseases, physiological changes such as vitreous syneresis. Further research is needed to translate these insights into clinical applications, although the intrinsic protein disorder and its association with LLPS appears to play a role in vitreous proteome function.

Crohn's Patient Serum Proteomics Reveals Response Signature for Infliximab but not Vedolizumab.

BACKGROUND: Crohn's disease is a chronic inflammatory bowel disease that affects the gastrointestinal tract. Common biologic families used to treat Crohn's are tumor necrosis factor (TNF)-α blockers (infliximab and adalimumab) and immune cell adhesion blockers (vedolizumab). Given their differing mechanisms of action, the ability to monitor response and predict treatment efficacy via easy-to-obtain blood draws remains an unmet need. METHODS: To investigate these gaps in knowledge, we leveraged 2 prospective cohorts (LOVE-CD, TAILORIX) and profiled their serum using high-dimensional isobaric-labeled proteomics before treatment and 6 weeks after treatment initiation with either vedolizumab or infliximab. RESULTS: The proportion of patients endoscopically responding to treatment was comparable among infliximab and vedolizumab cohorts; however, the impact of vedolizumab on patient sera was negligible. In contrast, infliximab treatment induced a robust response including increased blood-gas regulatory response proteins, and concomitant decreases in inflammation-related proteins. Further analysis comparing infliximab responders and nonresponders revealed a lingering innate immune enrichments in nonresponders and a unique protease regulation signature related to clotting cascades in responders. Lastly, using samples prior to infliximab treatment, we highlight serum protein biomarkers that potentially predict a positive response to infliximab treatment. CONCLUSIONS: These results will positively impact the determination of appropriate patient treatment and inform the selection of clinical trial outcome metrics.

Measuring long-term exposure to wildfire PM2.5 in California: Time-varying inequities in environmental burden.

Wildfires have become more frequent and intense due to climate change and outdoor wildfire fine particulate matter (PM2.5) concentrations differ from relatively smoothly varying total PM2.5. Thus, we introduced a conceptual model for computing long-term wildfire PM2.5 and assessed disproportionate exposures among marginalized communities. We used monitoring data and statistical techniques to characterize annual wildfire PM2.5 exposure based on intermittent and extreme daily wildfire PM2.5 concentrations in California census tracts (2006 to 2020). Metrics included: 1) weeks with wildfire PM2.5 < 5 µg/m3; 2) days with non-zero wildfire PM2.5; 3) mean wildfire PM2.5 during peak exposure week; 4) smoke waves (≥2 consecutive days with <15 µg/m3 wildfire PM2.5); and 5) mean annual wildfire PM2.5 concentration. We classified tracts by their racial/ethnic composition and CalEnviroScreen (CES) score, an environmental and social vulnerability composite measure. We examined associations of CES and racial/ethnic composition with the wildfire PM2.5 metrics using mixed-effects models. Averaged 2006 to 2020, we detected little difference in exposure by CES score or racial/ethnic composition, except for non-Hispanic American Indian and Alaska Native populations, where a 1-SD increase was associated with higher exposure for 4/5 metrics. CES or racial/ethnic × year interaction term models revealed exposure disparities in some years. Compared to their California-wide representation, the exposed populations of non-Hispanic American Indian and Alaska Native (1.68×, 95% CI: 1.01 to 2.81), white (1.13×, 95% CI: 0.99 to 1.32), and multiracial (1.06×, 95% CI: 0.97 to 1.23) people were over-represented from 2006 to 2020. In conclusion, during our study period in California, we detected disproportionate long-term wildfire PM2.5 exposure for several racial/ethnic groups.

Multiple Dimensions of Environmental Justice and Oil and Gas Development in Pennsylvania.

Background: Community socioeconomic deprivation (CSD) may be related to higher oil and natural gas development (OGD) exposure. We tested for distributive and benefit-sharing environmental injustice in Pennsylvania's Marcellus Shale by examining (1) whether OGD and waste disposal occurred disproportionately in more deprived communities and (2) discordance between the location of land leased for OGD and where oil and gas rights owners resided. Materials and Methods: Analyses took place at the county subdivision level and considered OGD wells, waste disposal, and land lease agreement locations from 2005 to 2019. Using 2005-2009 American Community Survey data, we created a CSD index relevant to community vulnerability in suburban/rural areas. Results: In adjusted regression models accounting for spatial dependence, we observed no association between the CSD index and conventional or unconventional drilled well presence. However, a higher CSD index was linearly associated with odds of a subdivision having an OGD waste disposal site and receiving a larger volume of waste. A higher percentage of oil and gas rights owners lived in the same county subdivision as leased land when the community was least versus most deprived (66% vs. 56% in same county subdivision), suggesting that individuals in more deprived communities were less likely to financially benefit from OGD exposure. Discussion and Conclusions: We observed distributive environmental injustice with respect to well waste disposal and benefit-sharing environmental injustice related to oil and rights owner's residential locations across Pennsylvania's Marcellus Shale. These results add evidence of a disparity between exposure and benefits resulting from OGD.

Giant polyketide synthase enzymes biosynthesize a giant marine polyether biotoxin.

Prymnesium parvum are harmful haptophyte algae that cause massive environmental fish-kills. Their polyketide polyether toxins, the prymnesins, are amongst the largest nonpolymeric compounds in nature, alongside structurally-related health-impacting "red-tide" polyether toxins whose biosynthetic origins have been an enigma for over 40 years. Here we report the 'PKZILLAs', massive P. parvum polyketide synthase (PKS) genes, whose existence and challenging genomic structure evaded prior detection. PKZILLA-1 and -2 encode giant protein products of 4.7 and 3.2 MDa with 140 and 99 enzyme domains, exceeding the largest known protein titin and all other known PKS systems. Their predicted polyene product matches the proposed pre-prymnesin precursor of the 90-carbon-backbone A-type prymnesins. This discovery establishes a model system for microalgal polyether biosynthesis and expands expectations of genetic and enzymatic size limits in biology.

A bacterial sialidase mediates early-life colonization by a pioneering gut commensal.

The early microbial colonization of the gastrointestinal tract can have long-term impacts on development and health. Keystone species, including Bacteroides spp., are prominent in early life and play crucial roles in maintaining the structure of the intestinal ecosystem. However, the process by which a resilient community is curated during early life remains inadequately understood. Here, we show that a single sialidase, NanH, in Bacteroides fragilis mediates stable occupancy of the intestinal mucosa in early life and regulates a commensal colonization program. This program is triggered by sialylated glycans, including those found in human milk oligosaccharides and intestinal mucus. NanH is required for vertical transmission from dams to pups and promotes B. fragilis dominance during early life. Furthermore, NanH facilitates commensal resilience and recovery after antibiotic treatment in a defined microbial community. Collectively, our study reveals a co-evolutionary mechanism between the host and microbiota mediated through host-derived glycans to promote stable colonization.

Ligand-Dependent Mechanisms of C-C Chemokine Receptor 5 (CCR5) Trafficking Revealed by APEX2 Proximity Labeling Proteomics.

CC chemokine receptor 5 (CCR5) contributes to inflammatory responses by driving cell migration and scavenging chemokine to shape directional chemokine gradients. A drug against CCR5 has been approved for blocking HIV entry into cells. However, targeting CCR5 for the treatment of inflammatory diseases and cancer has had limited success because of the complex biology and pharmacology of this receptor. CCR5 is activated by many natural and engineered chemokines that elicit distinct receptor signaling and trafficking responses, including some that sequester the receptor inside the cell. The sequestration phenomenon may be therapeutically exploitable, but the mechanisms by which different ligands traffic CCR5 to different cellular locations are poorly understood. Here we employed live cell ascorbic acid peroxidase proximity labeling and quantitative mass spectrometry proteomics for unbiased discovery of temporally resolved protein neighborhoods of CCR5 following stimulation with its endogenous agonist, CCL5, and two CCL5 variants that promote intracellular retention of the receptor. Along with targeted pharmacological assays, the data reveals distinct ligand-dependent CCR5 trafficking patterns with temporal resolution. All three chemokines internalize CCR5 via ß-arrestin- dependent, clathrin-mediated endocytosis but to different extents, with different kinetics and with varying dependencies on GPCR kinase subtypes. The agonists differ in their ability to target the receptor to lysosomes for degradation, as well as to the Golgi compartment and the trans-Golgi network, and these trafficking patterns translate into distinct levels of ligand scavenging. The results provide insight into the molecular mechanisms behind CCR5 intracellular sequestration and suggest actionable patterns for the development of chemokine-based CCR5 targeting molecules. Significance Statement: CCR5 plays a crucial role in the immune system and is important in numerous physiological and pathological processes such as inflammation, cancer and HIV transmission. Along with its functional diversity, different CCR5 ligands can induce distinct receptor signaling responses and trafficking behaviors; the latter includes intracellular receptor sequestration which offers a potential therapeutic strategy for inhibiting CCR5 function. Using time-resolved proximity labeling proteomics and targeted pharmacological experiments, this study reveals the molecular basis for receptor sequestration including information that can be exploited for the development of CCR5 targeting molecules that promote retention of the receptor inside the cell.

A bacterial sialidase mediates early life colonization by a pioneering gut commensal.

The early microbial colonization of the gastrointestinal tract can lead to long-term impacts in development and overall human health. Keystone species, including Bacteroides spp ., play a crucial role in maintaining the structure, diversity, and function of the intestinal ecosystem. However, the process by which a defined and resilient community is curated and maintained during early life remains inadequately understood. Here, we show that a single sialidase, NanH, in Bacteroides fragilis mediates stable occupancy of the intestinal mucosa and regulates the commensal colonization program during the first weeks of life. This program is triggered by sialylated glycans, including those found in human milk oligosaccharides and intestinal mucus. After examining the dynamics between pioneer gut Bacteroides species in the murine gut, we discovered that NanH enables vertical transmission from dams to pups and promotes B. fragilis dominance during early life. Furthermore, we demonstrate that NanH facilitates commensal resilience and recovery after antibiotic treatment in a defined microbial community. Collectively, our study reveals a co-evolutionary mechanism between the host and the microbiota mediated through host-derived glycans to promote stable intestinal colonization.

Intrinsic disorder in PRAME and its role in uveal melanoma.

INTRODUCTION: The PReferentially expressed Antigen in MElanoma (PRAME) protein has been shown to be an independent biomarker for increased risk of metastasis in Class 1 uveal melanomas (UM). Intrinsically disordered proteins and regions of proteins (IDPs/IDPRs) are proteins that do not have a well-defined three-dimensional structure and have been linked to neoplastic development. Our study aimed to evaluate the presence of intrinsic disorder in PRAME and the role these structureless regions have in PRAME( +) Class 1 UM. METHODS: A bioinformatics study to characterize PRAME's propensity for the intrinsic disorder. We first used the AlphaFold tool to qualitatively assess the protein structure of PRAME. Then we used the Compositional Profiler and a set of per-residue intrinsic disorder predictors to quantify the intrinsic disorder. The Database of Disordered Protein Prediction (D2P2) platform, IUPred, FuzDrop, fIDPnn, AUCpred, SPOT-Disorder2, and metapredict V2 allowed us to evaluate the potential functional disorder of PRAME. Additionally, we used the Search Tool for the Retrieval of Interacting Genes (STRING) to analyze PRAME's potential interactions with other proteins. RESULTS: Our structural analysis showed that PRAME contains intrinsically disordered protein regions (IDPRs), which are structureless and flexible. We found that PRAME is significantly enriched with serine (p-value < 0.05), a disorder-promoting amino acid. PRAME was found to have an average disorder score of 16.49% (i.e., moderately disordered) across six per-residue intrinsic disorder predictors. Our IUPred analysis revealed the presence of disorder-to-order transition (DOT) regions in PRAME near the C-terminus of the protein (residues 475-509). The D2P2 platform predicted a region from approximately 140 and 175 to be highly concentrated with post-translational modifications (PTMs). FuzDrop predicted the PTM hot spot of PRAME to be a droplet-promoting region and an aggregation hotspot. Finally, our analysis using the STRING tool revealed that PRAME has significantly more interactions with other proteins than expected for randomly selected proteins of the same size, with the ability to interact with 84 different partners (STRING analysis result: p-value < 1.0 × 10-16; model confidence: 0.400). CONCLUSION: Our study revealed that PRAME has IDPRs that are possibly linked to its functionality in the context of Class 1 UM. The regions of functionality (i.e., DOT regions, PTM sites, droplet-promoting regions, and aggregation hotspots) are localized to regions of high levels of disorder. PRAME has a complex protein-protein interaction (PPI) network that may be secondary to the structureless features of the polypeptide. Our findings contribute to our understanding of UM and suggest that IDPRs and DOT regions in PRAME may be targeted in developing new therapies for this aggressive cancer. Video Abstract.

Meditation-induced bloodborne factors as an adjuvant treatment to COVID-19 disease.

The COVID-19 pandemic has resulted in significant morbidity and mortality worldwide. Management of the pandemic has relied mainly on SARS-CoV-2 vaccines, while alternative approaches such as meditation, shown to improve immunity, have been largely unexplored. Here, we probe the relationship between meditation and COVID-19 disease and directly test the impact of meditation on the induction of a blood environment that modulates viral infection. We found a significant inverse correlation between length of meditation practice and SARS-CoV-2 infection as well as accelerated resolution of symptomology of those infected. A meditation "dosing" effect was also observed. In cultured human lung cells, blood from experienced meditators induced factors that prevented entry of pseudotyped viruses for SARS-CoV-2 spike protein of both the wild-type Wuhan-1 virus and the Delta variant. We identified and validated SERPINA5, a serine protease inhibitor, as one possible protein factor in the blood of meditators that is necessary and sufficient for limiting pseudovirus entry into cells. In summary, we conclude that meditation can enhance resiliency to viral infection and may serve as a possible adjuvant therapy in the management of the COVID-19 pandemic.

Toward Language Justice in Environmental Health Sciences in the United States: A Case for Spanish as a Language of Science.

BACKGROUND: Increasingly, marginalized communities are disproportionately facing the worsening effects of environmental hazards, including air pollution, water pollution, and climate change. Language isolation and accessibility has been understudied as a determinant of health. Spanish, despite being the second-most common language in the United States with some 41.8 million speakers, has been neglected among environmental health scientists. Building capacity in high-quality Spanish-language science communication, both for scientific and nonscientific audiences, can yield improvements in health disparities research, public health literacy, international collaborations, and diversity and inclusion efforts. OBJECTIVES: In this article, we discuss the context of language diversity in environmental health sciences and offer recommendations for improving science communication in Spanish. DISCUSSION: English is currently the predominant language for scientific discourse, but Spanish and other non-English languages are routinely used by many environmental health science students and professionals, as well as much of the public. To more effectively conduct and communicate environmental health work in Spanish, we suggest that researchers and scientific institutions a) foster structural changes, b) train emerging scholars and support established researchers, c) tap into community ways of knowing, and d) leverage emerging technologies. https://doi.org/10.1289/EHP12306.

Methods in Public Health Environmental Justice Research: a Scoping Review from 2018 to 2021.

PURPOSE OF REVIEW: The volume of public health environmental justice (EJ) research produced by academic institutions increased through 2022. However, the methods used for evaluating EJ in exposure science and epidemiologic studies have not been catalogued. Here, we completed a scoping review of EJ studies published in 19 environmental science and epidemiologic journals from 2018 to 2021 to summarize research types, frameworks, and methods. RECENT FINDINGS: We identified 402 articles that included populations with health disparities as a part of EJ research question and met other inclusion criteria. Most studies (60%) evaluated EJ questions related to socioeconomic status (SES) or race/ethnicity. EJ studies took place in 69 countries, led by the US (n = 246 [61%]). Only 50% of studies explicitly described a theoretical EJ framework in the background, methods, or discussion and just 10% explicitly stated a framework in all three sections. Among exposure studies, the most common area-level exposure was air pollution (40%), whereas chemicals predominated personal exposure studies (35%). Overall, the most common method used for exposure-only EJ analyses was main effect regression modeling (50%); for epidemiologic studies the most common method was effect modification (58%), where an analysis evaluated a health disparity variable as an effect modifier. Based on the results of this scoping review, current methods in public health EJ studies could be bolstered by integrating expertise from other fields (e.g., sociology), conducting community-based participatory research and intervention studies, and using more rigorous, theory-based, and solution-oriented statistical research methods.

Intrinsic Disorder in the Human Tear Proteome.

Purpose: We aimed to characterize the proteome of human tears and assess for the presence of intrinsically disordered proteins (IDPs). IDPs, despite lacking a rigid three-dimensional structure, maintain biological functionality and could shed light on the molecular interactions within tears. Methods: We analyzed a dataset of 1475 proteins identified in the tear film of three healthy subjects. We employed several computational tools, including the Compositional Profiler, Rapid Intrinsic Disorder Analysis Online, Search Tool for the Retrieval of Interacting Genes, and Database of Disordered Protein Predictors to evaluate the intrinsic disorder, protein interactions, and functional characterization of the disordered regions within this proteome. Results: Our analysis showed a notable inclination toward intrinsic disorder. Two out of 10 order-promoting residues and five out of 10 disorder-promoting residues were found enriched. Using the Predictor of Natural Disordered Regions (PONDR) VSL2 output, 95% of these proteins were classified as highly or moderately disordered. We revealed an extensive protein-protein interaction network with significant interaction enrichment. The most disordered proteins exhibited higher disorder binding sites and diverse posttranslational modifications compared to the most ordered ones. Conclusions: To the best of our knowledge, our study is the first comprehensive analysis of intrinsic disorder in the human tear film proteome, and it revealed an abundance of IDPs and their role in protein function and interaction networks. These findings suggest that variations in the intrinsic disorder of a tear film could be impacted by systemic and ocular conditions, offering promising avenues for disease biomarker identification and drug target development. Further research is needed to understand the implications of these findings in human health and disease.

Intrinsic disorder may drive the interaction of PROS1 and MERTK in uveal melanoma.

BACKGROUND: Class 2 uveal melanomas are associated with the inactivation of the BRCA1 ((breast cancer type 1 susceptibility protein)-associated protein 1 (BAP1)) gene. Inactivation of BAP1 promotes the upregulation of vitamin K-dependent protein S (PROS1), which interacts with the tyrosine-protein kinase Mer (MERTK) receptor on M2 macrophages to induce an immunosuppressive environment. METHODS: We simulated the interaction of PROS1 with MERTK with ColabFold. We evaluated PROS1 and MERTK for the presence of intrinsically disordered protein regions (IDPRs) and disorder-to-order (DOT) regions to understand their protein-protein interaction (PPI). We first evaluated the structure of each protein with AlphaFold. We then analyzed specific sequence-based features of the PROS1 and MERTK with a suite of bioinformatics tools. RESULTS: With high-resolution, moderate confidence, we successfully modeled the interaction between PROS1 and MERTK (predicted local distance difference test score (pDLLT) = 70.68). Our structural analysis qualitatively demonstrated IDPRs (i.e., spaghetti-like entities) in PROS1 and MERK. PROS1 was 23.37 % disordered, and MERTK was 23.09 % disordered, classifying them as moderately disordered and flexible proteins. PROS1 was significantly enriched in cysteine, the most order-promoting residue (p-value <0.05). Our IUPred analysis demonstrated that there are two disorder-to-order transition (DOT) regions in PROS1. MERTK was significantly enriched in proline, the most disorder-promoting residue (p-value <0.05), but did not contain DOT regions. Our STRING analysis demonstrated that the PPI network between PROS1 and MERTK is more complex than their assumed one-to-one binding (p-value <2.0 × 10-6). CONCLUSION: Our findings present a novel prediction for the interaction between PROS1 and MERTK. Our findings show that PROS1 and MERTK contain elements of intrinsic disorder. PROS1 has two DOT regions that are attractive immunotherapy targets. We recommend that IDPRs and DOT regions found in PROS1 and MERTK should be considered when developing immunotherapies targeting this PPI.

Fructose-1,6-bisphosphatase is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness.

Insulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen and lipids. How these activities are coordinated to prevent hypoglycemia and hepatosteatosis is unclear. Fructose-1,6-bisphosphatase (FBP1) is rate controlling for gluconeogenesis. However, inborn human FBP1 deficiency does not cause hypoglycemia unless accompanied by fasting or starvation, which also trigger paradoxical hepatomegaly, hepatosteatosis, and hyperlipidemia. Hepatocyte FBP1-ablated mice exhibit identical fasting-conditional pathologies along with AKT hyperactivation, whose inhibition reversed hepatomegaly, hepatosteatosis, and hyperlipidemia but not hypoglycemia. Surprisingly, fasting-mediated AKT hyperactivation is insulin dependent. Independently of its catalytic activity, FBP1 prevents insulin hyperresponsiveness by forming a stable complex with AKT, PP2A-C, and aldolase B (ALDOB), which specifically accelerates AKT dephosphorylation. Enhanced by fasting and weakened by elevated insulin, FBP1:PP2A-C:ALDOB:AKT complex formation, which is disrupted by human FBP1 deficiency mutations or a C-terminal FBP1 truncation, prevents insulin-triggered liver pathologies and maintains lipid and glucose homeostasis. Conversely, an FBP1-derived complex disrupting peptide reverses diet-induced insulin resistance.

Proteome allocation is linked to transcriptional regulation through a modularized transcriptome.

It has proved challenging to quantitatively relate the proteome to the transcriptome on a per-gene basis. Recent advances in data analytics have enabled a biologically meaningful modularization of the bacterial transcriptome. We thus investigated whether matched datasets of transcriptomes and proteomes from bacteria under diverse conditions could be modularized in the same way to reveal novel relationships between their compositions. We found that; 1) the modules of the proteome and the transcriptome are comprised of a similar list of gene products, 2) the modules in the proteome often represent combinations of modules from the transcriptome, 3) known transcriptional and post-translational regulation is reflected in differences between two sets of modules, allowing for knowledge-mapping when interpreting module functions, and 4) through statistical modeling, absolute proteome allocation can be inferred from the transcriptome alone. Quantitative and knowledge-based relationships can thus be found at the genome-scale between the proteome and transcriptome in bacteria.

Temporal Trends of Racial and Socioeconomic Disparities in Population Exposures to Upstream Oil and Gas Development in California.

People living near oil and gas development are exposed to multiple environmental stressors that pose health risks. Some studies suggest these risks are higher for racially and socioeconomically marginalized people, which may be partly attributable to disparities in exposures. We examined whether racially and socioeconomically marginalized people in California are disproportionately exposed to oil and gas wells and associated hazards. We longitudinally assessed exposure to wells during three time periods (2005-2009, 2010-2014, and 2015-2019) using sociodemographic data at the census block group-level. For each block group and time period, we assessed exposure to new, active, retired, and plugged wells, and cumulative production volume. We calculated risk ratios to determine whether marginalized people disproportionately resided near wells (within 1 km). Averaged across the three time periods, we estimated that 1.1 million Californians (3.0%) lived within 1 km of active wells. Nearly 9 million Californians (22.9%) lived within 1 km of plugged wells. The proportion of Black residents near active wells was 42%-49% higher than the proportion of Black residents across California, and the proportion of Hispanic residents near active wells was 4%-13% higher than their statewide proportion. Disparities were greatest in areas with the highest oil and gas production, where the proportion of Black residents was 105%-139% higher than statewide. Socioeconomically marginalized residents also had disproportionately high exposure to wells. Though oil and gas production has declined in California, marginalized communities persistently had disproportionately high exposure to wells, potentially contributing to health disparities.