Medicine JournalFeeds

Adaptation of HIV-1 envelope gp120 to humoral immunity at a population level.

Nat Med. 2010 Aug 29;

Authors: Bunnik EM, Euler Z, Welkers MR, Boeser-Nunnink BD, Grijsen ML, Prins JM, Schuitemaker H

By comparing HIV-1 variants from people who became infected at the beginning of the epidemic and from people who have recently contracted the virus, we observed an enhanced resistance of the virus to antibody neutralization over time, accompanied by an increase in the length of the variable loops and in the number of potential N-linked glycosylation sites on the HIV-1 envelope gp120 subunit. The enhanced neutralization resistance of HIV-1 in contemporary seroconverters coincided with the poorer elicitation of neutralizing antibody responses, which may have implications for vaccine design.

PMID: 20802498 [PubMed - as supplied by publisher]

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Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance.

Nat Med. 2010 Aug 29;

Authors: López M, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi VR, Morgan DA, Schoenmakers E, Agassandian K, Lage R, de Morentin PB, Tovar S, Nogueiras R, Carling D, Lelliott C, Gallego R, Orešič M, Chatterjee K, Saha AK, Rahmouni K, Diéguez C, Vidal-Puig A

Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone-induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.

PMID: 20802499 [PubMed - as supplied by publisher]

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Clinical microfluidics for neutrophil genomics and proteomics.

Nat Med. 2010 Aug 29;

Authors: Kotz KT, Xiao W, Miller-Graziano C, Qian WJ, Russom A, Warner EA, Moldawer LL, De A, Bankey PE, Petritis BO, Camp DG, Rosenbach AE, Goverman J, Fagan SP, Brownstein BH, Irimia D, Xu W, Wilhelmy J, Mindrinos MN, Smith RD, Davis RW, Tompkins RG, Toner M, , Baker HV, Balis UG, Billiar TR, Calvano SE, Cobb JP, Cuschieri J, Finnerty CC, Gamelli RL, Gibran NS, Harbrecht BG, Hayden DL, Hennessy L, Herndon DN, Jeschke MG, Johnson JL, Klein MB, Lowry SF, Maier RV, Mason PH, McDonald-Smith GP, Minei JP, Moore EE, Nathens AB, O Keefe GE, Rahme LG, Remick DG, Schoenfeld DA, Shapiro MB, Sperry J, Storey JD, Tibshirani R, Warren HS, West MA, Wispelwey B, Wong WH

Neutrophils have key roles in modulating the immune response. We present a robust methodology for rapidly isolating neutrophils directly from whole blood with ‘on-chip’ processing for mRNA and protein isolation for genomics and proteomics. We validate this device with an ex vivo stimulation experiment and by comparison with standard bulk isolation methodologies. Last, we implement this tool as part of a near-patient blood processing system within a multi-center clinical study of the immune response to severe trauma and burn injury. The preliminary results from a small cohort of subjects in our study and healthy controls show a unique time-dependent gene expression pattern clearly demonstrating the ability of this tool to discriminate temporal transcriptional events of neutrophils within a clinical setting.

PMID: 20802500 [PubMed - as supplied by publisher]

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Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson’s disease.

Nat Med. 2010 Aug 22;

Authors: Lee BD, Shin JH, Vankampen J, Petrucelli L, West AB, Ko HS, Lee YI, Maguire-Zeiss KA, Bowers WJ, Federoff HJ, Dawson VL, Dawson TM

Leucine-rich repeat kinase-2 (LRRK2) mutations are a common cause of Parkinson’s disease. Here we identify inhibitors of LRRK2 kinase that are protective in in vitro and in vivo models of LRRK2-induced neurodegeneration. These results establish that LRRK2-induced degeneration of neurons in vivo is kinase dependent and that LRRK2 kinase inhibition provides a potential new neuroprotective paradigm for the treatment of Parkinson’s disease.

PMID: 20729864 [PubMed - as supplied by publisher]

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Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson’s disease.

Nat Med. 2010 Aug 22;

Authors: Lee BD, Shin JH, Vankampen J, Petrucelli L, West AB, Ko HS, Lee YI, Maguire-Zeiss KA, Bowers WJ, Federoff HJ, Dawson VL, Dawson TM

Leucine-rich repeat kinase-2 (LRRK2) mutations are a common cause of Parkinson’s disease. Here we identify inhibitors of LRRK2 kinase that are protective in in vitro and in vivo models of LRRK2-induced neurodegeneration. These results establish that LRRK2-induced degeneration of neurons in vivo is kinase dependent and that LRRK2 kinase inhibition provides a potential new neuroprotective paradigm for the treatment of Parkinson’s disease.

PMID: 20729864 [PubMed - as supplied by publisher]

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Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use-dependent inhibitor of dopamine synthesis.

Nat Med. 2010 Aug 22;

Authors: Yao L, Fan P, Arolfo M, Jiang Z, Olive MF, Zablocki J, Sun HL, Chu N, Lee J, Kim HY, Leung K, Shryock J, Blackburn B, Diamond I

There is no effective treatment for cocaine addiction despite extensive knowledge of the neurobiology of drug addiction. Here we show that a selective aldehyde dehydrogenase-2 (ALDH-2) inhibitor, ALDH2i, suppresses cocaine self-administration in rats and prevents cocaine- or cue-induced reinstatement in a rat model of cocaine relapse-like behavior. We also identify a molecular mechanism by which ALDH-2 inhibition reduces cocaine-seeking behavior: increases in tetrahydropapaveroline (THP) formation due to inhibition of ALDH-2 decrease cocaine-stimulated dopamine production and release in vitro and in vivo. Cocaine increases extracellular dopamine concentration, which activates dopamine D2 autoreceptors to stimulate cAMP-dependent protein kinase A (PKA) and protein kinase C (PKC) in primary ventral tegmental area (VTA) neurons. PKA and PKC phosphorylate and activate tyrosine hydroxylase, further increasing dopamine synthesis in a positive-feedback loop. Monoamine oxidase converts dopamine to 3,4-dihydroxyphenylacetaldehyde (DOPAL), a substrate for ALDH-2. Inhibition of ALDH-2 enables DOPAL to condense with dopamine to form THP in VTA neurons. THP selectively inhibits phosphorylated (activated) tyrosine hydroxylase to reduce dopamine production via negative-feedback signaling. Reducing cocaine- and craving-associated increases in dopamine release seems to account for the effectiveness of ALDH2i in suppressing cocaine-seeking behavior. Selective inhibition of ALDH-2 may have therapeutic potential for treating human cocaine addiction and preventing relapse.

PMID: 20729865 [PubMed - as supplied by publisher]

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Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use-dependent inhibitor of dopamine synthesis.

Nat Med. 2010 Aug 22;

Authors: Yao L, Fan P, Arolfo M, Jiang Z, Olive MF, Zablocki J, Sun HL, Chu N, Lee J, Kim HY, Leung K, Shryock J, Blackburn B, Diamond I

There is no effective treatment for cocaine addiction despite extensive knowledge of the neurobiology of drug addiction. Here we show that a selective aldehyde dehydrogenase-2 (ALDH-2) inhibitor, ALDH2i, suppresses cocaine self-administration in rats and prevents cocaine- or cue-induced reinstatement in a rat model of cocaine relapse-like behavior. We also identify a molecular mechanism by which ALDH-2 inhibition reduces cocaine-seeking behavior: increases in tetrahydropapaveroline (THP) formation due to inhibition of ALDH-2 decrease cocaine-stimulated dopamine production and release in vitro and in vivo. Cocaine increases extracellular dopamine concentration, which activates dopamine D2 autoreceptors to stimulate cAMP-dependent protein kinase A (PKA) and protein kinase C (PKC) in primary ventral tegmental area (VTA) neurons. PKA and PKC phosphorylate and activate tyrosine hydroxylase, further increasing dopamine synthesis in a positive-feedback loop. Monoamine oxidase converts dopamine to 3,4-dihydroxyphenylacetaldehyde (DOPAL), a substrate for ALDH-2. Inhibition of ALDH-2 enables DOPAL to condense with dopamine to form THP in VTA neurons. THP selectively inhibits phosphorylated (activated) tyrosine hydroxylase to reduce dopamine production via negative-feedback signaling. Reducing cocaine- and craving-associated increases in dopamine release seems to account for the effectiveness of ALDH2i in suppressing cocaine-seeking behavior. Selective inhibition of ALDH-2 may have therapeutic potential for treating human cocaine addiction and preventing relapse.

PMID: 20729865 [PubMed - as supplied by publisher]

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Advanced antisense therapies for postexposure protection against lethal filovirus infections.

Nat Med. 2010 Aug 22;

Authors: Warren TK, Warfield KL, Wells J, Swenson DL, Donner KS, Van Tongeren SA, Garza NL, Dong L, Mourich DV, Crumley S, Nichols DK, Iversen PL, Bavari S

Currently, no vaccines or therapeutics are licensed to counter Ebola or Marburg viruses, highly pathogenic filoviruses that are causative agents of viral hemorrhagic fever. Here we show that administration of positively charged phosphorodiamidate morpholino oligomers (PMOplus), delivered by various dosing strategies initiated 30-60 min after infection, protects >60% of rhesus monkeys against lethal Zaire Ebola virus (ZEBOV) and 100% of cynomolgus monkeys against Lake Victoria Marburg virus (MARV) infection. PMOplus may be useful for treating these and other highly pathogenic viruses in humans.

PMID: 20729866 [PubMed - as supplied by publisher]

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Therapeutic cell engineering with surface-conjugated synthetic nanoparticles.

Nat Med. 2010 Aug 15;

Authors: Stephan MT, Moon JJ, Um SH, Bershteyn A, Irvine DJ

A major limitation of cell therapies is the rapid decline in viability and function of the transplanted cells. Here we describe a strategy to enhance cell therapy via the conjugation of adjuvant drug-loaded nanoparticles to the surfaces of therapeutic cells. With this method of providing sustained pseudoautocrine stimulation to donor cells, we elicited marked enhancements in tumor elimination in a model of adoptive T cell therapy for cancer. We also increased the in vivo repopulation rate of hematopoietic stem cell grafts with very low doses of adjuvant drugs that were ineffective when given systemically. This approach is a simple and generalizable strategy to augment cytoreagents while minimizing the systemic side effects of adjuvant drugs. In addition, these results suggest therapeutic cells are promising vectors for actively targeted drug delivery.

PMID: 20711198 [PubMed - as supplied by publisher]

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Transgenic mice with a diverse human T cell antigen receptor repertoire.

Nat Med. 2010 Aug 8;

Authors: Li LP, Lampert JC, Chen X, Leitao C, Popović J, Müller W, Blankenstein T

Because of tolerance mechanisms, it has been hard to identify the T cell receptors (TCRs) of high-avidity T cells against self (for example, tumor) antigens. TCRs that are specific for foreign human antigens from the nontolerant T cell repertoire can be identified in mice. Moreover, if mice are constructed to express the human TCR repertoire, they can be used to analyze the unskewed repertoire against human self antigens. Here we generated transgenic mice with the entire human TCRalphabeta gene loci (1.1 and 0.7 Mb), whose T cells express a diverse human TCR repertoire that compensates for mouse TCR deficiency. A human major histocompatibility class I transgene increases the generation of CD8(+) T cells with human compared to mouse TCRs. Functional CD8(+) T cells against several human tumor antigens were induced, and those against the Melan-A melanoma antigen used similar TCRs to those that have been detected in T cell clones from individuals with autoimmune vitiligo or melanoma. These mice will allow researchers to identify pathogenic and therapeutic human TCRs.

PMID: 20693993 [PubMed - as supplied by publisher]

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