tbuckley/cabot-search huggingface dataset:
Staphylococcal lipoteichoic acid inhibits delayed-type hypersensitivity reactions via the platelet-activating factor receptor
Authors: Qiwei Zhang, Nico Mousdicas, Qiaofang Yi, Mohammed Al-Hassani, Steven D. Billings, Susan M. Perkins, Katherine M. Howard, Satoshi Ishii, Takao Shimizu, Jeffrey B. Travers
Journal: Journal of Clinical Investigation (2005)

Staphylococcus aureus infections are known triggers for skin inflammation and can modulate immune responses. The present studies used model systems consisting of platelet-activating factor receptor-positive and -negative (PAF-R-positive and -negative) cells and PAF-R-deficient mice to demonstrate that staphylococcal lipoteichoic acid (LTA), a constituent of Gram-positive bacteria cell walls, acts as a PAF-R agonist. We show that LTA stimulates an immediate intracellular Ca2+ flux only in PAF-R-positive cells. Intradermal injections of LTA and the PAF-R agonist 1-hexadecyl-2-N-methylcarbamoyl glycerophosphocholine (CPAF) induced cutaneous inflammation in wild-type but not PAF-R-deficient mice. Systemic exposure to LTA or CPAF inhibited delayed-type hypersensitivity (DTH) reactions to the chemical dinitrofluorobenzene only in PAF-R-expressing mice. The inhibition of DTH reactions was abrogated by the addition of neutralizing antibodies to IL-10. Finally, we measured levels of LTA that were adequate to stimulate PAF-R in vitro on the skin of subjects with infected atopic dermatitis. Based on these studies, we propose that LTA exerts immunomodulatory effects via the PAF-R through production of the Th2 cytokine IL-10. These findings show a novel mechanism by which staphylococcal infections can inhibit Th1 reactions and thus worsen Th2 skin diseases, such as atopic dermatitis.
Effect of Milk Thistle (<i>Silybum marianum</i>) on the Pharmacokinetics of Irinotecan
Authors: Nielka P.H. van Erp, Sharyn D. Baker, Ming Zhao, Michelle A. Rudek, Henk-Jan Guchelaar, Johan W.R. Nortier, Alex Sparreboom, Hans Gelderblom
Journal: Clinical Cancer Research (2005)

Milk thistle (Silybum marianum) is one of the most commonly used herbal therapies, and its principal constituent silybin significantly inhibits cytochrome P450 isoform 3A4 (CYP3A4) and UDP glucuronosyltransferase isoform 1A1 (UGT1A1) in vitro. Here, we investigated whether milk thistle affects the pharmacokinetics of irinotecan, a substrate for CYP3A4 and UGT1A1, in humans.Six cancer patients were treated with irinotecan (dose, 125 mg/m(2)) given as a 90-minute infusion once every week. Four days before the second dose, patients received 200 mg milk thistle, thrice a day, for 14 consecutive days. Pharmacokinetic studies of irinotecan and its metabolites 7-ethyl-10-hydroxycamptothecin (SN-38), 7-ethyl-10-[3,4,5-trihydroxy-pyran-2-carboxylic acid]-camptothecin (SN-38-glucuronide), and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin were done during the first three irinotecan administrations.Short-term (4 days) or more prolonged intake of milk thistle (12 days) had no significant effect on irinotecan clearance (mean, 31.2 versus 25.4 versus 25.6 L/h; P = 0.16). The area under the curve ratio of SN-38 and irinotecan was slightly decreased by milk thistle (2.58% versus 2.23% versus 2.17%; P = 0.047), whereas the relative extent of glucuronidation of SN-38 was similar (10.8 versus 13.5 versus 13.1; P = 0.64). Likewise, the area under the curve ratio of 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin and irinotecan was unaffected by milk thistle (0.332 versus 0.285 versus 0.337; P = 0.53). The maximum plasma concentrations of silybin ranged between 0.0249 and 0.257 micromol/L.Silybin concentrations after intake of milk thistle are too low to significantly affect the function of CYP3A4 and UGT1A1 in vivo, indicating that milk thistle is unlikely to alter the disposition of anticancer drugs metabolized by these enzymes.
Zerumbone Down-regulates Chemokine Receptor CXCR4 Expression Leading to Inhibition of CXCL12-Induced Invasion of Breast and Pancreatic Tumor Cells
Authors: Bokyung Sung, Sonia Jhurani, Kwang Seok Ahn, Yoichi Mastuo, Tingfang Yi, Sushovan Guha, Mingyao Liu, Bharat B. Aggarwal
Journal: Cancer Research (2008)

CXC chemokine receptor 4 (CXCR4), initially linked with leukocyte trafficking, is now known to be expressed in various tumors including breast, ovary, prostate, gastrointestinal, head and neck, bladder, brain, and melanoma. This receptor mediates homing of tumor cells to specific organs that express the ligand CXCL12 for this receptor. Thus, agents that can down-regulate CXCR4 expression have potential against cancer metastasis. In this study, we report the identification of zerumbone, a component of subtropical ginger (Zingiber zerumbet), as a regulator of CXCR4 expression. This sesquiterpene down-regulated the expression of CXCR4 on HER2-overexpressing breast cancer cells in a dose- and time-dependent manner. The decrease in CXCR4 by zerumbone was found to be not cell type specific as its expression was abrogated in leukemic, skin, kidney, lung, and pancreatic cancer cell lines. The down-regulation of CXCR4 was not due to proteolytic degradation but rather to transcriptional regulation, as indicated by down-regulation of mRNA expression, inhibition of nuclear factor-kappaB activity, and suppression of chromatin immunoprecipitation activity. Suppression of CXCR4 expression by zerumbone correlated with the inhibition of CXCL12-induced invasion of both breast and pancreatic cancer cells. An analogue of zerumbone, alpha-humulene, which lacks the carbonyl group, was found to be inactive in inducing CXCR4 down-regulation. Overall, our results show that zerumbone is a novel inhibitor of CXCR4 expression and thus has a potential in the suppression of cancer metastasis.
Molecular Mechanisms of Toxicant-Induced Immunosuppression: Role of Second Messengers
Authors: M P Holsapple, J G Karras, J A Ledbetter, G L Schieven, S W Burchiel, D R Davila, A R Shatz, N E Kaminski
Journal: The Annual Review of Pharmacology and Toxicology (1996)

Over the past two decades, deadly coronaviruses, with the most recent being the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) 2019 pandemic, have majorly challenged public health. The path for virus invasion into humans and other ...Read More
HIV-1 Genes vpr and nef Synergistically Damage Podocytes, Leading to Glomerulosclerosis
Authors: Yiqin Zuo, Taiji Matsusaka, Jianyong Zhong, Ji Ma, Li-jun Ma, Zaher Hanna, Paul Jolicoeur, Agnes B. Fogo, Iekuni Ichikawa
Journal: Journal of the American Society of Nephrology (2006)

This study aimed to identify the causative gene for HIV-1 associated nephropathy, a paradigmatic podocytopathy. A previous study demonstrated that transgenic expression of nonstructural HIV-1 genes selectively in podocytes in mice with FVB/N genetic background resulted in podocyte injury and glomerulosclerosis. In this study, transgenic mice that expressed individual HIV-1 genes in podocytes were generated. Five of six transgenic mice that expressed vpr developed podocyte damage and glomerulosclerosis. Analysis of an established vpr transgenic line revealed that transgenic mice on FVB/N but not on C57BL/6 genetic background developed podocyte injury by 8 wk of age, with later glomerulosclerosis. Four of 11 transgenic mice that expressed nef also developed podocyte injury. One transgenic line was established from the nef founder mouse with the mildest phenotype. Transgenic mice in this line developed mesangial expansion at 3 wk of age and mild focal podocyte damage at 10 wk of age. Mating with FVB/N mice did not augment nephropathy. None of the transgenic mice that expressed vif, tat, rev, or vpu in podocytes, even with the FVB/N genetic background, developed podocyte injury. For testing effects of simultaneous expression of vpr and nef, these two lines were mated. All nef:vpr double-transgenic mice showed severe podocyte injury and glomerulosclerosis by 4 wk of age. In contrast, all vpr or nef single-transgenic mice in the same litter uniformly showed no or much milder podocyte injury. These findings indicate that vpr and nef each can induce podocyte injury with a prominent synergistic interaction.
Adaptability of innate motor patterns and motor control mechanisms
Authors: M. B. Berkinblit, A. G. Feldman, O. I. Fukson
Journal: Behavioral and Brain Sciences (1986)

Abstract The following factors underlying behavioral plasticity are discussed: (1) reflex adaptability and its role in the voluntary control of movement, (2) degrees of freedom and motor equivalence, and (3) the problem of the discrete organization of motor behavior. Our discussion concerns a variety of innate motor patterns, with emphasis on the wiping reflex in the frog. It is proposed that central regulation of stretch reflex thresholds governs voluntary control over muscle force and length. This suggestion is an integral part of the equilibrium-point hypothesis, two versions of which are compared. Kinematic analysis of the wiping reflex in the spinal frog has shown that each stimulated skin site is associated with a group of different but equally effective trajectories directed to the target site. Such phenomena reflect the principle of motor equivalence -the capacity of the neuronal structures responsible for movement to select one or another of a set of possible trajectories leading to the goal. Redundancy of degrees of freedom at the neuronal level as well as at the mechanical level of the body's joints makes motor equivalence possible. This sort of equivalence accommodates the overall flexibility of motor behavior. An integrated behavioral act or a single movement consists of dynamic components. We distinguish six components for the wiping reflex, each associated with a certain functional goal, specific body positions, and motor-equivalent movement patterns. The nervous system can combine the available components in various ways in forming integrated behavioral sequences. The significance of command neuronal organization is discussed with respect to (1) the combinatory strategy of the nervous system and (2) the relation between continuous and discrete forms of motor control. We conclude that voluntary movements are effected by the central nervous system with the help of the mechanisms that underlie the variability and modifiability of innate motor patterns.
Bronchoalveolar lavage in pulmonary mycotoxicosis (organic dust toxic syndrome).
Authors: R Lecours, M Laviolette, Y Cormier
Journal: Thorax (1986)

Two cases of pulmonary mycotoxicosis (organic dust toxic syndrome) are described in which bronchoalveolar lavage was undertaken during the acute phase and after recovery. Both cases occurred after exposure to mould dust in a silo in the course of removing the top mouldy layer of silage or oats at the start of unloading. The workers suffered an acute febrile illness accompanied by cough and dyspnoea. One patient had impaired ventilatory function and both had arterial desaturation in the acute phase. There was mild impairment of diffusing capacity (transfer factor). Bronchoscopy showed inflammation of the bronchial mucosa in one patient. Fungal spores were cultured from the lavage fluid in both patients. In both patients there was an increase in the percentage of neutrophils in the lavage fluid without increase in lymphocytes. The immunoglobulin concentration in the lavage fluid was normal. At the follow up lavage the neutrophils had returned to normal while a mild lymphocytosis of the lavage fluid was seen in both patients.
Oxygenation Indexes and Degrees of Lung Injury
Authors: Mohamad F. El-Khatib
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

El-Khatib MF, 2004, CHEST, V125, P592, DOI 10.1378-chest.125.2.592; Villar J, 2007, AM J RESP CRIT CARE, V176, P795, DOI 10.1164-rccm.200610-15340C
Hyper IgM syndrome associated with defective CD40-mediated B cell activation.
Authors: M E Conley, M Larché, V R Bonagura, A R Lawton, R H Buckley, S M Fu, E Coustan-Smith, H G Herrod, D Campana
Journal: Journal of Clinical Investigation (1994)

Recent studies show that most patients with X-linked hyper IgM syndrome have defects in the gene for CD40 ligand.We evaluated 17 unrelated males suspected of having X- linked hyper IgM syndrome.Activated T cells from 13 of the 17 patients failed to bind a soluble CD40 construct.In these patients, the sequence of CD40 ligand demonstrated mutations.By contrast, T cells from the remaining four patients exhibited normal binding to the CD40 construct.Sequencing of the cDNA for CD40 ligand from these pa- tients did not show mutations.The possibility that hyper IgM syndrome in these four patients was due to abnormalit- ies in the B cell response to CD40-mediated signals was examined.Peripheral blood lymphocytes were stimulated with anti-CD40 alone, IL4 alone or anti-CD40 plus IL4.In comparison with B cells from controls or patients with hyper IgM syndrome and mutant CD40 ligand, B cells from the patients with hyper IgM syndrome and normal CD40 ligand were defective in their ability to secrete IgE (P < 0.02) or express activation markers, CD25 and CD23 (P < 0.02) in response to stimulation with anti-CD40.The failure of these B cells to respond to CD40-mediated activation could not be attributed to a generalized deficiency in B cell activation because IL4 induced normal up-regulation of CD23 and CD25 expression.These findings indicate that hyper IgM syndrome may result from defects in expression of CD40 ligand by activated T cells or defects in CD40-mediated signal transduction in B cells. (
Phenylethylamine, a possible link to the antidepressant effects of exercise?: Figure 1
Authors: A Szabo, E Billett, J Turner
Journal: British Journal of Sports Medicine (2001)

Objectives —To determine in this pilot study whether aerobic exercise affects phenylacetic acid concentration in the urine. Methods —Twenty healthy men provided 24 hour urine samples on two consecutive days for the determination of phenylacetic acid levels. Before and during day 1, subjects refrained from physical activity; on day 2 subjects ran on a treadmill at 70% of their maximal heart rate reserve (MHRR) for 30 minutes. Results —The 24 hour mean urinary concentration of phenylacetic acid was increased by 77% after exercise. Conclusion —As phenylacetic acid concentration in urine reflects phenylethylamine level, which is known to have antidepressant effects, phenylethylamine may be linked to the therapeutic effects of physical exercise on depression.
Ubiquitin-specific protease 14 regulates c-Jun N-terminal kinase signaling at the neuromuscular junction
Authors: Jada H Vaden, Bula J Bhattacharyya, Ping-Chung Chen, Jennifer A Watson, Andrea G Marshall, Scott E Phillips, Julie A Wilson, Gwendalyn D King, Richard J Miller, Scott M Wilson
Journal: Molecular Neurodegeneration (2015)

Ubiquitin-specific protease 14 (USP14) is one of three proteasome-associated deubiquitinating enzymes that remove ubiquitin from proteasomal substrates prior to their degradation. In vitro evidence suggests that inhibiting USP14's catalytic activity alters the turnover of ubiquitinated proteins by the proteasome, although whether protein degradation is accelerated or delayed seems to be cell-type and substrate specific. For example, combined inhibition of USP14 and the proteasomal deubiquitinating enzyme UCH37 halts protein degradation and promotes apoptosis in multiple myeloma cells, whereas USP14 inhibition alone accelerates the degradation of aggregate-prone proteins in immortalized cell lines. These findings have prompted interest in USP14 as a therapeutic target both inside and outside of the nervous system. However, loss of USP14 in the spontaneously occurring ataxia mouse mutant leads to a dramatic neuromuscular phenotype and early perinatal lethality, suggesting that USP14 inhibition may have adverse consequences in the nervous system. We therefore expressed a catalytically inactive USP14 mutant in the mouse nervous system to determine whether USP14's catalytic activity is required for neuromuscular junction (NMJ) structure and function. Mice expressing catalytically inactive USP14 in the nervous system exhibited motor deficits, altered NMJ structure, and synaptic transmission deficits that were similar to what is observed in the USP14-deficient ataxia mice. Acute pharmacological inhibition of USP14 in wild type mice also reduced NMJ synaptic transmission. However, there was no evidence of altered proteasome activity when USP14 was inhibited either genetically or pharmacologically. Instead, these manipulations increased the levels of non-proteasome targeting ubiquitin conjugates. Specifically, we observed enhanced proteasome-independent ubiquitination of mixed lineage kinase 3 (MLK3). Consistent with the direct activation of MLK3 by ubiquitination, we also observed increased activation of its downstrea targets MAP kinase kinase 4 (MKK4) and c-Jun N-terminal kinase (JNK). In vivo inhibition of JNK improved motor function and synapse structure in the USP14 catalytic mutant mice. USP14's catalytic activity is required for nervous system structure and function and has an ongoing role in NMJ synaptic transmission. By regulating the ubiquitination status of protein kinases, USP14 can coordinate the activity of intracellular signaling pathways that control the development and activity of the NMJ.
HUMAN MIXED LEUKOCYTE CULTURE: IDENTIFICATION OF THE PROLIFERATING LYMPHOCYTE SUBPOPULATION BY SEX CHROMOSOME MARKERS
Authors: Hans-Peter Lohrmann, Jacqueline Whang-Peng
Journal: The Journal of Experimental Medicine (1974)

The nature of the cells which proliferate in response to allogeneic histoincompatible lymphocytes in human mixed leukocyte cultures (MLC) was investigated. Direct information on the differentiation of proliferating cells was obtained in an in vitro chimeric system with T- and B-cell sex chromosome markers. Highly purified T and B cells were prepared from the peripheral blood of three pairs of HL-A genotype identical, MLC-negative siblings of opposite sex by E-rosette sedimentation techniques. Recombined T and B cells of the siblings were stimulated with allogeneic cells, and karyotype analysis of proliferating cells performed. 96% of the proliferating cells were found to carry the sex chromosome marker of the respective T-cell population. These results indicate that proliferation in human MLCs is a feature of T cells.
Spontaneous chylothorax revealing a mediastinal and abdominal lymph node tuberculosis
Authors: Wided Ben Hamad, Jihen Ben Amar, Besma Dhahri, Mohamed Ali Baccar, Salwa Azzabi, Hichem Aouina, Hend Bouacha
Journal: European Respiratory Journal (2014)

Introduction: Chylothorax, an uncommon cause of pleural effusion, results from the accumulation of lymph in the pleural space due to damage or obstruction of the thoracic duct. The high content of triglycerides and the presence of chylomicrons set the diagnosis of chylothorax.  Spontaneous chylothorax is a rare condition; lymph node tuberculosis is an exceptional etiology of chylothorax.  Method: We report an exceptional case of 62 year old woman referred to our hospital complaining of right sided chest pain, fever, non-productive cough and weight loss of 6 kg over the preceding three weeks.  Results: Chest examination revealed absent breath sound on right side. Chest X-ray revealed an opaque right hemithorax suggestive of pleural effusion fluid. Erythrocyte sedimentation rate was 38 mm/hour. The pleural aspirate was milky in appearance, with 122 mmol/l triglyceride and 45 mmol/l cholesterol. A computed tomographic scan of the thorax showed a fluid collection with necrotic mediastinal and abdominal lymph nodes. The patient had a mediastinoscopy with biopsy of lymph nodes concluded to tuberculosis. The patient clinically improved and his pleural effusion also completely resolved with anti-tuberculosis treatment.  Conclusion: A possible explanation for the development of a chylothorax in our patient is obstruction of the thoracic duct by tuberculous lymphadenopathy with subsequent increase in pressure in the surrounding lymphatic system and leaking of chyle into the pleural space.
Seeking the right targets: gene therapy advances in pulmonary arterial hypertension
Authors: R.D. Machado
Journal: European Respiratory Journal (2012)

Pulmonary arterial hypertension (PAH) is a grave vascular disorder characterised by the obstruction and occlusion of the small pulmonary arteries, primarily through the abnormal proliferation of the endothelial and smooth muscle layers. A clinical diagnosis of pulmonary hypertension (PH) is made when the mean pulmonary arterial pressure ( P pa) is ≥25 mmHg at rest. An additional criterion to differentiate PAH from other forms of PH requires that pulmonary arterial wedge pressure be ≥15 mmHg [1, 2]. The disease is typically fatal due to right heart failure as a result of the pathological increases in pulmonary vascular resistance. While the majority of the patient population develop spontaneous or idiopathic PAH and PAH associated with other disorders, for example, HIV infection, connective tissue disease or exposure to risk factors such as appetite suppressants containing dex/fenfluramine (associated PAH), some 10% display familial transmission. In families, PAH is an autosomal dominant trait with a sex bias favouring females and penetrance as low as 20%, features that suggest that, while a Mendelian condition, PAH displays features of complex disease [1, 2].

Traditional positional cloning approaches identified the causative gene for familial PAH as BMPR2 , encoding a type-II receptor of the transforming growth factor (TGF)-β signalling family [3, 4]. Currently, deleterious germ-line mutations have been detected in ∼70% of families analysed and 25% of idiopathic cases [5, 6]. The recent re-classification of mutation carriers with or without a family history as heritable PAH (HPAH), at the 4th World symposium on Pulmonary Hypertension (Dana Point, CA, USA) in 2008, indicates the growing recognition of the central importance of BMPR2 dysfunction in pathogenesis [7]. The majority of BMPR2 mutation in HPAH predicts premature truncation of the transcript and, …
MAGNITUDE OF ALCOHOL-RELATED MORTALITY AND MORBIDITY AMONG U.S. COLLEGE STUDENTS AGES 18–24: Changes from 1998 to 2001
Authors: Ralph Hingson, Timothy Heeren, Michael Winter, Henry Wechsler
Journal: Annual Review of Public Health (2005)

▪ Abstract Integrating data from the National Highway Traffic Safety Administration, the Centers for Disease Control and Prevention, national coroner studies, census and college enrollment data for 18–24-year-olds, the National Household Survey on Drug Abuse, and the Harvard College Alcohol Survey, we calculated the alcohol-related unintentional injury deaths and other health problems among college students ages 18–24 in 1998 and 2001. Among college students ages 18–24 from 1998 to 2001, alcohol-related unintentional injury deaths increased from nearly 1600 to more than 1700, an increase of 6% per college population. The proportion of 18–24-year-old college students who reported driving under the influence of alcohol increased from 26.5% to 31.4%, an increase from 2.3 million students to 2.8 million. During both years more than 500,000 students were unintentionally injured because of drinking and more than 600,000 were hit/assaulted by another drinking student. Greater enforcement of the legal drinking age of 21 and zero tolerance laws, increases in alcohol taxes, and wider implementation of screening and counseling programs and comprehensive community interventions can reduce college drinking and associated harm to students and others.