Person: Mitchell, James
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Mitchell
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James
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Mitchell, James
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Publication Connectomes across development reveal principles of brain maturation(Cold Spring Harbor Laboratory, 2020-04-30) Witvliet, Daniel; Mulcahy, Ben; Mitchell, James; Meirovitch, Yaron; Berger, Daniel; Wu, Yuelong; Liu, Yufang; Koh, Wan Xian; Parvathala, Rajeev; Holmyard, Douglas; Schalek, Richard; Shavit, Nir; Chisholm, Andrew; Lichtman, Jeff; Samuel, Aravi; Zhen, MeiFrom birth to adulthood, an animal’s nervous system changes as its body grows and its behaviours mature. The form and extent of circuit remodelling across the connectome is unknown. We used serial-section electron microscopy to reconstruct the full brain of eight isogenic C. elegans individuals across postnatal stages to learn how it changes with age. The overall geometry of the nervous system is preserved from birth to adulthood. Upon this constant scaffold, substantial changes in chemical synaptic connectivity emerge. Comparing connectomes among individuals reveals substantial connectivity differences that make each brain partly unique. Comparing connectomes across maturation reveals consistent wiring changes between different neurons. These changes alter the strength of existing connections and create new connections. Collective changes in the network alter information processing. Over development, the central decision-making circuitry is maintained whereas sensory and motor pathways substantially remodel. With age, the brain progressively becomes more feedforward and discernibly modular. Developmental connectomics reveals principles that underlie brain maturation.Publication Connexin43 Inhibition Prevents Human Vein Grafts Intimal Hyperplasia(Public Library of Science, 2015) Longchamp, Alban; Allagnat, Florent; Alonso, Florian; Kuppler, Christopher; Dubuis, Céline; Ozaki, Charles-Keith; Mitchell, James; Berceli, Scott; Corpataux, Jean-Marc; Déglise, Sébastien; Haefliger, Jacques-AntoineVenous bypass grafts often fail following arterial implantation due to excessive smooth muscle cells (VSMC) proliferation and consequent intimal hyperplasia (IH). Intercellular communication mediated by Connexins (Cx) regulates differentiation, growth and proliferation in various cell types. Microarray analysis of vein grafts in a model of bilateral rabbit jugular vein graft revealed Cx43 as an early upregulated gene. Additional experiments conducted using an ex-vivo human saphenous veins perfusion system (EVPS) confirmed that Cx43 was rapidly increased in human veins subjected ex-vivo to arterial hemodynamics. Cx43 knock-down by RNA interference, or adenoviral-mediated overexpression, respectively inhibited or stimulated the proliferation of primary human VSMC in vitro. Furthermore, Cx blockade with carbenoxolone or the specific Cx43 inhibitory peptide 43gap26 prevented the burst in myointimal proliferation and IH formation in human saphenous veins. Our data demonstrated that Cx43 controls proliferation and the formation of IH after arterial engraftment.Publication A review of the biomedical innovations for healthy longevity(Impact Journals LLC, 2017) Moskalev, Alexey; Anisimov, Vladimir; Aliper, Aleksander; Artemov, Artem; Asadullah, Khusru; Belsky, Daniel; Baranova, Ancha; de Grey, Aubrey; Dixit, Vishwa Deep; Debonneuil, Edouard; Dobrovolskaya, Eugenia; Fedichev, Peter; Fedintsev, Alexander; Fraifeld, Vadim; Franceschi, Claudio; Freer, Rosie; Fülöp, Tamas; Feige, Jerome; Gems, David; Gladyshev, Vadim; Gorbunova, Vera; Irincheeva, Irina; Jager, Sibylle; Jazwinski, S. Michal; Kaeberlein, Matt; Kennedy, Brian; Khaltourina, Daria; Kovalchuk, Igor; Kovalchuk, Olga; Kozin, Sergey; Kulminski, Alexander; Lashmanova, Ekaterina; Lezhnina, Ksenia; Liu, Guang Hui; Longo, Valter; Mamoshina, Polina; Maslov, Alexander; de Magalhaes, Joao Pedro; Mitchell, James; Mitnitski, Arnold; Nikolsky, Yuri; Ozerov, Ivan; Pasyukova, Elena; Peregudova, Darya; Popov, Vasily; Proshkina, Ekaterina; Putin, Evgeny; Rogaev, Evgeny; Rogina, Blanka; Schastnaya, Jane; Seluanov, Andrey; Shaposhnikov, Mikhail; Simm, Andreas; Skulachev, Vladimir; Skulachev, Maxim; Solovev, Ilya; Spindler, Stephen; Stefanova, Natalia; Suh, Yousin; Swick, Andrew; Tower, John; Gudkov, Andrei V.; Vijg, Jan; Voronkov, Andrey; West, Michael; Wagner, Wolfgang; Yashin, Anatoliy; Zemskaya, Nadezhda; Zhumadilov, Zhaxybay; Zhavoronkov, AlexPublication Short-term Preoperative Dietary Restriction Is Neuroprotective in a Rat Focal Stroke Model(Public Library of Science, 2014) Varendi, Kärt; Airavaara, Mikko; Anttila, Jenni; Vose, Sarah; Planken, Anu; Saarma, Mart; Mitchell, James; Andressoo, Jaan-OlleStroke is a major complication of cardiovascular surgery, resulting in over 100,000 deaths and over a million postoperative encephalopathies annually in the US and Europe. While mitigating damage from stroke after it occurs has proven elusive, opportunities to reduce the incidence and/or severity of stroke prior to surgery in at-risk individuals remain largely unexplored. We tested the potential of short-term preoperative dietary restriction to provide neuroprotection in rat models of focal stroke. Rats were preconditioned with either three days of water-only fasting or six days of a protein free diet prior to induction of transient middle cerebral artery occlusion using two different methods, resulting in either a severe focal stroke to forebrain and midbrain, or a mild focal stroke localized to cortex only. Infarct volume, functional recovery and molecular markers of damage and protection were assessed up to two weeks after reperfusion. Preoperative fasting for 3 days reduced infarct volume after severe focal stroke. Neuroprotection was associated with modulation of innate immunity, including elevation of circulating neutrophil chemoattractant C-X-C motif ligand 1 prior to ischemia and suppression of striatal pro-inflammatory markers including tumor necrosis factor α, its receptor and downstream effector intercellular adhesion molecule-1 after reperfusion. Similarly, preoperative dietary protein restriction for 6 days reduced ischemic injury and improved functional recovery in a milder cortical infarction model. Our results suggest that short-term dietary restriction regimens may provide simple and translatable approaches to reduce perioperative stroke severity in high-risk elective vascular surgery.Publication Interventions to Slow Aging in Humans: Are We Ready?(John Wiley & Sons, Ltd, 2015) Longo, Valter D; Antebi, Adam; Bartke, Andrzej; Barzilai, Nir; Brown-Borg, Holly M; Caruso, Calogero; Curiel, Tyler J; de Cabo, Rafael; Franceschi, Claudio; Gems, David; Ingram, Donald K; Johnson, Thomas E; Kennedy, Brian K; Kenyon, Cynthia; Klein, Samuel; Kopchick, John J; Lepperdinger, Guenter; Madeo, Frank; Mirisola, Mario G; Mitchell, James; Passarino, Giuseppe; Rudolph, Karl L; Sedivy, John M; Shadel, Gerald S; Sinclair, David; Spindler, Stephen R; Suh, Yousin; Vijg, Jan; Vinciguerra, Manlio; Fontana, LuigiThe workshop entitled ‘Interventions to Slow Aging in Humans: Are We Ready?’ was held in Erice, Italy, on October 8–13, 2013, to bring together leading experts in the biology and genetics of aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was consensus that there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. Essential pathways have been identified, and behavioral, dietary, and pharmacologic approaches have emerged. Although many gene targets and drugs were discussed and there was not complete consensus about all interventions, the participants selected a subset of the most promising strategies that could be tested in humans for their effects on healthspan. These were: (i) dietary interventions mimicking chronic dietary restriction (periodic fasting mimicking diets, protein restriction, etc.); (ii) drugs that inhibit the growth hormone/IGF-I axis; (iii) drugs that inhibit the mTOR–S6K pathway; or (iv) drugs that activate AMPK or specific sirtuins. These choices were based in part on consistent evidence for the pro-longevity effects and ability of these interventions to prevent or delay multiple age-related diseases and improve healthspan in simple model organisms and rodents and their potential to be safe and effective in extending human healthspan. The authors of this manuscript were speakers and discussants invited to the workshop. The following summary highlights the major points addressed and the conclusions of the meeting.Publication Dietary restriction protects against experimental cerebral malaria via leptin modulation and T cell mTORC1 suppression(2014) Mejia, Pedro; Treviño-Villarreal, J. Humberto; Hine, Christopher; Harputlugil, Eylul; Lang, Samantha; Calay, Ediz; Rogers, Rick; Wirth, Dyann; Duraisingh, Manoj; Mitchell, JamesHost nutrition can affect the outcome of parasitic diseases through metabolic effects on host immunity and/or the parasite. Here we show that modulation of mouse immunometabolism through brief restriction of food intake (dietary restriction, DR) prevents neuropathology in experimental cerebral malaria (ECM). While no effects are detected on parasite growth, DR reduces parasite accumulation in peripheral tissues including brain, and increases clearance in the spleen. Leptin, a host-derived adipokine linking appetite, energy balance and immune function, is required for ECM pathology and its levels are reduced upon DR. Recombinant leptin abrogates DR benefits, while pharmacological or genetic inhibition of leptin signaling protects against ECM. DR reduces mTORC1 activity in T cells, and this effect is abrogated upon leptin administration. Furthermore, mTORC1 inhibition with rapamycin prevents ECM pathology. Our results suggest that leptin and mTORC1 provide a novel mechanistic link between nutrition, immunometabolism and ECM pathology, with potential therapeutic implications for cerebral malaria.Publication The First International Mini-Symposium on Methionine Restriction and Lifespan(Frontiers Media S.A., 2014) Ables, Gene P.; Brown-Borg, Holly M.; Buffenstein, Rochelle; Church, Christopher D.; Elshorbagy, Amany K.; Gladyshev, Vadim; Huang, Tsang-hai; Miller, Richard A.; Mitchell, James; Richie, John P.; Rogina, Blanka; Stipanuk, Martha H.; Orentreich, David S.; Orentreich, NormanIt has been 20 years since the Orentreich Foundation for the Advancement of Science, under the leadership Dr. Norman Orentreich, first reported that low methionine (Met) ingestion by rats extends lifespan (Orentreich et al., 1993). Since then, several studies have replicated the effects of dietary methionine restricted (MR) in delaying age-related diseases (Richie et al., 1994; Miller et al., 2005; Ables et al., 2012; Sanchez-Roman and Barja, 2013). We report the abstracts from the First International Mini-Symposium on Methionine Restriction and Lifespan held in Tarrytown, NY, September 2013. The goals were (1) to gather researchers with an interest in MR and lifespan, (2) to exchange knowledge, (3) to generate ideas for future investigations, and (4) to strengthen relationships within this community. The presentations highlighted the importance of research on cysteine, growth hormone (GH), and ATF4 in the paradigm of aging. In addition, the effects of dietary restriction or MR in the kidneys, liver, bones, and the adipose tissue were discussed. The symposium also emphasized the value of other species, e.g., the naked mole rat, Brandt's bat, and Drosophila, in aging research. Overall, the symposium consolidated scientists with similar research interests and provided opportunities to conduct future collaborative studies (Figure 3).Publication Health benefits of late-onset metformin treatment every other week in mice(Nature Publishing Group UK, 2017) Alfaras, Irene; Mitchell, Sarah J.; Mora, Hector; Lugo, Darisbeth Rosario; Warren, Alessandra; Navas-Enamorado, Ignacio; Hoffmann, Vickie; Hine, Christopher; Mitchell, James; Le Couteur, David G.; Cogger, Victoria C.; Bernier, Michel; de Cabo, RafaelChronic 1% metformin treatment is nephrotoxic in mice, but this dose may nonetheless confer health benefits if given intermittently rather than continuously. Here, we examined the effects of 1% metformin given every-other week (EOW) or two consecutive weeks per month (2WM) on survival of 2-year-old male mice fed standard chow. EOW and 2WM mice had comparable life span compared with control mice. A significant reduction in body weight within the first few weeks of metformin treatment was observed without impact on food consumption and energy expenditure. Moreover, there were differences in the action of metformin on metabolic markers between the EOW and 2WM groups, with EOW metformin conferring greater benefits. Age-associated kidney lesions became more pronounced with metformin, although without pathological consequences. In the liver, metformin treatment led to an overall reduction in steatosis and was accompanied by distinct transcriptomic and metabolomic signatures in response to EOW versus 2WM regimens. Thus, the absence of adverse outcomes associated with chronic, intermittent use of 1% metformin in old mice has clinical translatability into the biology of aging in humans.Publication A single rapamycin dose protects against late-stage experimental cerebral malaria via modulation of host immunity, endothelial activation and parasite sequestration(BioMed Central, 2017) Mejia, Pedro; Treviño-Villarreal, J. Humberto; Reynolds, Justin; De Niz, Mariana; Thompson, Andrew; Marti, Matthias; Mitchell, JamesBackground: Maladaptive immune responses during cerebral malaria (CM) result in high mortality despite opportune anti-malarial chemotherapy. Rapamycin, an FDA-approved immunomodulator, protects against experimental cerebral malaria (ECM) in mice through effects on the host. However, the potential for reduced adaptive immunity with chronic use, combined with an incomplete understanding of mechanisms underlying protection, limit translational potential as an adjunctive therapy in CM. Results: The results presented herein demonstrate that a single dose of rapamycin, provided as late as day 4 or 5 post-infection, protected mice from ECM neuropathology and death through modulation of distinct host responses to infection. Rapamycin prevented parasite cytoadherence in peripheral organs, including white adipose tissue, via reduction of CD36 expression. Rapamycin also altered the splenic immune response by reducing the number of activated T cells with migratory phenotype, while increasing local cytotoxic T cell activation. Finally, rapamycin reduced brain endothelial ICAM-1 expression concomitant with reduced brain pathology. Together, these changes potentially contributed to increased parasite elimination while reducing CD8 T cell migration to the brain. Conclusions: Rapamycin exerts pleotropic effects on host immunity, vascular activation and parasite sequestration that rescue mice from ECM, and thus support the potential clinical use of rapamycin as an adjunctive therapy in CM.Publication Plasmodium gametocytes display homing and vascular transmigration in the host bone marrow(American Association for the Advancement of Science, 2018) De Niz, Mariana; Meibalan, Elamaran; Mejia, Pedro; Ma, Siyuan; Brancucci, Nicolas M. B.; Agop-Nersesian, Carolina; Mandt, Rebecca; Ngotho, Priscilla; Hughes, Katie R.; Waters, Andrew P.; Huttenhower, Curtis; Mitchell, James; Martinelli, Roberta; Frischknecht, Friedrich; Seydel, Karl B.; Taylor, Terrie; Milner, Danny; Heussler, Volker T.; Marti, MatthiasTransmission of Plasmodium parasites to the mosquito requires the formation and development of gametocytes. Studies in infected humans have shown that only the most mature forms of Plasmodium falciparum gametocytes are present in circulation, whereas immature forms accumulate in the hematopoietic environment of the bone marrow. We used the rodent model Plasmodium berghei to study gametocyte behavior through time under physiological conditions. Intravital microscopy demonstrated preferential homing of early gametocyte forms across the intact vascular barrier of the bone marrow and the spleen early during infection and subsequent development in the extravascular environment. During the acute phase of infection, we observed vascular leakage resulting in further parasite accumulation in this environment. Mature gametocytes showed high deformability and were found entering and exiting the intact vascular barrier. We suggest that extravascular gametocyte localization and mobility are essential for gametocytogenesis and transmission of Plasmodium to the mosquito.