Biology subjects

Srinivasan, S.

Publications and source records attributed to Srinivasan, S..

At least 127 records · Page 7Linked to original sources

bioRxiv2020

Mis-annotated multi nucleotide variants in public cancer genomics datasets can lead to inaccurate mutation calls with significant implications

BackgroundNext generation sequencing is widely used in cancer to profile tumors and detect variants. Most somatic variant callers used in these pipelines identify variants at the lowest possible granularity - single nucleotide variants (SNVs). As a result, multiple adjacent SNVs are called individually instead of as a multi-nucleotide variant (MNV). The problem with this level of granularity is that the amino acid change from the individual SNVs within a codon could be different from the amino acid change based on the MNV that results from combining the SNVs. Most variant annotation tools do not account for this, leading to incorrect conclusions about the downstream effects of the variants. MethodHere, we used Variant Call Files (VCFs) from the TCGA Mutect2 caller, and developed a solution to merge SNVs to MNVs. Our custom script takes the phasing information from the SNV VCFs and based on a gene model, determines if SNVs are at the same codon and need to be merged into a MNV prior to variant annotation. ResultsWe analyzed 10,383 VCFs from TCGA and found 12,141 MNVs that were incorrectly annotated. Strikingly, the analysis of seven commonly mutated genes from 178 studies from cBioPortal revealed that MNVs were consistently missed in 20 of these studies, while they were correctly annotated in 15 more recent studies. The best and most common example of MNVs was found at the BRAF V600 locus, where several public datasets reported separate BRAF V600E and BRAF V600M variants, instead of a single merged V600K variant. ConclusionWhile some datasets merged MNVs correctly, many public datasets have not been corrected for this problem. As a best practice for variant calling, we recommend that MNVs be accounted for in NGS processing pipelines, thus improving analyses on the impact of somatic variants in cancer genomics.

genomics↗

bioRxiv2020

Hidden features of the malaria vectormosquito, Anopheles stephensi ,revealed by a high-quality referencegenome

BackgroundThe mosquito Anopheles stephensi is a vector of urban malaria in Asia that recently invaded Africa. Studying the genetic basis of vectorial capacity and engineering genetic interventions are both impeded by limitations of a vectors genome assembly. The existing assemblies of An. stephensi are draft-quality and contain thousands of sequence gaps, potentially missing genetic elements important for its biology and evolution. ResultsTo access previously intractable genomic regions, we generated a reference-grade genome assembly and full transcript annotations that achieve a new standard for reference genomes of disease vectors. Here, we report novel species-specific transposable element families and insertions in functional genetic elements, demonstrating the widespread role of TEs in genome evolution and phenotypic variation. We discovered 29 previously hidden members of insecticide resistance genes, uncovering new candidate genetic elements for the widespread insecticide resistance observed in An. stephensi. We identified 2.4 Mb of the Y-chromosome and seven new male-linked gene candidates, representing the most extensive coverage of the Y-chromosome in any mosquito. By tracking full length mRNA for >15 days following blood feeding, we discover distinct roles of previously uncharacterized genes in blood metabolism and female reproduction. The Y-linked heterochromatin landscape reveals extensive accumulation of long-terminal repeat retrotransposons throughout the evolution and degeneration of this chromosome. Finally, we identify a novel Y-linked putative transcription factor that is expressed constitutively through male development and adulthood, suggesting an important role throughout male development. ConclusionCollectively, these results and resources underscore the significance of previously hidden genomic elements in the biology of malaria mosquitoes and will accelerate development of genetic control strategies of malaria transmission.

genomics↗

bioRxiv2020

A Feedforward Loop Governs The Relationship Between Lipid Metabolism And Longevity

The relationship between lipid metabolism and longevity remains unclear. In particular although fat oxidation is essential for weight loss, whether it is remains beneficial when sustained for long periods, and the extent to which it may alter lifespan remains an important unanswered question. Here we develop an experimental handle in the C. elegans model system, that uncovers the mechanisms that connect long-term fat oxidation with longevity. We find that sustained {square}-oxidation, via activation of the conserved triglyceride lipase ATGL-1, triggers a feedforward transcriptional loop that involves the mito-nuclear transcription factor ATFS-1, and a previously unknown and highly conserved repressor of ATGL-1 called HLH-11/AP4. This feedforward loop orchestrates the dual control of fat oxidation and lifespan protection, shielding the organism from life-shortening mitochondrial stress in the face of continuous fat oxidation. Thus, we uncover one mechanism by which fat oxidation can be sustained for long periods without deleterious effects on longevity.

cell biology↗

bioRxiv2020

A near-chromosome level genome assembly of Anopheles stephensi

Malaria remains a major healthcare risk to growing economies like India and a chromosome-level reference genome of Anopheles stephensi is critical for successful vector management and an understanding of vector evolution. We report a chromosome-level assembly of an Indian strain from draft genomes of two strains using a homology-based iterative approach. The resulting assembly with an L50 of 9 had long enough scaffolds for building 90% of the three chromosomes using physical markers. The sequencing of individuals reveals a genetic diversity ten times higher than what is reported. Based on the developmental transcriptome and orthology of the 54 olfactory receptors (ORs) to those of other Anopheles species, we identify olfactory receptors with the potential for host recognition in the genus Anopheles. A comparative analysis of the genomes suggests limited inter-chromosomal gene flow and chromosomal arm switching with a potential role in adaptive radiation within the genus Anopheles.

genomics↗

bioRxiv2020

Individualized System for Augmenting Ventilator Efficacy (iSAVE):A Rapidly deployable system to expand ventilator capacity

The COVID-19 pandemic is overwhelming healthcare systems worldwide. A significant portion of COVID-19 patients develop pneumonia and acute respiratory distress syndrome (ARDS), necessitating ventilator support. Some health systems do not have the capacity to accommodate this surge in ventilator demand, leading to shortages and inevitable mortality. Some clinicians have, of necessity, jerry-rigged ventilators to support multiple patients, but these devices lack protected air streams or individualized controls for each patient. Moreover, some have not been tested under conditions of ARDS. We have developed the Individualized System for Augmenting Ventilator Efficacy (iSAVE), a rapidly deployable platform to more safely use a single ventilator to simultaneously support multiple critically-ill patients. The iSAVE enables patient-specific volume and pressure control and incorporates safety features to mitigate cross-contamination between patients and flow changes due to patient interdependencies within the respiratory circuit. Here we demonstrate through simulated and in vivo pig evaluation the capacity of the iSAVE to support a range of respiratory clinical states. By leveraging off-the-shelf components that are readily available to intensive care unit (ICU) caregivers, the iSAVE could potentially be translated for human application to expand the ventilation capacity of hospitals using existing ventilators, minimizing the need to procure additional ventilators.

physiology↗

bioRxiv2020

Structural genomics and interactomics of 2019 Wuhan novel coronavirus, 2019-nCoV, indicate evolutionary conserved functional regions of viral proteins

During its first month, the recently emerged 2019 Wuhan novel coronavirus (2019-nCoV) has already infected many thousands of people in mainland China and worldwide and took hundreds of lives. However, the swiftly spreading virus also caused an unprecedentedly rapid response from the research community facing the unknown health challenge of potentially enormous proportions. Unfortunately, the experimental research to understand the molecular mechanisms behind the viral infection and to design a vaccine or antivirals is costly and takes months to develop. To expedite the advancement of our knowledge we leverage the data about the related coronaviruses that is readily available in public databases, and integrate these data into a single computational pipeline. As a result, we provide a comprehensive structural genomics and interactomics road-maps of 2019-nCoV and use these information to infer the possible functional differences and similarities with the related SARS coronavirus. All data are made publicly available to the research community at http://korkinlab.org/wuhan

bioinformatics↗

bioRxiv2020

Cdc42 is required for lymphatic branching, maturation and valve formation during embryonic development

Cdc42, a Ras-related GTPase that regulates the actin cytoskeleton, was recently shown to play an indispensable role in vasculogenesis and endothelial cell (EC) survival. Here, we determined whether Cdc42 also contributes to lymphatic development by generated two different Cdc42 knockout mice lines by crossing Cdc42/flox mice with either vascular endothelial cadherin-Cre (Cdh5-Cre) mice or Prox1-CreERT2 mice. Our results demonstrated that depleting ECs of Cdc42 expression resulted in embryonic lethality with severe edema. Whole-mount immunofluorescence staining of both knockout embryos showed that the deletion of Cdc42 in ECs impaired lymphatic vessel branching and that the lymphatic lumen size significantly increased. Moreover, we found that the inactivation of Cdc42 compromised mesenteric collecting lymphatic vessel maturation and prevented valve formation. We go on to show that Cdc42 can be activated by vascular endothelial growth factor c (VEGFc) in cultured human dermal lymphatic ECs (HDLECs), and that knocking down Cdc42 expression in these cells using siRNA decreased VEGFc-induced focal adhesion kinase (FAK) phosphorylation. These findings, when taken together with the fact that inactivating FAK plus one allele of Cdc42 in ECs was sufficient to recapitulate the phenotypes of the Cdc42 EC knockout embryos, suggests that Cdc42 and FAK interact genetically during lymphatic development. In addition, Cdc42 and FAK regulated signal transduction is essential for blood and lymphatic vessel separation. Taken together, our data highlights the important role played by Cdc42 in the development of the lymphatic system.

developmental biology↗

bioRxiv2019

Zoonotic tuberculosis in India: looking beyond Mycobacterium bovis

BackgroundZoonotic tuberculosis (zTB) is the transmission of Mycobacterium tuberculosis complex (MTBC) subspecies from animals to humans. zTB is generally quantified by determining the proportion of human isolates that are Mycobacterium bovis. Although India has the worlds largest number of human TB cases and the largest cattle population, where bovine TB is endemic, the burden of zTB is unknown. MethodsTo obtain estimates of zTB in India, a PCR-based approach was applied to sub-speciate positive MGIT(R) cultures from 940 patients (548 pulmonary, 392 extrapulmonary disease) at a large referral hospital in India. Twenty-five isolates of interest were subject to whole genome sequencing (WGS) and compared with 715 publicly available MTBC sequences from South Asia. FindingsA conclusive identification was obtained for 939 samples; wildtype M. bovis was not identified (95% CI: 0 - 0.4%). There were 912 M. tuberculosis sensu stricto (97.0%, 95% CI: 95.7 - 98.0), 7 M. orygis (95% CI: 0.3 - 1.5%); 5 M. bovis BCG, and 15 non-tuberculous mycobacteria. WGS analysis of 715 MTBC sequences again identified no M. bovis (95% CI: 0 - 0.4%). Human and cattle MTBC isolates were interspersed within the M. orgyis and M. tuberculosis sensu stricto lineages. InterpretationM. bovis prevalence in humans is an inadequate proxy of zTB in India. The recovery of M. orygis from humans, together with the finding of M. tuberculosis in cattle, underscores the need for One Health investigations to assess the burden of zTB in countries with endemic bovine TB. FundingBill & Melinda Gates Foundation, Canadian Institutes for Health Research

microbiology↗

bioRxiv2019

Human iPSC modeling elucidates mutation-specific responses to gene therapy in a genotypically diverse dominant maculopathy

Dominantly inherited disorders are not typically considered therapeutic candidates for gene augmentation. Here, we utilized patient-specific induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) to test the potential of gene augmentation to treat Best disease, a dominant macular dystrophy caused by over 200 missense mutations in BEST1. Gene augmentation in iPSC-RPE fully restored BEST1 calcium-activated chloride channel activity and improved rhodopsin degradation in iPSC-RPE models of recessive bestrophinopathy and dominant Best disease caused by two different ion binding domain mutations. A dominant Best disease iPSC-RPE model that did not respond to gene augmentation showed normalization of BEST1 channel activity following CRISPR-Cas9 editing of the mutant allele. We then tested gene editing in all three dominant Best disease iPSC-RPE models, which produced premature stop codons exclusively within the mutant BEST1 alleles. Single-cell profiling demonstrated no adverse perturbation of RPE transcriptional programs in any model, although off-target analysis detected a silent genomic alteration in one model. These results suggest that gene augmentation is a viable first-line approach for some dominant Best disease patients and that non-responders are candidates for alternate approaches such as genome editing. However, testing genome editing strategies for on-target efficiency and off-target events using patient-matched iPSC-RPE model systems is warranted. In summary, personalized iPSC-RPE models can be used to select among a growing list of gene therapy options to maximize safety and efficacy while minimizing time and cost. Similar scenarios likely exist for other genotypically diverse channelopathies, expanding the therapeutic landscape for affected patients. SignificanceDominantly inherited disorders pose distinct challenges for gene therapies, particularly in the face of extreme mutational diversity. We tested whether a broad gene replacement strategy could reverse the cellular phenotype of Best disease, a dominant blinding condition that targets retinal pigment epithelium (RPE). Using RPE generated from patient-specific induced pluripotent stem cells (iPSCs), we show that gene replacement functionally overcomes some, but not all, of the tested mutations. In comparison, all dominant Best disease models tested were phenotypically corrected after mutation-specific genome editing, although one off-target genomic alteration was discovered. Our results support a two-tiered approach to gene therapy for Best disease, guided by safety and efficacy testing in iPSC-RPE models to maximize personal and public health value.

genetics↗

bioRxiv2019

Enriching human interactome with functional mutations to detect high-impact network modules underlying complex diseases

Progress in high-throughput -omics technologies moves us one step closer to the datacalypse in life sciences. In spite of the already generated volumes of data, our knowledge of the molecular mechanisms underlying complex genetic diseases remains limited. Increasing evidence shows that biological networks are essential, albeit not sufficient, for the better understanding of these mechanisms. The identification of disease-specific functional modules in the human interactome can provide a more focused insight into the mechanistic nature of the disease. However, carving a disease network module from the whole interactome is a difficult task. In this paper, we propose a computational framework, DIMSUM, which enables the integration of genome-wide association studies (GWAS), functional effects of mutations, and protein-protein interaction (PPI) network to improve disease module detection. Specifically, our approach incorporates and propagates the functional impact of non-synonymous single nucleotide polymorphisms (nsSNPs) on PPIs to implicate the genes that are most likely influenced by the disruptive mutations, and to identify the module with the greatest impact. Comparison against state-of-the-art seed-based module detection methods shows that our approach could yield modules that are biologically more relevant and have stronger association with the studied disease. We expect for our method to become a part of the common toolbox for disease module analysis, facilitating discovery of new disease markers.

bioinformatics↗

bioRxiv2019

GATA2 controls lymphatic endothelial cell junctional integrity and lymphovenous valve morphogenesis through miR-126

Mutations in the transcription factor GATA2 cause lymphedema. GATA2 is necessary for the development of lymphatic valves (LVs) and lymphovenous valves (LVVs), and for the patterning of lymphatic vessels. Here, we report that GATA2 is not necessary for valvular endothelial cell (VEC) differentiation. Instead, GATA2 is required for VEC maintenance and morphogenesis. GATA2 is also necessary for the expression of cell junction molecules VE-Cadherin and Claudin5 in lymphatic vessels. We identified miR-126 as a target of GATA2, and miR-126-/- embryos recapitulate the phenotypes of mice lacking GATA2. Primary human lymphatic endothelial cells (HLECs) lacking GATA2 (GATA2{Delta}HLEC) have altered expression of Claudin5 and VE-Cadherin, and blocking miR-126 activity in HLECs phenocopies these changes in expression. Importantly, overexpression of miR-126 in GATA2{Delta}HLEC significantly rescues the cell junction defects. Thus, our work defines a new mechanism of GATA2 and uncovers miR-126 as a novel regulator of mammalian lymphatic vascular development.\n\nNon-standard abbreviationsLECs, lymphatic endothelial cells; LVs, lymphatic valves; LV-ECs, lymphatic valve-forming endothelial cells; LVVs, lymphovenous valves; LVV-ECs, lymphovenous valve-forming endothelial cells; HLEC, primary human LECs; OSS, Oscillatory shear stress; IHC, immunohistochemistry.

developmental biology↗

bioRxiv2019

Comparison of miRNA profiling methods using synthetic miRNA pools and standardized exRNA samples reveals substantial performance differences

MicroRNAs (miRNAs) found in biofluids play functional roles in health and in disease pathogenesis, underpinning their potential as clinical biomarkers. Several platforms for measurement of extracellular RNAs have recently become available. We evaluated the reproducibility, accuracy, sensitivity, and specificity of four miRNA quantification platforms, including one widely used discovery approach (small RNA-seq) and three targeted platforms (FirePlex, EdgeSeq, and nCounter). Using pools of synthetic miRNAs, we observed that reproducibility was highest for RNA-seq and EdgeSeq, that all three targeted platforms had lower bias than RNA-seq, and that RNA-seq had the best ability to distinguish between present and absent sequences. Overall reproducibility was lower for plasma samples than synthetic miRNA pools. We compared expression of placental miRNAs in plasma from pregnant and non-pregnant women and observed expected differences with RNA-seq and EdgeSeq, but not FirePlex or nCounter. We conclude that differences in performance among miRNA profiling platforms impact their relative utility as potential assay systems for clinical biomarkers.

genomics↗

bioRxiv2019

Knowledge-guided analysis of ‘omics’ data using the KnowEnG cloud platform

We present KnowEnG, a free-to-use computational system for analysis of genomics data sets, designed to accelerate biomedical discovery. It includes tools for popular bioinformatics tasks such as gene prioritization, sample clustering, gene set analysis and expression signature analysis. The system offers knowledge-guided data-mining and machine learning algorithms, where user-provided data are analyzed in light of prior information about genes, aggregated from numerous knowledge-bases and encoded in a massive Knowledge Network. KnowEnG adheres to FAIR principles: its tools are easily portable to diverse computing environments, run on the cloud for scalable and cost-effective execution of compute-intensive and data-intensive algorithms, and are interoperable with other computing platforms. They are made available through multiple access modes including a web-portal, and include specialized visualization modules. We present use cases and re-analysis of published cancer data sets using KnowEnG tools and demonstrate its potential value in democratization of advanced tools for the modern genomics era.

cancer biology↗

bioRxiv2019

Mycobacterium tuberculosis reactivates HIV via exosomes mediated resetting of cellular redox potential and bioenergetics

The synergy between Mycobacterium tuberculosis (Mtb) and HIV-1 interferes with therapy and facilitates pathogenesis of both human pathogens. Fundamental mechanisms by which Mtb exacerbates HIV-1 are not clear. Here, we show that exosomes secreted by macrophages infected with Mtb, including drug-resistant clinical strains, reactivate HIV-1 by inducing oxidative stress. Mechanistically, Mtb-specific exosomes realign mitochondrial and non-mitochondrial oxygen consumption rate (OCR) and modulates the expression of genes mediating oxidative stress response, inflammation, and HIV-1 transactivation. Proteomics revealed the enrichment of several host factors (e.g., HIF-1, galectins, Hsp90) known to promote HIV-1 reactivation in the Mtb-specific exosomes. Treatment with a known antioxidant, N-acetyl cysteine, or with the inhibitors of host factors galectins and Hsp90 attenuated HIV-1 reactivation by Mtb-specific exosomes. Our findings uncovered new paradigms for understanding the redox and bioenergetics basis of HIV-TB co-infection, which will enable the design of effective therapeutic strategies.

microbiology↗

bioRxiv2019

Bioinformatic Methods and Bridging of Assay Results for Reliable Tumor Mutational Burden Assessment in Non-Small Cell Lung Cancer

IntroductionTumor mutational burden (TMB) has emerged as a clinically relevant biomarker that may be associated with immune checkpoint inhibitor efficacy. Standardization of TMB measurement is essential for implementing diagnostic tools to guide treatment.\n\nObjectiveHere we describe the in-depth evaluation of bioinformatic TMB analysis by whole exome sequencing (WES) in formalin-fixed, paraffin-embedded samples from a phase 3 clinical trial.\n\nMethodsIn the CheckMate 026 clinical trial, TMB was retrospectively assessed in 312 patients with non-small cell lung cancer (58% of the intent-to-treat population) who received first-line nivolumab treatment or standard-of-care chemotherapy. We examined the sensitivity of TMB assessment to bioinformatic filtering methods and assessed concordance between TMB data derived by WES and the FoundationOne(R) CDx assay.\n\nResultsTMB scores comprising synonymous, indel, frameshift, and nonsense mutations (all mutations) were 3.1-fold higher than data including missense mutations only, but values were highly correlated (Spearmans r = 0.99). Scores from CheckMate 026 samples including missense mutations only were similar to those generated from data in The Cancer Genome Atlas, but those including all mutations were generally higher. Using databases for germline subtraction (instead of matched controls) showed a trend for race-dependent increases in TMB scores. WES and FoundationOne CDx outputs were highly correlated (Spearmans r = 0.90).\n\nConclusionsParameter variation can impact TMB calculations, highlighting the need for standardization. Encouragingly, differences between assays could be accounted for by empirical calibration, suggesting that reliable TMB assessment across assays, platforms, and centers is achievable.\n\nKey PointsO_LITumor mutational burden (TMB) is a clinically relevant biomarker for efficacy of immunotherapy in patients with cancer\nC_LIO_LIVariations in TMB assessment parameters can shift the final TMB value. Harmonization and standardization are important to the successful clinical implementation of TMB testing\nC_LIO_LITMB values assessed by different methods are highly correlated. Harmonization of TMB testing in patients with cancer is therefore achievable\nC_LI

bioinformatics↗

bioRxiv2019

Red blood cell-derived extracellular vesicles mediate intercellular communication in ischemic heart failure

Extracellular vesicles (EV) mediate intercellular signaling by transferring their cargo to recipient cells. Red blood cell (RBC)-derived EVs constitute a significant proportion of circulating EVs and have been implicated in regulating immune responses. Here, we describe a transgenic mouse model for fluorescent-based mapping of RBC-EV target cells based on the functional transfer of EV-contained Cre-recombinase to target cells. In a murine model of ischemic heart failure, we detect an increase in RBC-EV-targeted cardiomyocytes in the hearts and microglial cells in the brains. Cells targeted by RBC-EVs present an enrichment of genes implicated in cell proliferation and metabolism pathways compared to non-recombined (non-targeted) cells. Cardiomyocytes targeted by RBC-EVs are more likely to demonstrate cellular markers of DNA synthesis and proliferation, suggesting functional significance of EV-mediated signaling. In conclusion, we leverage our mouse model for mapping of RBC-EV targets in murine ischemic heart failure to demonstrate quantitative and qualitative changes in RBC-EV recipients.

cell biology↗

bioRxiv2019

Significant enrichment of Herpesvirus interactors in GWAS data suggests causal inferences for the association between Epstein Barr virus and multiple sclerosis

We exploited genetic information to assess the role of non-genetic factors in multifactorial diseases. To this aim we isolated candidate \"interactomes\" (i.e. groups of genes whose products are known to physically interact with environmental exposures and biological processes, plausibly relevant for disease pathogenesis) and analyzed nominal statistical evidence of association with genetic predisposition to multiple sclerosis (MS) and other inflammatory and non-inflammatory complex disorders. The interaction between genotype and Herpesviruses emerged as specific for MS, with Epstein Barr virus (EBV) showing higher levels of significance compared to Human Herpesvirus 8 (HHV8) and, more evidently, to cytomegalovirus (CMV). In accord with this result, when we classified the MS-associated genes contained in the interactomes into canonical pathways, the analysis converged towards biological functions of B cells, in particular the CD40 pathway. When we analyzed peripheral blood transcriptomes in persons with MS, we found a significant dysregulation of MS-associated genes belonging to the EBV interactome in primary progressive MS. This study indicates that the interaction between herpesviruses and predisposing genetic background is of causal significance in MS, and provides a mechanistic explanation for the long-recognized association between EBV and this condition.

neuroscience↗

bioRxiv2019

Intestinal peroxisomal fatty acid β-oxidation regulates neural serotonin signaling through a feedback mechanism

The ability to coordinate behavioral responses with metabolic status is fundamental to the maintenance of energy homeostasis. In numerous species including C. elegans and mammals, neural serotonin signaling regulates a range of food-related behaviors. However, the mechanisms that integrate metabolic information with serotonergic circuits are poorly characterized. Here, we identify metabolic, molecular, and cellular components of a circuit that links peripheral metabolic state to serotonin-regulated behaviors in C. elegans. We find that blocking the entry of fatty acyl-CoAs into peroxisomal {beta}-oxidation in the intestine results in blunting of the effects of neural serotonin signaling on feeding and egg-laying behaviors. Comparative genomics and metabolomics revealed that interfering with intestinal peroxisomal {beta}-oxidation results in a modest global transcriptional change but significant changes to the metabolome, including a large number of changes in ascaroside and phospholipid species, some of which affect feeding behavior. We also identify body cavity neurons and an ether-a-go-go related (EAG) potassium channel that functions in these neurons as key cellular components of the circuitry linking peripheral metabolic signals to regulation of neural serotonin signaling. These data raise the possibility that the effects of serotonin on satiety may have their origins in feedback, homeostatic metabolic responses from the periphery.

physiology↗