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Found 37048 matches. Displaying 51-60
Lee UJ, Mortola EN, Kim EJ, Long MY
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Evolution and maintenance of phenotypic plasticity

BIOSYSTEMS 2022 DEC; 222(?):? Article 104791
We introduce a novel framework for exploring the evolutionary consequences of phenotypic plasticity (adaptive and non-adaptive) integrating both genic and epigenetic effects on phenotype via stochastic differential equations and in-silico selection. In accordance with the most significant results derived from prior models, we demonstrate how plasticity is differentially favored when subjected to small vs large environmental shifts, how plasticity is transiently favorable while accommodating a new environment, and how plasticity decreases during epochs where the environment remains stable (canalization). In contrast to these models, however, by allowing the same phenotypic value to be produced via two different paths, i.e. deterministic, genic, vs stochastic, epigenetic mechanisms, we demonstrate when genic contributions alone cannot produce an optimal phenotype, plastic, epigenetic contributions will instead fully accommodate new environments, allowing for both adaptive and non-adaptive plasticity to evolve. Furthermore, we show that while rates of phenotypic accommodation are relatively constant under a wide range of selective conditions, selection will favor the most efficient route to adaptation: deterministic, genic response, or stochastic, plastic response. As a result, plasticity may evolve or canalization may occur within a given epoch depending on the relative mutation rate of genic and epigenetic contributions to phenotype, highlighting the importance of genetic conflict on the evolution of plasticity.
Xi L, Garcet S, Ye Z, Hung K, Hassan-Zahraee M, Kieras E, Krueger JG, Hyde C, Peeva E
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A shared tissue transcriptome signature and pathways in psoriasis and ulcerative colitis

SCIENTIFIC REPORTS 2022 NOV 17; 12(1):? Article 19740
Despite multiple efficacious therapies in common between psoriasis (PS) and Ulcerative Colitis (UC), mechanisms underlying their common pathophysiology remain largely unclear. Here we sought to establish a link by evaluating expression differences and pathway alterations in diseased tissues. We identified two sets of differentially expressed genes (DEGs) between lesional and nonlesional tissues in meta-analyses of data collected from baseline samples in 3 UC and then 3 PS available clinical studies from Pfizer. A shared gene signature was defined by 190 DEGs common to both diseases. Commonly dysregulated pathways identified via enrichment analysis include interferon signaling, partly driven by genes IFI6, CXCL9, CXCL10 and CXCL11, which may attract chemotaxis of Th1 cells to inflammatory sites; IL-23 pathway (IL-23A, CCL20, PI3, CXCL1, LCN2); and Th17 pathway except IL-17A. Elevated expression of costimulatory molecules ICOS and CTLA4 suggests ongoing T-cell activation in both diseases. The clinical value of the shared signature is demonstrated by a gene set improvement score reflecting post-treatment molecular improvement for each disease. This is the first study using transcriptomic meta-analysis to define a tissue gene signature and pathways dysregulated in both PS and UC. These findings suggest immune mechanisms may initiate and sustain inflammation similarly in the two diseases.
Schneeberger M, Brice NL, Pellegrino K, Parolari L, Shaked JT, Page KJ, Marchildon F, Barrows DW, Carroll TS, Tolpiko T, Mulligan VM, Newman R, Doyle K, Burli R, Barker DF, Glen A, Ortuno MJ, Nectow AR, Renier N, Cohen P, Carlton M, Heintz N, Friedman JM
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Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction

NATURE METABOLISM 2022 NOV; 4(11):1495-+
Food intake and body weight are tightly regulated by neurons within specific brain regions, including the brainstem, where acute activation of dorsal raphe nucleus (DRN) glutamatergic neurons expressing the glutamate transporter Vglut3 (DRNVglut3) drive a robust suppression of food intake and enhance locomotion. Activating Vglut3 neurons in DRN suppresses food intake and increases locomotion, suggesting that modulating the activity of these neurons might alter body weight. Here, we show that DRNVglut3 neurons project to the lateral hypothalamus (LHA), a canonical feeding center that also reduces food intake. Moreover, chronic DRNVglut3 activation reduces weight in both leptin-deficient (ob/ob) and leptin-resistant diet-induced obese (DIO) male mice. Molecular profiling revealed that the orexin 1 receptor (Hcrtr1) is highly enriched in DRN Vglut3 neurons, with limited expression elsewhere in the brain. Finally, an orally bioavailable, highly selective Hcrtr1 antagonist (CVN45502) significantly reduces feeding and body weight in DIO. Hcrtr1 is also co-expressed with Vglut3 in the human DRN, suggesting that there might be a similar effect in human. These results identify a potential therapy for obesity by targeting DRNVglut3 neurons while also establishing a general strategy for developing drugs for central nervous system disorders. Schneeberger et al. show that glutamatergic neurons within the dorsal raphe nucleus of the brainstem are enriched with the orexin 1 receptor Hcrtr1, which can be pharmacologically targeted to treat obesity in mice.
Collier AD, Yasmin N, Chang GQ, Karatayev O, Khalizova N, Fam M, Abdulai AR, Yu BY, Leibowitz SF
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Embryonic ethanol exposure induces ectopic Hcrt and MCH neurons outside hypothalamus in rats and zebrafish: Role in ethanol-induced behavioural disturbances

ADDICTION BIOLOGY 2022 NOV; 27(6):? Article e13238
Embryonic exposure to ethanol increases the risk for alcohol use disorder in humans and stimulates alcohol-related behaviours in different animal models. Evidence in rats and zebrafish suggests that this phenomenon induced by ethanol at low-moderate concentrations involves a stimulatory effect on neurogenesis and density of hypothalamic neurons expressing the peptides, hypocretin/orexin (Hcrt) and melanin-concentrating hormone (MCH), known to promote alcohol consumption. Building on our report in zebrafish showing that ethanol induces ectopic expression of Hcrt neurons outside the hypothalamus, we investigated here whether embryonic ethanol exposure also induces ectopic peptide neurons in rats similar to zebrafish and affects their morphological characteristics and if these ectopic neurons are functional and have a role in the ethanol-induced disturbances in behaviour. We demonstrate in rats that ethanol at a low-moderate dose, in addition to increasing Hcrt and MCH neurons in the lateral hypothalamus where they are normally concentrated, induces ectopic expression of these peptide neurons further anterior in the nucleus accumbens core and ventromedial caudate putamen where they have not been previously observed and causes morphological changes relative to normally located hypothalamic neurons. Similar to rats, embryonic ethanol exposure at a low-moderate dose in zebrafish induces ectopic Hcrt neurons anterior to the hypothalamus and alters their morphology. Notably, laser ablation of these ectopic Hcrt neurons blocks the behavioural effects induced by ethanol exposure, including increased anxiety and locomotor activity. These findings suggest that the ectopic peptide neurons are functional and contribute to the ethanol-induced behavioural disturbances related to the overconsumption of alcohol.
de Castro MV, Silva MVR, Naslavsky MS, Scliar MO, Nunes K, Passos-Bueno MR, Castelli EC, Magawa JY, Adami FL, Moretti AIS, de Oliveira VL, Boscardin SB, Cunha-Neto E, Kalil J, Jouanguy E, Bastard P, Casanova JL, Quinones-Vega M, Sosa-Acosta P, de Guedes JS, de Almeida NP, Nogueira FCS, Domont GB, Santos KS, Zatz M
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The oldest unvaccinated Covid-19 survivors in South America

IMMUNITY & AGEING 2022 NOV 16; 19(1):? Article 57
Background Although older adults are at a high risk of severe or critical Covid-19, there are many cases of unvaccinated centenarians who had a silent infection or recovered from mild or moderate Covid-19. We studied three Brazilian supercentenarians, older than 110 years, who survived Covid-19 in 2020 before being vaccinated. Results Despite their advanced age, humoral immune response analysis showed that these individuals displayed robust levels of IgG and neutralizing antibodies (NAbs) against SARS-CoV-2. Enrichment of plasma proteins and metabolites related to innate immune response and host defense was also observed. None presented autoantibodies (auto-Abs) to type I interferon (IFN). Furthermore, these supercentenarians do not carry rare variants in genes underlying the known inborn errors of immunity, including particular inborn errors of type I IFN. Conclusion These observations suggest that their Covid-19 resilience might be a combination of their genetic background and their innate and adaptive immunity.
Renert-Yuval Y, Pavel AB, Bose S, Gomez-Arias PJ, Rangel SM, Estrada YD, Paller AS, Guttman-Yassky E
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Tape strips capture atopic dermatitis-related changes in nonlesional skin throughout maturation

ALLERGY 2022 NOV; 77(11):3445-3447
Sokal A, Bastard P, Chappert P, Barba-Spaeth G, Fourati S, Vanderberghe A, Lagouge-Roussey P, Meyts I, Gervais A, Bouvier-Alias M, Azzaoui I, Fernandez I, de la Selle A, Zhang Q, Bizien L, Pellier I, Linglart A, Rothenbuhler A, Marcoux E, Anxionnat R, Cheikh N, Leger J, Amador-Borrero B, Fouyssac F, Menut V, Goffard JC, Storey C, Demily C, Mallebranche C, Troya J, Pujol A, Zins M, Tiberghien P, Gray PE, McNaughton P, Sullivan A, Peake J, Levy R, Languille L, Rodiguez-Gallego C, Boisson B, Gallien S, Neven B, Michel M, Godeau B, Abel L, Rey FA, Weill JC, Reynaud CA, Tangye SG, Casanova JL, Mahevas M
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Human type I IFN deficiency does not impair B cell response to SARS-CoV-2 mRNA vaccination

JOURNAL OF EXPERIMENTAL MEDICINE 2022 NOV 7; 220(1):? Article e20220258
Intact B cell responses to SARS-CoV-2 mRNA vaccines in patients with genetic or acquired type I IFN deficiencies suggest that type I IFNs induced by mRNA vaccines are not required for vaccine efficacy. Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response to mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well as young patients with autoantibodies neutralizing type I IFNs due to autoimmune polyendocrine syndrome type-1 (APS-1) and older individuals with age-associated autoantibodies to type I IFNs. The receptor-binding domain spike protein (RBD)-specific memory B cell response in all patients was quantitatively and qualitatively similar to healthy donors. Sustained germinal center responses led to accumulation of somatic hypermutations in immunoglobulin heavy chain genes. The amplitude and duration of, and viral neutralization by, RBD-specific IgG serological response were also largely unaffected by TLR7, IRF7, or IFNAR1 deficiencies up to 7 mo after vaccination in all patients. These results suggest that induction of type I IFN is not required for efficient generation of a humoral response against SARS-CoV-2 by mRNA vaccines.
Sarhan D, Eisinger S, He F, Bergsland M, Pelicano C, Driescher C, Westberg K, Benitez II, Humoud R, Palano G, Li SJ, Carannante V, Muhr J, Onfelt B, Schlisio S, Ravetch JV, Heuchel R, Lohr MJ, Karlsson MCI
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Targeting myeloid suppressive cells revives cytotoxic anti-tumor responses in pancreatic cancer

ISCIENCE 2022 NOV 18; 25(11):? Article 105317
Immunotherapy for cancer that aims to promote T cell anti-tumor activity has changed current clinical practice, where some previously lethal cancers have now become treatable. However, clinical trials with low response rates have been disappointing for pancreatic ductal adenocarcinoma (PDAC). One suggested explanation is the accumulation of dominantly immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells in the tumor microenvironment (TME). Using retrospectively collected tumor specimens and transcriptomic data from PDAC, we demonstrate that expression of the scavenger receptor MARCO correlates with poor prognosis and a lymphocyte-excluding tumor phenotype. PDAC cell lines produce IL-10 and induce high expression of MARCO in myeloid cells, and this was further enhanced during hypoxic conditions. These myeloid cells suppressed effector T and natural killer (NK) cells and blocked NK cell tumor infiltration and tumor killing in a PDAC 3D-spheroid model. Anti-human MARCO (anti-hMARCO) antibody targeting triggered the repolarization of tumor-associated macrophages and activated the inflammasome machinery, resulting in IL-18 production. This in turn enhanced T cell and NK cell functions. The targeting of MARCO thus remodels the TME and represents a rational approach to make immunotherapy more efficient in PDAC patients.
Toh H, Yang CT, Formenti G, Raja K, Yan L, Tracey A, Chow W, Howe K, Bergeron LA, Zhang GJ, Haase B, Mountcastle J, Fedrigo O, Fogg J, Kirilenko B, Munegowda C, Hiller M, Jain A, Kihara D, Rhie A, Phillippy AM, Swanson SA, Jiang P, Clegg DO, Jarvis ED, Thomson JA, Stewart R, Chaisson MJP, Bukhman YV
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A haplotype-resolved genome assembly of the Nile rat facilitates exploration of the genetic basis of diabetes

BMC BIOLOGY 2022 NOV 8; 20(1):? Article 245
Background The Nile rat (Avicanthis niloticus) is an important animal model because of its robust diurnal rhythm, a cone-rich retina, and a propensity to develop diet-induced diabetes without chemical or genetic modifications. A closer similarity to humans in these aspects, compared to the widely used Mus musculus and Rattus norvegicus models, holds the promise of better translation of research findings to the clinic. Results We report a 2.5 Gb, chromosome-level reference genome assembly with fully resolved parental haplotypes, generated with the Vertebrate Genomes Project (VGP). The assembly is highly contiguous, with contig N50 of 11.1 Mb, scaffold N50 of 83 Mb, and 95.2% of the sequence assigned to chromosomes. We used a novel workflow to identify 3613 segmental duplications and quantify duplicated genes. Comparative analyses revealed unique genomic features of the Nile rat, including some that affect genes associated with type 2 diabetes and metabolic dysfunctions. We discuss 14 genes that are heterozygous in the Nile rat or highly diverged from the house mouse. Conclusions Our findings reflect the exceptional level of genomic resolution present in this assembly, which will greatly expand the potential of the Nile rat as a model organism.
Nguyenla X, Wehri E, Van Dis E, Biering SB, Yamashiro LH, Zhu C, Stroumza J, Dugast-Darzacq C, Graham TGW, Wang XT, Jockusch S, Tao CAJ, Chien MC, Xie W, Patel DJ, Meyer C, Garzia A, Tuschl T, Russo JJ, Ju JY, Naar AM, Stanley S, Schaletzky J
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Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells

SCIENTIFIC REPORTS 2022 NOV 2; 12(1):? Article 18506
SARS coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic with significant mortality and morbidity. At this time, the only FDA-approved therapeutic for COVID-19 is remdesivir, a broad-spectrum antiviral nucleoside analog. Efficacy is only moderate, and improved treatment strategies are urgently needed. To accomplish this goal, we devised a strategy to identify compounds that act synergistically with remdesivir in preventing SARS-CoV-2 replication. We conducted combinatorial high-throughput screening in the presence of submaximal remdesivir concentrations, using a human lung epithelial cell line infected with a clinical isolate of SARS-CoV-2. This identified 20 approved drugs that act synergistically with remdesivir, many with favorable pharmacokinetic and safety profiles. Strongest effects were observed with established antivirals, Hepatitis C virus nonstructural protein 5A (HCV NS5A) inhibitors velpatasvir and elbasvir. Combination with their partner drugs sofosbuvir and grazoprevir further increased efficacy, increasing remdesivir's apparent potency > 25-fold. We report that HCV NS5A inhibitors act on the SARS-CoV-2 exonuclease proofreader, providing a possible explanation for the synergy observed with nucleoside analog remdesivir. FDA-approved Hepatitis C therapeutics Epclusa (R) (velpatasvir/sofosbuvir) and Zepatier (R) (elbasvir/grazoprevir) could be further optimized to achieve potency and pharmacokinetic properties that support clinical evaluation in combination with remdesivir.