bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dendritic Cell Subsets Differentially Sense and Respond to Listeria monocytogenes Infection both In Vitro and In Vivo
Authors: Mitchell Latoya M. , Grayson Jason M. , Hiltbold Elizabeth M. 
Published: June 2021

Dendritic cells (DC) bridge the innate and adaptive immune systems and are important for protection against the intracellular, bacterial pathogen Listeria monocytogenes (Lm). DC can be generated in vitro by treating bone marrow with the cytokines GM‐CSF or Flt3L and can be isolated in vivo from tissues such as the spleen. Current studies show that GM‐CSF DC are representative of monocyte‐derived, inflammatory DC found in vivo, while Flt3L DC correlate to three resident, splenic DC subsets – CD8α+/CD24+DC, CD11b+DC, and B220+ DC. Our goal is to determine how these different DC subsets recognize and respond to Lm infection.Our previous data indicate that Flt3L DC induce surface costimulatory molecules and cytokines in response to both wild‐type and Hly− strains of Lm in contrast to GM‐CSF DC, which mature in response to wild‐type Lm. The response to Hly− Lm in Flt3L DC was dependent on MyD88 but not TRIF or TLR7. Upon isolation of B220+ and CD11b+ DC subsets from Flt3L DC cultures, CD11b+ DC underwent robust maturation and became infected to a higher percentage than the B220+ DC. In vivo data indicate that splenic DC subsets respond differentially to wild‐type Lm infection but lack a response to Hly−. In addition, the peak of costimulatory molecule upregulation was dependent upon the infectious dose. Taken together, our data support differential responses of DC subsets to Lm infection. 1R01AI057770‐01A1
Regulation of Innate Immune Responses by Mycobacterium Tuberculosis Gene Products
Authors: Medeiros Jennifer , Hansen Eric , van Oers Nicolai S.C. 
Published: June 2021

Mycobacterium tuberculosis (Mtb), which causes tuberculosis (TB), infects 1/3 of the world's population. Many humans cannot effectively clear Mtb, requiring prolonged multi‐antibiotic drug therapies. This problem is compounded with multi‐ and extremely drug resistant strains of TB. We hypothesize that a number of genes in the Mtb genome inhibit innate immune effector cells.To identify such gene products, we developed an innate immune response colorimetric reporter assay in macrophages and dendritic cells (DCs) infected with a non‐pathogenic strain, Mycobacterium smegmatis (Msm). In this assay, a murine IL‐6 promoter was cloned into an enhanced green fluorescence protein expression vector. DCs and macrophages exposed to Msm exhibited a 5–15 fold increase in GFP expression. Protein kinase G and protein tyrosine phosphatase B did not suppress IL‐6 driven GFP. We are currently cloning a Mtb‐encoded plasmid library into Msm. Recombinant Msm clones are being used to screen for Mtb genes that suppress IL‐6‐driven inflammatory responses. Suppressive clones will be sequenced and characterized for their capacity to suppress innate inflammatory pathways.The identification of Mtb‐encoded effector molecules that regulate the immune response is vital for the development of novel therapeutic treatments of tuberculosis. Supported by High‐Impact/High‐Risk Award, UT Southwestern Medical Center
Influence of bone age and allelic variants of the vitamin D receptor (VDR) gene on bone mass indices in adolescent boys
Authors: Diógenes Maria Eduarda Leão , Oliveira Karla F. , Bezerra Flávia F. , Koury Josely C. , Oliveira‐Junior Astrogildo Vianna , Cabello Giselda M.K. , Cabello Pedro , Mendonça Laura M.C. , Donangelo Carmen M. 
Published: June 2021

The aim of this study was to evaluate the influence of bone age and FokI polymorphism on bone mass indices in healthy adolescent boys (11–14y, n=47). Bone age was assessed by left hand x‐ray. Total body bone mineral density (TBMD) and content (TBMC) were assessed by DXA. Plasma testosterone and serum PTH were measured by radioimuno‐ and chemiluminescent assay – respectively. VDR genotypes were determined by PCR amplification and enzymatic digestion of the products with FokI.These results indicate that bone age is the main factor affecting bone indices. Moreover, differences in TBMD, TBMD‐Zscore and TBMC due to bone age appear to be less pronounced in adolescents with FF compared to those with Ff + ff genotypes.Financial support: CNPq and FAPERJ (Brazil).
SOX2 immunoreactivity in cortical dysplasia and in tumors with composite glial and neuronal histologic features: Evidence for a common route of histogenesis
Authors: Eschbacher Jennifer Mary , Coons Stephen William 
Published: June 2021

A number of tumors, most commonly dysembryoplastic neuroepithelial tumor (DNET) and ganglioglioma, demonstrate histologic and/or immunohistochemistry features suggesting both glial and neuronal differentiation. The lineage and etiology of these low‐grade glioneuronal tumors is unclear. Based on their similar immunohistochemistry features and common association with cortical dysplasia, we hypothesize that these entities may share a common route of histogenesis. Pleomorphic xanthoastrocytoma (PXA) also demonstrates both glial and neuronal markers. The basis for this, along with its lineage and relation to ganglioglioma, is also unclear. Using immunohistochemistry analysis, we evaluated for expression of SOX2, a neural stem cell marker, in 27 tumors with glioneuronal features and 7 cases of cortical dysplasia. We found scattered SOX2 immunoreactive cells in 22/27 tumors, including 10/10 DNETs, 8/10 PXAs, and 4/7 gangliogliomas. All 7 cases of cortical dysplasia demonstrated SOX2 immunoreactivity in dysplastic areas only. In uninvolved cortex, and in eight normal control autopsy brain sections, we found no SOX2 positive cells. Our results suggest that these entities may share a common lineage and may arise from a multipotent stem cell.This research was funded and supported by Barrow Neurological Institute.
Prognostic value of tumor microinvasion and metalloproteinases expression in intracranial pediatric ependymomas
Authors: Snuderl Matija , Chi Susan N. , DeSantis Stacia , Stemmer‐Rachamimov Anat , Betensky Rebecca A. , DeGirolami Umberto , Kieran Mark W. 
Published: June 2021

Ependymomas often appear well circumscribed on imaging and histology, but many recur despite gross total resection (GTR). The current WHO histologic grading system does not accurately predict the clinical behavior. The aim of this study is to determine histological and immunohistochemical features that would better correlate with prognosis of ependymomas treated with GTR. In a retrospective study, we analyzed 41 pediatric ependymomas for microinvasion and for expression of invasion associated proteins, metalloproteinases MMP2 and MMP14 and correlated the findings with clinical outcome. We found GTR to have significant positive influence on both overall survival (OAS) and progression free survival (PFS). In 28 patients that underwent GTR, microinvasion was a predictor of poor OAS (p= 0.003) as well as PFS (p=0.03). Furthermore, GTR tumors with high expression of MMP2 and MMP14 had significantly shorter OAS (p= 0.02 and p=0.002 respectively). Our data show that tumor microinvasion into adjacent brain and tumor expression of MMP2 and MMP14 are significant predictors of both OAS and PFS in pediatric ependymomas and these are useful prognostic markers that may help stratify patients for adjuvant treatments.Research support: DFCI BTCF 9999056.
Tau Negative FTLD Without Abnormal TDP‐43 Immunoreactivity
Authors: Josephs Keith A. , Stroh Alex , Dickson Dennis W. 
Published: June 2021

Objective: To determine whether all cases of tau‐negative frontotemporal lobar degeneration (FTLD) show abnormal TDP‐43 immunoreactivity.Design/methods: The neuropathological database at Mayo Clinic, Florida, was queried to identify all cases of tau‐negative FTLD. Forty cases were identified that underwent analysis with TDP‐43 immunohistochemistry. Cases without abnormal TDP‐43 immunoreactivity were further analyzed with H&E, PAS and silver stains, and with immunohistochemistry for phosphorylated tau, alpha‐synuclein, ubiquitin, neurofilament, alpha‐internexin and p62.Results: Of the 40 cases, 3 did not show abnormal TDP‐43 immunoreactivity. Cases 1 and 3 had clinical features of behavioral variant FTD while case 2 had features of the corticobasal syndrome. Case 3 had a positive family history. Case 1 had a pathological diagnosis of dementia lacking distinctive histology (DLDH) and case 2 basophilic inclusion body disease. Case 3 had ubiquitin‐positive but TDP‐43 negative neuronal inclusions and dystrophic neurites.Conclusion: Not all cases of tau‐negative FTLD have abnormal TDP‐43 immunoreactivity; basophilic inclusion body disease and DLDH are rare examples that do not. Given the positive family history and histological findings in case 3, there likely exists a yet to be identified gene and protein associated with tau negative FTLD.
Diagnosis and grading of the Parkinson's disease phenotype
Authors: Richfield Eric Karl , Prasad Kavita , Rhodes Roy , Beach Tom , Zhang Jing 
Published: June 2021

We examined criteria for the diagnosis and grading of the Parkinson's disease phenotype (PDP) using postmortem tissue and clinical features.We used cases of the PDP, incidental Lewy body disease (ILBD), other neurodegenerative diseases and control subjects. We stained paraffin slides and free‐floating tissue sections from different academic centers for H&E. StereoInvestigator (MBF, Williston VT) was used for counting. Features counted included: neuromelanin (NM) containing neurons, NM+ cells, NM– neurons, NM+ macrophages (MPs), NM+ clusters of MPs, free NM, LBs, pale bodies and other intraneuronal inclusions. Principle component analysis followed by linear discriminant analysis will be used with other clinical features to compare the levels of these morphological factors.Data presented will include cases not used, counts from paraffin and free‐floating sections, repeat counting, inter‐rater reliability, and statistical analysis.Disagreements were identified. Criteria, counts, morphology, and time required for counting varied between the two methods. Both methods have advantages and disadvantages. The use of additional cases to refine this approach may demonstrate which method is superior and how they relate to each other.
Immune reconstitution inflammatory syndrome of the brain: clinicopathological study of six cases
Authors: Rushing Elisabeth J. , Liappis Angelike , Smirniotopoulos James D , Smith Alice B. , Henry James M. , Nelson Ann M. 
Published: June 2021

OBJECTIVES:Immune reconstitution inflammatory syndrome (IRIS) represents a spectrum of clinicopathological entities encountered in HIV‐infected patients who have received highly active, antiretroviral therapy (HAART). Diagnosis of is often challenging, treatment options are limited, and the prognosis variable. We present our experience with six cases, including one autopsy, with central nervous system (CNS) involvement. METHODS: All patients met the clinicopathological criteria for the diagnosis of IRIS. The study included 5 males and one female, ranging in age from 34 to 47 (mean, 41, S.D. 5.39) years. RESULTS: The spectrum of underlying CNS lesions included necrotizing meningoencephalitis in two cases, progressive multifocal leukoencephalopathy, and cryptococcal meningitis. In several patients, the disease had unusual features, and in some cases, this delayed the diagnosis. DISCUSSION: Greater awareness of IRIS may hasten accurate diagnosis and appropriate treatment. Although nonspecific, imaging findings reflect the underlying histopathologic conditions and may yield important clues to early diagnosis. In order to capture all suspected cases, early biopsy is recommended.
Cryptic Unbalanced t(4q;18q) In A Pediatric Patient with Neuropathologic Findings
Authors: Horbinski Craig Michael , Cody Jannine D. , Gunn Shelly R. , Sathanoori Malini , Hu Jie , Vockley Gerard , Surti Urvashi 
Published: June 2021

Objective: To determine whether a pediatric patient with a phenotype resembling the 18q deletion syndrome but a normal karyotype had any cryptic genetic aberrations.Methods: High‐resolution G‐band chromosome analysis, array comparative genomic hybridization (aCGH), and telomeric fluorescence in situ hybridization (FISH) were performed on DNA obtained from a peripheral blood sample.Results: FISH and aCGH detected a cryptic unbalanced translocation between 4q and 18q [der(18)t(4;18)(q35;q23)(4qtel+,18qtel‐)].Conclusions: Two other similar patients were identified in the literature. The known genes gained and deleted by this unbalanced translocation are enumerated, including deletion of myelin basic protein. An assessment of candidate genes for particular characteristics, including neurologic and developmental abnormalities (such as abnormal white matter myelination), is also included.Source of support: This data was collected as part of the patient's routine workup; no designated research support was utilized.
ROLE OF CARBONIC ANHYDRASE EXPRESSION IN HEPATOCYTE PROTECTION BY LATE PRECONDITIONING
Authors: Ndoungue Valerie , Alchera Elisa , Imarisio Chiara , Ponte Caterina Dal , Monga Guido , Albano Emanuele , Carini Rita 
Published: June 2021

Liver ischemic preconditioning improves reperfusion damage during hepatic surgery and transplantation. However, the mechanisms involved are still poorly understood. This study investigated the role of carbonic anhydrase IX (CAIX), a transmembrane enzyme that catalyzes bicarbonate production, in the protective effects associated with the late phase of liver preconditioning.Late preconditioning was induced in primary cultured rat hepatocytes by a transient (10 min) hypoxic stress or by 15 min incubation with the adenosine A2A receptors agonist CGS21680 (5μ mol/L) 24 h before the exposure to 90 min hypoxia.Late preconditioning prevented hepatocytes killing and ameliorated intracellular acidosis and Na+ accumulation during hypoxia. Such effects were associated with the expression of CAIX. Blocking the transduction of preconditioning signals by PKC and PI3‐kinase with chelerythrine or wortmannin abolished CAIX expression and the protective action of late preconditioning. The inhibition of CAIX with acetazolamide or the block of bicarbonate influx through the Cl−/HCO−3 exchanger with SITS also reverted the protective effects of late preconditioning on intracellular acidosis and Na+ accumulation.We conclude that the induction of late preconditioning in liver cells involve the expression of CAIX that increases hepatocyte tolerance to ischemia by maintaining intracellular Na+ homeostasis.
The Effects of Chronic Administration of The GABAB Receptor Agonist Baclofen on Spontaneous And Cocaine‐Induced Behavior in Rats.
Authors: CARMO GAIL PEREIRA DO , KING GEORGE 
Published: June 2021

There is increasing evidence that the GABAB receptor agonist baclofen may have potential as a therapeutic agent in cocaine abuse. Research demonstrates that baclofen effectively reduces the stimulant and reinforcing effects of cocaine. However, the effects of chronic baclofen exposure on cocaine‐induced behaviors have not been systematically examined.OBJECTIVE: The present study evaluated the behavioral responses to cocaine challenge following continuous baclofen administration.METHODS: Sprague‐Dawley rats were pretreated with baclofen (0, 0.31, 0.625, 1.25 mg/kg/day) continuously for 14 days, and withdrawn for 7 days. Body weights of all subjects were monitored during withdrawal. Following withdrawal, subjects received a cocaine (0, 7.5, 15 mg/kg) challenge, and locomotor activity and rearing were recorded for 60 min.RESULTS: The highest dose of baclofen (1.25 mg/kg/day) increased spontaneous locomotion during withdrawal. However, baclofen did not alter body weights or rearing, suggesting that the effects of baclofen were not due to non‐specific increases in behavior. Additionally, the 1.25 mg/kg/day baclofen dose significantly decreased locomotor activity and rearing induced by 15 mg/kg cocaine.CONCLUSIONS: The current findings provide further evidence that chronic baclofen treatment produces enduring alterations in spontaneous and cocaine‐induced locomotor activity.
The FAAH inhibitor URB‐597 ameliorates cannabinoid withdrawal in mice
Authors: Schlosburg Joel Evan , LA Carlson Brittany , Lichtman Aron H 
Published: June 2021

Administration of Δ9‐tetrahydrocannabinol (THC) has been demonstrated to ameliorate the severity of withdrawal symptoms in rodents and humans. The purpose of the current investigation was to determine if upregulation of the endogenous cannabinoid anandamide would reduce the physical withdrawal signs in a mouse model of cannabinoid dependence. By blocking the primary enzyme responsible for anandamide degradation, fatty acid amide hydrolase (FAAH), the influence of elevated anandamide levels was examined on somatic signs of withdrawal in THC‐dependent mice. While FAAH (−/−) mice showed similar withdrawal profiles to normal mice, acute administration of the FAAH inhibitor URB‐597 significantly diminished the severity of withdrawal symptoms in wild type mice, but not in FAAH (−/−) mice. Unlike THC, repeated injections of high doses of URB‐597 failed to lead to cannabinoid dependence. These findings suggest that FAAH inhibitors lack dependence liability, but FAAH may prove a promising therapeutic target to treat cannabis dependence.Research supported by: PO1DA017259, RO1DA15197, RO1DA015683
Modulation of the Reinforcing and Discriminative Stimulus Effects of Cocaine by the Dopamine D3 Receptor Partial Agonist CJB 090 [N‐(4‐(4‐(2,3‐Dichlorophenyl)piperazin‐4‐(pyridine‐2‐yl)benzamide] in Squirrel Monkeys
Authors: Achat‐Mendes Cindy , Platt Donna M. , Spealman Roger D. , Newman Amy H. 
Published: June 2021

Dopamine D3 receptor mechanisms have been implicated repeatedly in the behavioral effects of cocaine. This study evaluated the effects of the D3 receptor partial agonist CJB 090 in monkeys trained to: 1) discriminate cocaine from vehicle, 2) self‐administer cocaine on a second order fixed‐interval, fixed‐ratio schedule of i.v. drug injection or 3) self‐administer food on a comparable second order schedule of food delivery. In cocaine discrimination studies, CJB 090 did not substitute for cocaine, but significantly attenuated cocaine's discriminative stimulus effects when administered as a pretreatment. CJB 090 also significantly attenuated the partial cocaine‐like stimulus effects of the D3 receptor agonist PD128907, but enhanced the partial cocaine‐like stimulus effects of the D2 receptor agonist sumanirole. In self‐administration studies, CJB 090 did not attenuate responding maintained by i.v. injections of cocaine at a dose that reduced responding maintained by food. In a separate group of monkeys, observational tests revealed that CJB 090 did not induce scratching or biting (species‐typical effects of D2/3 receptor agonists) or catalepsy (typical effect of D2/3 receptor antagonists). The results provide little evidence that CJB 090 reduced cocaine's reinforcing effects. However they do suggest that CJB 090, acting primarily via a D3 receptor mechanism, antagonized the discriminative stimulus effects of cocaine at a dose that did not induce adverse observable effects.Supported by DA011054, NIDA‐IRP, RR00168. We thank J. Cao for CJB 090 synthesis.
Gender differences in 5‐HT induced hypotension
Authors: Davis Robert Patrick , Diaz Jessica Lynn , Watts Stephanie Wengert 
Published: June 2021

Recent studies have shown that 5‐hydroxytryptamine; (5‐HT) has a hypotensive effect in male DOCA‐salt hypertensive rats. Studies have also shown that males have higher blood pressure when compared with age matched pre‐menopausal women. We hypothesized that the hypotensive effects of 5‐HT infusion would result in a greater blood pressure fall in female rats when compared with males. Serotonin and vehicle were administered via osmotic pump (25ug/kg/min) for seven days to male and female normotensive rats. Arterial blood pressure was monitored via radiotelemetry. After twenty‐four hours, female pressure fell to 79 ± 2.14 mmHg, while male pressure fell to 97 ± 2.67 mmHg.Animals were sacrificed seven days later, and intravascular 5‐HT measurements were made. Female rats had greater intravascular arterial and venous 5‐HT concentrations than males. 5‐HT concentrations were greatest in female veins (Jugular 56.502 ± 6.25 ng/mg protein) compared to arteries (Carotid 10.818 ± 1.34 ng/mg protein). These results suggest that 5‐HT has a greater effect on the female cardiovascular system when compared with the male. Finally, this study is the first to show greater concentrations of 5‐HT in female veins when compared with males.
Inhibitory phosphorylation of TASK‐1 is associated with atrial fibrillation
Authors: Harleton Erin , Besana Alessandra , Argenziano Michael , Robinson Richard B. , Feinmark Steven J. 
Published: June 2021

Activation of the platelet‐activating factor (PAF) receptor leads to inhibition of TASK‐1, a two pore‐domain potassium channel. PAF‐induced TASK‐1 inhibition requires the activity of PKCε and causes repolarization abnormalities in isolated murine ventricular myocytes. We have previously shown that TASK‐1 current is absent from atrial myocytes derived from humans suffering from atrial fibrillation (AF). We now show that AF‐associated loss of TASK‐1 current occurs in spite of significantly higher levels of channel protein expression in AF atrium as compared to atrial tissue from patients in normal sinus rhythm, suggesting regulation by post‐translational modification. TASK‐1 current was restored in atrial myocytes by PP2A treatment, showing that inhibition in AF was phosphorylation‐dependent. We have made a construct of human TASK‐1 carboxy‐terminus fused to glutathione‐S‐transferase and made site‐directed mutants of potential PKC sites. Kinase reactions of these constructs with PKCε identified the phosphorylation site as T383, a result that was confirmed by LC‐MS/MS analysis. Similar mutations in the full length channel abrogated the ability of PAF to inhibit TASK‐1 current in whole cell patch clamp studies. These data provide an exciting new marker, and possible therapeutic target, for AF, the most common human arrhythmia.Supported by NIH grants 5R01HL070105‐04, 5TL1RR024158‐02 and Servier
Dopamine receptor interacting proteins: unraveling the receptor signalplex
Authors: Hazelwood Lisa A , Free R Benjamin , Cabrera David M , Sibley David R 
Published: June 2021

Dopamine receptors (DARs) are known to exist as constituents of a large macromolecular complex of interacting proteins, termed the signalplex. These interacting proteins may be transmembrane or cytosolic, and can play a variety of roles in receptor trafficking, function or desensitization. To identify interacting partners, we have employed a co‐immunoprecipitation assay for D1 and D2 DARs from both mouse brain and transfected cell lines. When coupled with mass spectrometry (MS) sequencing, these experiments have allowed detection and subsequent peptide‐matching to more than 50 proteins within a non‐redundant protein database. Among the novel interacting proteins identified through these experiments were various subunits of the Na+,K+‐ATPase (NKA) and the regulatory protein sorting nexin 25 (SNX25). Studies have revealed multiple isoforms of SNX25 that influence DAR expression and function, possibly via sorting or internalization of the receptors. Experiments with the NKA have shown that the DARs and NKA can reciprocally regulate one another, providing a control mechanism for both receptor signaling and cellular ion balance. These data offer insights into the cellular components of the DAR signalplex, and indicate that interacting proteins can influence the DARs at various stages of receptor processing and function. LAH and RBF contributed equally to this work.Support Contributed By: NINDS/NIH and the NIGMS PRAT Program (LAH)