Serologic Evidence of Recent Infection with Highly Pathogenic Avian Influenza A(H5) Virus Among Dairy Workers - Michigan and Colorado, June-August 2024.

Since April 2024, sporadic infections with highly pathogenic avian influenza (HPAI) A(H5) viruses have been detected among dairy farm workers in the United States. To date, infections have mostly been detected through worker monitoring, and have been mild despite the possibility of more severe illness. During June-August 2024, CDC collaborated with the Michigan Department of Health and Human Services and the Colorado Department of Public Health and Environment to implement cross-sectional serologic surveys to ascertain the prevalence of recent infection with HPAI A(H5) virus among dairy workers.

Wastewater Surveillance for Poliovirus in Selected Jurisdictions, United States, 2022-2023.

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.

An increased copy number of glycine decarboxylase (GLDC) associated with psychosis reduces extracellular glycine and impairs NMDA receptor function.

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.

Fragment-Based Discovery of a Series of Allosteric-Binding Site Modulators of β-Glucocerebrosidase.

β-Glucocerebrosidase (GBA/GCase) mutations leading to misfolded protein cause Gaucher's disease and are a major genetic risk factor for Parkinson's disease and dementia with Lewy bodies. The identification of small molecule pharmacological chaperones that can stabilize the misfolded protein and increase delivery of degradation-prone mutant GCase to the lysosome is a strategy under active investigation. Here, we describe the first use of fragment-based drug discovery (FBDD) to identify pharmacological chaperones of GCase.

Impact of Serine Racemase Deletion on Nicotine Discrimination.

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.

Passing the torch: The ascendance of the glutamatergic synapse in the pathophysiology of schizophrenia.

For nearly fifty years, the dopamine hypothesis has dominated our understanding of the pathophysiology of schizophrenia and provided the lone target for drug development. However, with the exception of clozapine, the dopamine D2 receptor antagonizing anti-psychotic drugs have little impact on the negative symptoms and cognitive deficits, aspects of the disorder that robustly predict outcome. Pathologic studies reveal cortical atrophy and wide-spread loss of glutamatergic synaptic spines, unexplained by dopaminergic malfunction.

A marker chromosome in psychosis identifies glycine decarboxylase (GLDC) as a novel regulator of neuronal and synaptic function in the hippocampus.

The biological significance of a small supernumerary marker chromosome that results in dosage alterations to chromosome 9p24.1, including triplication of the gene encoding glycine decarboxylase, in two patients with psychosis is unclear. In an allelic series of copy number variant mouse models, we identify that triplication of reduces extracellular glycine levels as determined by optical fluorescence resonance energy transfer (FRET) in dentate gyrus (DG) but not in CA1, 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 prepulse inhibition, startle habituation, latent inhibition, working memory, sociability and social preference.

Impact of schizophrenia GWAS loci converge onto distinct pathways in cortical interneurons vs glutamatergic neurons during development.

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.

Centralized COVID-19 Contact Tracing in a Home-Rule State.

Contact tracing is an evidence-based intervention to control many communicable diseases, including COVID-19. Before the COVID-19 pandemic, contact tracing in Michigan focused on HIV, sexually transmitted infections, and tuberculosis, and it was conducted by state and local health department staff. Within 2 weeks of the first reported COVID-19 cases in Michigan in March 2020, the existing public health workforce was overwhelmed by the need for contact tracing and daily symptom monitoring.

Influenza A(H3N2) Outbreak on a University Campus - Michigan, October-November 2021.

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.

Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 () through structure-guided optimization of our previously published isoindolinone lead ().

Clinical evidence that a dysregulated master neural network modulator may aid in diagnosing schizophrenia.

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.

Dopaminergic neuromodulation of prefrontal cortex activity requires the NMDA receptor coagonist d-serine.

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 D and D receptors.

Altered neural oscillations and behavior in a genetic mouse model of NMDA receptor hypofunction.

Abnormalities in electroencephalographic (EEG) biomarkers occur in patients with schizophrenia and those clinically at high risk for transition to psychosis and are associated with cognitive impairment. Converging evidence suggests N-methyl-D-aspartate receptor (NMDAR) hypofunction plays a central role in the pathophysiology of schizophrenia and likely contributes to biomarker impairments. Thus, characterizing these biomarkers is of significant interest for early diagnosis of schizophrenia and development of novel treatments.

Utilizing public health data to geotarget hepatitis C virus elimination approaches in urban and rural Michigan.

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.

Factors regulating serine racemase and d-amino acid oxidase expression in the mouse striatum.

d-Serine plays an important role in modulating N-methyl-d-aspartate receptor (NMDAR) neurotransmission in the mammalian brain by binding to the receptor's glycine modulatory site (GMS). The cytosolic enzyme serine racemase (SR) converts L-serine to d-serine, while the peroxisomal enzyme d-amino acid oxidase (DAAO) catalyzes the breakdown of d-serine. Although it is important to understand how the activities of SR and DAAO regulate d-serine levels, very little is known about the mechanisms that regulate the expression of SR and DAAO.

Postsynaptic Serine Racemase Regulates NMDA Receptor Function.

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.

Activated microglia cause metabolic disruptions in developmental cortical interneurons that persist in interneurons from individuals with schizophrenia.

The mechanisms by which prenatal immune activation increase the risk for neuropsychiatric disorders are unclear. Here, we generated developmental cortical interneurons (cINs)-which are known to be affected in schizophrenia (SCZ) when matured-from induced pluripotent stem cells (iPSCs) derived from healthy controls (HCs) and individuals with SCZ and co-cultured them with or without activated microglia. Co-culture with activated microglia disturbed metabolic pathways, as indicated by unbiased transcriptome analyses, and impaired mitochondrial function, arborization, synapse formation and synaptic GABA release.

The Discovery and Characterization of Targeted Perikaryal-Specific Brain Lesions With Excitotoxins.

The neurotoxic action of glutamic acid was first described by Lucas and Newhouse, who demonstrated neural degeneration in the inner layers of the neonatal mouse retina after systemic treatment with L-glutamate. Olney extended these findings by showing that neuronal degeneration affected other brain structures including neurons within the arcuate nucleus of the hypothalamus and the area postrema, that the lesion spared axons passing through these areas, and that the neurotoxic potency of glutamate analogs correlated with their excitatory potency, resulting in the designation "excitotoxins." As this method affected only a small number of brain regions, it was not suitable for targeted brain lesions.

Trends in Morbidity, Mortality, and Cost of Hospitalizations Associated With Infectious Disease Sequelae of the Opioid Epidemic.

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.