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1.
Mol Psychiatry ; 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-39210012

RESUMO

Glycine is an obligatory co-agonist at excitatory NMDA receptors in the brain, especially in the dentate gyrus, which has been postulated to be crucial for the development of psychotic associations and memories with psychotic content. Drugs modulating glycine levels are in clinical development for improving cognition in schizophrenia. However, the functional relevance of the regulation of glycine metabolism by endogenous enzymes is unclear. Using a chromosome-engineered allelic series in mice, we report that a triplication of the gene encoding the glycine-catabolizing enzyme glycine decarboxylase (GLDC) - as found on a small supernumerary marker chromosome in patients with psychosis - reduces extracellular glycine levels as determined by optical fluorescence resonance energy transfer (FRET) in dentate gyrus (DG) and suppresses long-term potentiation (LTP) in mPP-DG synapses but not in CA3-CA1 synapses, reduces the activity of biochemical pathways implicated in schizophrenia and mitochondrial bioenergetics, and displays deficits in schizophrenia-like behaviors which are in part known to be dependent on the activity of the dentate gyrus, e.g., prepulse inhibition, startle habituation, latent inhibition, working memory, sociability and social preference. Our results demonstrate that Gldc negatively regulates long-term synaptic plasticity in the dentate gyrus in mice, suggesting that an increase in GLDC copy number possibly contributes to the development of psychosis in humans.

2.
Emerg Infect Dis ; 30(11): 2279-2287, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39447148

RESUMO

Wastewater testing can inform public health action as a component of polio outbreak response. During 2022-2023, a total of 7 US jurisdictions (5 states and 2 cities) participated in prospective or retrospective testing of wastewater for poliovirus after a paralytic polio case was identified in New York state. Two distinct vaccine-derived poliovirus type 2 viruses were detected in wastewater from New York state and New York City during 2022, representing 2 separate importation events. Of those viruses, 1 resulted in persistent community transmission in multiple New York counties and 1 paralytic case. No poliovirus was detected in the other participating jurisdictions (Connecticut, New Jersey, Michigan, and Illinois and Chicago, IL). The value of routine wastewater surveillance for poliovirus apart from an outbreak is unclear. However, these results highlight the ongoing risk for poliovirus importations into the United States and the need to identify undervaccinated communities and increase vaccination coverage to prevent paralytic polio.


Assuntos
Poliomielite , Poliovirus , Águas Residuárias , Humanos , Estados Unidos/epidemiologia , Poliomielite/epidemiologia , Poliomielite/prevenção & controle , Poliomielite/virologia , Águas Residuárias/virologia , Surtos de Doenças , História do Século XXI
3.
MMWR Morb Mortal Wkly Rep ; 73(37): 804-809, 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39298357

RESUMO

As part of the response to the highly pathogenic avian influenza A(H5N1) virus outbreak in U.S. cattle and poultry and the associated human cases, CDC and partners are monitoring influenza A virus levels and detection of the H5 subtype in wastewater. Among 48 states and the District of Columbia that performed influenza A testing of wastewater during May 12-July 13, 2024, a weekly average of 309 sites in 38 states had sufficient data for analysis, and 11 sites in four states reported high levels of influenza A virus. H5 subtype testing was conducted at 203 sites in 41 states, with H5 detections at 24 sites in nine states. For each detection or high level, CDC and state and local health departments evaluated data from other influenza surveillance systems and partnered with wastewater utilities and agriculture departments to investigate potential sources. Among the four states with high influenza A virus levels detected in wastewater, three states had corresponding evidence of human influenza activity from other influenza surveillance systems. Among the 24 sites with H5 detections, 15 identified animal sources within the sewershed or adjacent county, including eight milk-processing inputs. Data from these early investigations can help health officials optimize the use of wastewater surveillance during the upcoming respiratory illness season.


Assuntos
Surtos de Doenças , Virus da Influenza A Subtipo H5N1 , Influenza Aviária , Influenza Humana , Aves Domésticas , Águas Residuárias , Animais , Humanos , Águas Residuárias/virologia , Bovinos , Estados Unidos/epidemiologia , Influenza Humana/epidemiologia , Influenza Humana/virologia , Virus da Influenza A Subtipo H5N1/isolamento & purificação , Influenza Aviária/epidemiologia , Influenza Aviária/virologia , Vírus da Influenza A/isolamento & purificação , Doenças dos Bovinos/epidemiologia , Doenças dos Bovinos/virologia , Vigilância Epidemiológica Baseada em Águas Residuárias , Doenças das Aves Domésticas/epidemiologia , Doenças das Aves Domésticas/virologia
4.
Nicotine Tob Res ; 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38919117

RESUMO

INTRODUCTION: The high comorbidity between schizophrenia and cigarette smoking points to a possible shared heritable factor predisposing individuals with schizophrenia to nicotine addiction. The N-methyl-D-aspartate (NMDA) receptor has been highly implicated in both schizophrenia and nicotine addiction. METHODS: In the present study, we used mice with a null mutation on the serine racemase gene (srr), an established risk gene for schizophrenia, which encodes the enzyme to produce the NMDA receptor co-agonist D-serine, to model the pathology of schizophrenia and to determine whether NMDA receptor hypofunction reduced the ability of srr-/- mice to identify nicotine's subjective effects. Established nicotine discrimination procedures were used to train srr-/- and wild-type (WT) mice to discriminate 0.4 mg/kg nicotine under a 10-response fixed-ratio (FR10) schedule of food reinforcement. RESULTS: Results show that WT mice reliably acquired 0.4 mg/kg nicotine discrimination in about 54 training session, whereas srr-/- mice failed to acquire robust 0.4 mg/kg nicotine discrimination even after extended (>70) training sessions. These results show that NDMA receptor hypofunction in srr-/- mice decreased sensitivity to the interoceptive effects of nicotine. CONCLUSIONS: Projected to humans, NMDA receptor hypofunction caused by mutations to the serine racemase gene in schizophrenia may reduce sensitivity to nicotine's subjective effects leading to increased nicotine consumption to produce the same effects as those unaffected by schizophrenia. IMPLICATIONS: There is high comorbidity between schizophrenia and nicotine dependence as well as possible shared genetic risk factors between the two. The serine racemase knockout mouse (srr-/-) with NMDA receptor hypofunction has been developed a model for schizophrenia. We found that srr-/- mice were unable to acquire 0.4 mg/kg nicotine discrimination, whilst wild-type mice readily discriminated nicotine. These results show that decreased NMDA receptor function present in srr-/- mice and patients with schizophrenia may result in reduced sensitivity to nicotine's interoceptive effects, leading to increased nicotine consumption to produce the same subjective effects as those unaffected by schizophrenia.

5.
Proc Natl Acad Sci U S A ; 118(31)2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34330827

RESUMO

There are no validated biomarkers for schizophrenia (SCZ), a disorder linked to neural network dysfunction. We demonstrate that collapsin response mediator protein-2 (CRMP2), a master regulator of cytoskeleton and, hence, neural circuitry, may form the basis for a biomarker because its activity is uniquely imbalanced in SCZ patients. CRMP2's activity depends upon its phosphorylation state. While an equilibrium between inactive (phosphorylated) and active (nonphosphorylated) CRMP2 is present in unaffected individuals, we show that SCZ patients are characterized by excess active CRMP2. We examined CRMP2 levels first in postmortem brains (correlated with neuronal morphometrics) and then, because CRMP2 is expressed in lymphocytes as well, in the peripheral blood of SCZ patients versus age-matched unaffected controls. In the brains and, more starkly, in the lymphocytes of SCZ patients <40 y old, we observed that nonphosphorylated CRMP2 was higher than in controls, while phosphorylated CRMP2 remained unchanged from control. In the brain, these changes were associated with dendritic structural abnormalities. The abundance of active CRMP2 with insufficient opposing inactive p-CRMP2 yielded a unique lowering of the p-CRMP2:CRMP2 ratio in SCZ patients, implying a disruption in the normal equilibrium between active and inactive CRMP2. These clinical data suggest that measuring CRMP2 and p-CRMP2 in peripheral blood might reflect intracerebral processes and suggest a rapid, minimally invasive, sensitive, and specific adjunctive diagnostic aid for early SCZ: increased CRMP2 or a decreased p-CRMP2:CRMP2 ratio may help cinch the diagnosis in a newly presenting young patient suspected of SCZ (versus such mimics as mania in bipolar disorder, where the ratio is high).


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Rede Nervosa/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Esquizofrenia/diagnóstico , Biomarcadores/metabolismo , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas do Tecido Nervoso/genética
6.
Proc Natl Acad Sci U S A ; 118(23)2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34083436

RESUMO

Prefrontal control of cognitive functions critically depends upon glutamatergic transmission and N-methyl D-aspartate (NMDA) receptors, the activity of which is regulated by dopamine. Yet whether the NMDA receptor coagonist d-serine is implicated in the dopamine-glutamate dialogue in the prefrontal cortex (PFC) and other brain areas remains unexplored. Here, using electrophysiological recordings, we show that d-serine is required for the fine-tuning of glutamatergic neurotransmission, neuronal excitability, and synaptic plasticity in the PFC through the actions of dopamine at D1 and D3 receptors. Using in vivo microdialysis, we show that D1 and D3 receptors exert a respective facilitatory and inhibitory influence on extracellular levels and activity of d-serine in the PFC, with actions expressed primarily via the cAMP/protein kinase A (PKA) signaling cascade. Further, using functional magnetic resonance imaging (fMRI) and behavioral assessment, we show that d-serine is required for the potentiation of cognition by D3R blockade as revealed in a test of novel object recognition memory. Collectively, these results unveil a key role for d-serine in the dopaminergic neuromodulation of glutamatergic transmission and PFC activity, findings with clear relevance to the pathogenesis and treatment of diverse brain disorders involving alterations in dopamine-glutamate cross-talk.


Assuntos
Dopamina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Serina/metabolismo , Animais , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Knockout , Racemases e Epimerases/deficiência , Racemases e Epimerases/genética , Receptores Dopaminérgicos/metabolismo , Esquizofrenia , Transmissão Sináptica/efeitos dos fármacos
7.
Mol Psychiatry ; 27(10): 4218-4233, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35701597

RESUMO

Remarkable advances have been made in schizophrenia (SCZ) GWAS, but gleaning biological insight from these loci is challenging. Genetic influences on gene expression (e.g., eQTLs) are cell type-specific, but most studies that attempt to clarify GWAS loci's influence on gene expression have employed tissues with mixed cell compositions that can obscure cell-specific effects. Furthermore, enriched SCZ heritability in the fetal brain underscores the need to study the impact of SCZ risk loci in specific developing neurons. MGE-derived cortical interneurons (cINs) are consistently affected in SCZ brains and show enriched SCZ heritability in human fetal brains. We identified SCZ GWAS risk genes that are dysregulated in iPSC-derived homogeneous populations of developing SCZ cINs. These SCZ GWAS loci differential expression (DE) genes converge on the PKC pathway. Their disruption results in PKC hyperactivity in developing cINs, leading to arborization deficits. We show that the fine-mapped GWAS locus in the ATP2A2 gene of the PKC pathway harbors enhancer marks by ATACseq and ChIPseq, and regulates ATP2A2 expression. We also generated developing glutamatergic neurons (GNs), another population with enriched SCZ heritability, and confirmed their functionality after transplantation into the mouse brain. Then, we identified SCZ GWAS risk genes that are dysregulated in developing SCZ GNs. GN-specific SCZ GWAS loci DE genes converge on the ion transporter pathway, distinct from those for cINs. Disruption of the pathway gene CACNA1D resulted in deficits of Ca2+ currents in developing GNs, suggesting compromised neuronal function by GWAS loci pathway deficits during development. This study allows us to identify cell type-specific and developmental stage-specific mechanisms of SCZ risk gene function, and may aid in identifying mechanism-based novel therapeutic targets.


Assuntos
Esquizofrenia , Animais , Camundongos , Humanos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Estudo de Associação Genômica Ampla/métodos , Interneurônios/metabolismo , Neurônios/metabolismo , Encéfalo/metabolismo , Predisposição Genética para Doença/genética
8.
Transpl Infect Dis ; 25(3): e14059, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37005911

RESUMO

BACKGROUND: The Centers for Disease Control and Prevention led an investigation to determine if Strongyloides infection in a right kidney recipient was an existing chronic infection, or if the infection was transmitted from an infected organ donor. METHODS: Evidence regarding the organ donor and organ recipients Strongyloides testing, treatment, and risk factors were gathered and evaluated. The case classification algorithm created by the Disease Transmission Advisory Committee was utilized. RESULTS: The organ donor had risk factors for Strongyloides infection; the banked donor specimen, submitted for serology testing 112 days post-donor death, was positive. The right kidney recipient was negative for Strongyloides infection pretransplant. Strongyloides infection was diagnosed via small bowel and stomach biopsies. The left kidney recipient had risk factors for Strongyloides infection. Two posttransplant Strongyloides antibody tests were negative at 59 and 116 days posttransplant; repeat antibody tests returned positive at 158 and 190 days posttransplant. Examination of bronchial alveolar lavage fluid collected 110 days posttransplant from the heart recipient showed a parasite morphologically consistent with Strongyloides species. She subsequently developed complications from Strongyloides infection, including hyperinfection syndrome and disseminated strongyloidiasis. Based on the evidence from our investigation, donor-derived strongyloidiasis was suspected in one recipient and proven in two recipients. CONCLUSION: The results of this investigation support the importance of preventing donor-derived Strongyloides infections by laboratory-based serology testing of solid organ donors. Donor positive testing results would direct the monitoring and treatment of recipients to avoid severe complications.


Assuntos
Transplante de Órgãos , Strongyloides stercoralis , Estrongiloidíase , Animais , Feminino , Humanos , Estrongiloidíase/diagnóstico , Estrongiloidíase/tratamento farmacológico , Estrongiloidíase/parasitologia , Michigan , Ohio , Doadores de Tecidos , California , Transplante de Órgãos/efeitos adversos
10.
Cell Mol Neurobiol ; 42(1): 279-289, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32445040

RESUMO

D-serine is synthesized by serine racemase (SR) and is a co-agonist at forebrain N-methyl-D-aspartate receptors (NMDARs). D-serine and SR are expressed primarily in neurons, but not in quiescent astrocytes. In this study, we examined the localization of D-serine and SR in the mouse striatum and the effects of genetically silencing SR expression in GABAergic interneurons (iSR-/-). iSR-/- mice had substantially reduced SR expression almost exclusively in striatum, but only exhibited marginal D-serine reduction. SR positive cells in the striatum showed strong co-localization with dopamine- and cyclic AMP-regulated neuronal phosphoprotein (DARPP32) in wild type mice. Transgenic fluorescent reporter mice for either the D1 or D2 dopamine receptors exhibited a 65:35 ratio for co-localization with D1and D2 receptor positive cells, respectively. These results indicate that GABAergic medium spiny neurons receiving dopaminergic inputs in striatum robustly and uniformly express SR. In behavioral tests, iSR-/- mice showed a blunted response to the hedonic and stimulant effects of cocaine, without affecting anxiety-related behaviors. Because the cocaine effects have been shown in the constitutive SR-/- mice, the restriction of the blunted response to cocaine to iSR-/- mice reinforces the conclusion that D-serine in striatal GABAergic neurons plays an important role in mediating dopaminergic stimulant effects. Results in this study suggest that SR in striatal GABAergic neurons is synthesizing D-serine, not as a glutamatergic co-transmitter, but rather as an autocrine whereby the GABAergic neurons control the excitability of their NMDARs by determining the availability of the co-agonist, D-serine.


Assuntos
Neurônios , Racemases e Epimerases , Animais , Corpo Estriado/citologia , Camundongos , Camundongos Knockout , Neurônios/enzimologia , Racemases e Epimerases/metabolismo , Serina/metabolismo
11.
J Neurosci ; 40(50): 9564-9575, 2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33158959

RESUMO

d-serine is the primary NMDAR coagonist at mature forebrain synapses and is synthesized by the enzyme serine racemase (SR). However, our understanding of the mechanisms regulating the availability of synaptic d-serine remains limited. Though early studies suggested d-serine is synthesized and released from astrocytes, more recent studies have demonstrated a predominantly neuronal localization of SR. More specifically, recent work intriguingly suggests that SR may be found at the postsynaptic density, yet the functional implications of postsynaptic SR on synaptic transmission are not yet known. Here, we show an age-dependent dendritic and postsynaptic localization of SR and d-serine by immunohistochemistry and electron microscopy in mouse CA1 pyramidal neurons. In addition, using a single-neuron genetic approach in SR conditional KO mice from both sexes, we demonstrate a cell-autonomous role for SR in regulating synaptic NMDAR function at Schaffer collateral (CA3)-CA1 synapses. Importantly, single-neuron genetic deletion of SR resulted in the elimination of LTP at 1 month of age, which could be rescued by exogenous d-serine. Interestingly, there was a restoration of LTP by 2 months of age that was associated with an upregulation of synaptic GluN2B. Our findings support a cell-autonomous role for postsynaptic neuronal SR in regulating synaptic NMDAR function and suggests a possible autocrine mode of d-serine action.SIGNIFICANCE STATEMENT NMDARs are key regulators of neurodevelopment and synaptic plasticity and are unique in their requirement for binding of a coagonist, which is d-serine at most forebrain synapses. However, our understanding of the mechanisms regulating synaptic d-serine availability remains limited. d-serine is synthesized in the brain by the neuronal enzyme serine racemase (SR). Here, we show dendritic and postsynaptic localization of SR and d-serine in CA1 pyramidal neurons. In addition, using single-neuron genetic deletion of SR, we establish a role of postsynaptic SR in regulating NMDAR function. These results support an autocrine mode of d-serine action at synapses.


Assuntos
Dendritos/metabolismo , Células Piramidais/metabolismo , Racemases e Epimerases/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo , Fatores Etários , Animais , Região CA1 Hipocampal/metabolismo , Feminino , Masculino , Camundongos , Camundongos Knockout , Plasticidade Neuronal/fisiologia , Racemases e Epimerases/genética , Transmissão Sináptica/fisiologia
12.
J Viral Hepat ; 28(2): 440-444, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33184976

RESUMO

Using Michigan public health data, we assessed geographical access to specialist providers for hepatitis C virus (HCV) treatment in urban and rural areas in Michigan and explored correlates of HCV in these areas to help inform HCV elimination planning and resource allocations. We found higher HCV incidence in urban areas, lower treatment specialist access in rural areas, but few correlates of HCV across adult populations in both areas. State and local HCV elimination planning should include population-based screening among all adults and address geographical barriers to care.


Assuntos
Hepacivirus , Hepatite C , Adulto , Hepatite C/epidemiologia , Humanos , Michigan/epidemiologia , Saúde Pública , População Rural
14.
Mol Psychiatry ; 25(11): 2873-2888, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-31019265

RESUMO

Schizophrenia (SCZ) is a neurodevelopmental disorder. Thus, studying pathogenetic mechanisms underlying SCZ requires studying the development of brain cells. Cortical interneurons (cINs) are consistently observed to be abnormal in SCZ postmortem brains. These abnormalities may explain altered gamma oscillation and cognitive function in patients with SCZ. Of note, currently used antipsychotic drugs ameliorate psychosis, but they are not very effective in reversing cognitive deficits. Characterizing mechanisms of SCZ pathogenesis, especially related to cognitive deficits, may lead to improved treatments. We generated homogeneous populations of developing cINs from 15 healthy control (HC) iPSC lines and 15 SCZ iPSC lines. SCZ cINs, but not SCZ glutamatergic neurons, show dysregulated Oxidative Phosphorylation (OxPhos) related gene expression, accompanied by compromised mitochondrial function. The OxPhos deficit in cINs could be reversed by Alpha Lipoic Acid/Acetyl-L-Carnitine (ALA/ALC) but not by other chemicals previously identified as increasing mitochondrial function. The restoration of mitochondrial function by ALA/ALC was accompanied by a reversal of arborization deficits in SCZ cINs. OxPhos abnormality, even in the absence of any circuit environment with other neuronal subtypes, appears to be an intrinsic deficit in SCZ cINs.


Assuntos
Células-Tronco Pluripotentes Induzidas , Interneurônios/metabolismo , Interneurônios/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Esquizofrenia/patologia , Linhagem Celular , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/patologia , Masculino
15.
MMWR Morb Mortal Wkly Rep ; 70(49): 1712-1714, 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34882659

RESUMO

On November 10, 2021, the Michigan Department of Health and Human Services (MDHHS) was notified of a rapid increase in influenza A(H3N2) cases by the University Health Service (UHS) at the University of Michigan in Ann Arbor. Because this outbreak represented some of the first substantial influenza activity during the COVID-19 pandemic, CDC, in collaboration with the university, MDHHS, and local partners conducted an investigation to characterize and help control the outbreak. Beginning August 1, 2021, persons with COVID-19-like* or influenza-like illness evaluated at UHS received testing for SARS-CoV-2, influenza, and respiratory syncytial viruses by rapid multiplex molecular assay.† During October 6-November 19, a total of 745 laboratory-confirmed influenza cases were identified.§ Demographic information, genetic characterization of viruses, and influenza vaccination history data were reviewed. This activity was conducted consistent with applicable federal law and CDC policy.¶.


Assuntos
Surtos de Doenças , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Influenza Humana/epidemiologia , Influenza Humana/virologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Michigan/epidemiologia , Estudantes/estatística & dados numéricos , Universidades , Adulto Jovem
16.
J Infect Dis ; 222(Suppl 5): S451-S457, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32877550

RESUMO

BACKGROUND: Increases in fatal drug poisonings and hepatitis C infections associated with the opioid epidemic are relatively well defined, because passive surveillance systems for these conditions exist. Less described is the association between the opioid epidemic and skin, soft-tissue, and venous infections (SSTVIs), endocarditis, sepsis, and osteomyelitis. METHODS: Michigan hospitalizations between 2016 and 2018 that included an International Classification of Diseases, Tenth Revision, Clinical Modification, code indicating substance use were examined for codes indicative of infectious conditions associated with injecting drugs. Trends in these hospitalizations were examined, as were demographic characteristics, discharge disposition, payer, and cost data. RESULTS: Among hospitalized patients with a substance use diagnosis code, endocarditis, osteomyelitis, sepsis, and SSTVI hospitalizations increased by 33%, 35%, 24%, and 12%, respectively between 2016 and 2018. During this time frame, 1257 patients died or were discharged to hospice. All SSTVI hospitalizations resulted in >$1.3 billion in healthcare costs. Public insurance accounted for more than two-thirds of all hospitalization costs. CONCLUSIONS: This study describes a method for performing surveillance for infection-related sequelae of injection drug use. Endocarditis, osteomyelitis, sepsis, and SSTVI hospitalizations have increased year over year between 2016 and 2018. These hospitalizations result in significant morbidity, mortality, and healthcare costs and should be a focus of future surveillance and prevention efforts.


Assuntos
Infecções Bacterianas/epidemiologia , Custos de Cuidados de Saúde/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Transtornos Relacionados ao Uso de Opioides/complicações , Adolescente , Adulto , Infecções Bacterianas/economia , Infecções Bacterianas/microbiologia , Infecções Bacterianas/terapia , Monitoramento Epidemiológico , Feminino , Hospitalização/economia , Humanos , Masculino , Pessoa de Meia-Idade , Epidemia de Opioides/estatística & dados numéricos , Transtornos Relacionados ao Uso de Opioides/economia , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Estudos Retrospectivos , Estados Unidos/epidemiologia , Adulto Jovem
17.
Hum Mol Genet ; 27(2): 254-265, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29106556

RESUMO

Recent studies describe distinct DNA methylomes among phenotypic subclasses of neurons in the human brain, but variation in DNA methylation between common neuronal phenotypes distinguished by their function within distinct neural circuits remains an unexplored concept. Studies able to resolve epigenetic profiles at the level of microcircuits are needed to illuminate chromatin dynamics in the regulation of specific neuronal populations and circuits mediating normal and abnormal behaviors. The Illumina HumanMethylation450 BeadChip was used to assess genome-wide DNA methylation in stratum oriens GABAergic interneurons sampled by laser-microdissection from two discrete microcircuits along the trisynaptic pathway in postmortem human hippocampus from eight control, eight schizophrenia, and eight bipolar disorder subjects. Data were analysed using the minfi Bioconductor package in R software version 3.3.2. We identified 11 highly significant differentially methylated regions associated with a group of genes with high construct-validity, including multiple zinc finger of the cerebellum gene family members and WNT signaling factors. Genomic locations of differentially methylated regions were highly similar between diagnostic categories, with a greater number of differentially methylated individual cytosine residues between circuit locations in bipolar disorder cases than in schizophrenia or control (42, 7, and 7 differentially methylated positions, respectively). These findings identify distinct DNA methylomes among phenotypically similar populations of GABAergic interneurons functioning within separate hippocampal subfields. These data compliment recent studies describing diverse epigenotypes among separate neuronal subclasses, extending this concept to distinct epigenotypes within similar neuronal phenotypes from separate microcircuits within the human brain.


Assuntos
Transtorno Bipolar/genética , Neurônios GABAérgicos/fisiologia , Esquizofrenia/genética , Idoso , Idoso de 80 Anos ou mais , Transtorno Bipolar/fisiopatologia , Encéfalo/metabolismo , Cerebelo/metabolismo , Ilhas de CpG , Metilação de DNA , Epigênese Genética/genética , Feminino , Genoma , Hipocampo , Humanos , Interneurônios/metabolismo , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , Esquizofrenia/fisiopatologia , Transdução de Sinais , Lobo Temporal/metabolismo
18.
Neurochem Res ; 45(6): 1344-1353, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32189130

RESUMO

Shape-shifting, a phenomenon wide-spread in folklore, refers to the ability to physically change from one identity to another, typically from an innocuous entity to a destructive one. The amino acid D-serine over the last 25 years has "shape-shifted" into several identities: a purported glial transmitter activating N-methyl-D-aspartate receptors (NMDARs), a co-transmitter concentrated in excitatory glutamatergic neurons, an autocrine that is released at dendritic spines to prime their post-synaptic NMDARs for an instantaneous response to glutamate and an excitotoxic moiety released from inflammatory (A1) astrocytes. This article will review evidence in support of these scenarios and the artifacts that misled investigators of the true identity of D-serine.


Assuntos
Encéfalo/metabolismo , Agonistas de Aminoácidos Excitatórios/metabolismo , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/metabolismo , Serina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/farmacologia , Humanos , Neurônios/efeitos dos fármacos , Serina/farmacologia
19.
Proc Natl Acad Sci U S A ; 114(22): E4462-E4471, 2017 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-28500272

RESUMO

The molecular pathogenesis of bipolar disorder (BPD) is poorly understood. Using human-induced pluripotent stem cells (hiPSCs) to unravel such mechanisms in polygenic diseases is generally challenging. However, hiPSCs from BPD patients responsive to lithium offered unique opportunities to discern lithium's target and hence gain molecular insight into BPD. By profiling the proteomics of BDP-hiPSC-derived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). Active nonphosphorylated CRMP2, which binds cytoskeleton, is present throughout the neuron; inactive phosphorylated CRMP2, which dissociates from cytoskeleton, exits dendritic spines. CRMP2 elimination yields aberrant dendritogenesis with diminished spine density and lost lithium responsiveness (LiR). The "set-point" for the ratio of pCRMP2:CRMP2 is elevated uniquely in hiPSC-derived neurons from LiR BPD patients, but not with other psychiatric (including lithium-nonresponsive BPD) and neurological disorders. Lithium (and other pathway modulators) lowers pCRMP2, increasing spine area and density. Human BPD brains show similarly elevated ratios and diminished spine densities; lithium therapy normalizes the ratios and spines. Consistent with such "spine-opathies," human LiR BPD neurons with abnormal ratios evince abnormally steep slopes for calcium flux; lithium normalizes both. Behaviorally, transgenic mice that reproduce lithium's postulated site-of-action in dephosphorylating CRMP2 emulate LiR in BPD. These data suggest that the "lithium response pathway" in BPD governs CRMP2's phosphorylation, which regulates cytoskeletal organization, particularly in spines, modulating neural networks. Aberrations in the posttranslational regulation of this developmentally critical molecule may underlie LiR BPD pathogenesis. Instructively, examining the proteomic profile in hiPSCs of a functional agent-even one whose mechanism-of-action is unknown-might reveal otherwise inscrutable intracellular pathogenic pathways.


Assuntos
Transtorno Bipolar , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Lítio/farmacologia , Modelos Biológicos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Animais , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Transtorno Bipolar/fisiopatologia , Química Encefálica , Cálcio/metabolismo , Células Cultivadas , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Proteômica
20.
Neurobiol Dis ; 130: 104511, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31212068

RESUMO

Although ß-amyloid plaques are a well-recognized hallmark of Alzheimer's disease (AD) neuropathology, no drugs reducing amyloid burden have shown efficacy in clinical trials, suggesting that once AD symptoms emerge, disease progression becomes independent of Aß production. Reactive astrocytes are another neuropathological feature of AD, where there is an emergence of neurotoxic (A1) reactive astrocytes. We find that serine racemase (SR), the neuronal enzyme that produces the N-methyl-d-aspartate receptor (NMDAR) co-agonist d-serine, is robustly expressed in A1-reactive neurotoxic astrocytes in the hippocampus and entorhinal cortex of AD subjects and an AD rat model. Furthermore, we observe intracellular signaling changes consistent with increased extra-synaptic NMDAR activation, excitotoxicity and decreased neuronal survival. Thus, reducing neurotoxic d-serine release from A1 inflammatory astrocytes could have therapeutic benefit for mild to advanced AD, when anti-amyloid strategies are ineffective.


Assuntos
Doença de Alzheimer/enzimologia , Astrócitos/enzimologia , Córtex Entorrinal/enzimologia , Hipocampo/enzimologia , Racemases e Epimerases/metabolismo , Doença de Alzheimer/patologia , Animais , Modelos Animais de Doenças , Humanos , Ratos , Ratos Transgênicos
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