bluuebunny/crossref_metadata_2025_split huggingface dataset:
p38 MAPK inhibition suppresses the TLR-hypersensitive phenotype in FANCC- and FANCA-deficient mononuclear phagocytes
Authors: Anur Praveen , Yates Jane , Garbati Michael R. , Vanderwerf Scott , Keeble Winifred , Rathbun Keaney , Hays Laura E. , Tyner Jeffrey W. , Svahn Johanna , Cappelli Enrico , Dufour Carlo , Bagby Grover C. 
Published: January 2012

AbstractFanconi anemia, complementation group C (FANCC)–deficient hematopoietic stem and progenitor cells are hypersensitive to a variety of inhibitory cytokines, one of which, TNFα, can induce BM failure and clonal evolution in Fancc-deficient mice. FANCC-deficient macrophages are also hypersensitive to TLR activation and produce TNFα in an unrestrained fashion. Reasoning that suppression of inhibitory cytokine production might enhance hematopoiesis, we screened small molecules using TLR agonist–stimulated FANCC- and Fanconi anemia, complementation group A (FANCA)–deficient macrophages containing an NF-κB/AP-1–responsive reporter gene (SEAP). Of the 75 small molecules screened, the p38 MAPK inhibitor BIRB 796 and dasatinib potently suppressed TLR8-dependent expression of the reporter gene. Fanconi anemia (FA) macrophages were hypersensitive to the TLR7/8 activator R848, overproducing SEAP and TNFα in response to all doses of the agonist. Low doses (50nM) of both agents inhibited p38 MAPK–dependent activation of MAPKAPK2 (MK2) and suppressed MK2-dependent TNFα production without substantially influencing TNFα gene transcription. Overproduction of TNFα by primary FA cells was likewise suppressed by these agents and involved inhibition of MK2 activation. Because MK2 is also known to influence production and/or sensitivity to 2 other suppressive factors (MIP-1α and IFNγ) to which FA hematopoietic progenitor cells are uniquely vulnerable, targeting of p38 MAPK in FA hematopoietic cells is a rational objective for preclinical evaluation.
Macrophage LRP1 contributes to the clearance of von Willebrand factor
Authors: Rastegarlari Ghasem , Pegon Julie N. , Casari Caterina , Odouard Soline , Navarrete Ana-Maria , Saint-Lu Nathalie , van Vlijmen Bart J. , Legendre Paulette , Christophe Olivier D. , Denis Cécile V. , Lenting Peter J. 
Published: January 2012

AbstractThe relationship between low-density lipoprotein receptor–related protein-1 (LRP1) and von Willebrand factor (VWF) has remained elusive for years. Indeed, despite a reported absence of interaction between both proteins, liver-specific deletion of LRP1 results in increased VWF levels. To investigate this discrepancy, we used mice with a macrophage-specific deficiency of LRP1 (macLRP1−) because we previously found that macrophages dominate VWF clearance. Basal VWF levels were increased in macLRP1− mice compared with control mice (1.6 ± 0.4 vs 1.0 ± 0.4 U/mL). Clearance experiments revealed that half-life of human VWF was significantly increased in macLRP1− mice. Ubiquitous blocking of LRP1 or additional lipoprotein receptors by overexpressing receptor-associated protein in macLRP1− mice did not result in further rise of VWF levels (0.1 ± 0.2 U/mL), in contrast to macLRP1+ mice (rise in VWF, 0.8 ± 0.4 U/mL). This points to macLRP1 being the only lipoprotein receptor regulating VWF levels. When testing the mechanism(s) involved, we observed that VWF-coated beads adhered efficiently to LRP1 but only when exposed to shear forces exceeding 2.5 dyne/cm2, implying the existence of shear stress-dependent interactions. Furthermore, a mechanism involving β2-integrins that binds both VWF and LRP1 also is implicated because inhibition of β2-integrins led to increased VWF levels in control (rise, 0.19 ± 0.16 U/mL) but not in macLRP1− mice (0.08 ± 0.15 U/mL).
The IGHV1-69/IGHJ3 recombinations of unmutated CLL are distinct from those of normal B cells
Authors: Forconi Francesco , Potter Kathleen N. , Sozzi Elisa , Henderson Isla , Cencini Emanuele , Rossi Davide , Bomben Riccardo , Gattei Valter , Gaidano Gianluca , Packham Graham , Stevenson Freda K. 
Published: January 2012

AbstractIGHV1-69/51p1 is expressed by ∼ 30% of unmutated chronic lymphocytic leukemia (U-CLL) and combines with selected IGHD and IGHJ genes generating stereotypes if HCDR3 amino acid homology is > 60%. We had previously revealed stereotypic IGHV1-69/IGHJ6 rearrangements in normal naive B cells, thereby identifying potential counterparts of U-CLL. A different stereotypic IGHV1-69/IGHD3-16(RF2)/IGHJ3 rearrangement carrying the CAR(GGx)YD motif in the N1-region, recurrent in 6% IGHV1-69+ve CLL, is exceptionally sequence restricted, strongly suggestive of shared antigen recognition. We have now analyzed IGHV1-69/IGHJ3 rearrangements in circulating B cells of healthy individuals using several PCR-based approaches with IGHV1-69/IGHJ3 CLL sequences for reference. Stereotypes were found, but all were distinct from CLL. Remarkably, even a highly sensitive semi-nested PCR, specific for the CLL-expressed IGHV1-69/IGHD3-16(RF2)/IGHJ3 stereotype, failed to identify the CAR(GGx)YD sequence, although similar motifs were found. These highly specific B cells are not apparent in the accessible normal repertoire and may expand in response to rarely expressed antigens important in the pathogenesis of CLL.
Mathematical modelling and evaluation of the different routes of transmission of lumpy skin disease virus
Authors: Magori-Cohen Reuma , Louzoun Yoram , Herziger Yael , Oron Eldad , Arazi Alon , Tuppurainen Eeva , Shpigel Nahum Y , Klement Eyal 
Published: January 2012

AbstractLumpy skin disease (LSD) is a severe viral disease of cattle. Circumstantial evidence suggests that the virus is transmitted mechanically by blood-feeding arthropods. We compared the importance of transmission via direct and indirect contact in field conditions by using mathematical tools. We analyzed a dataset collected during the LSD outbreak in 2006 in a large dairy herd, which included ten separated cattle groups. Outbreak dynamics and risk factors for LSD were assessed by a transmission model. Transmission by three contact modes was modelled; indirect contact between the groups within a herd, direct contact or contact via common drinking water within the groups and transmission by contact during milking procedure. Indirect transmission was the only parameter that could solely explain the entire outbreak dynamics and was estimated to have an overall effect that was over 5 times larger than all other possible routes of transmission, combined. TheR0value induced by indirect transmission per the presence of an infectious cow for 1 day in the herd was 15.7, while theR0induced by direct transmission was 0.36. Sensitivity analysis showed that this result is robust to a wide range of assumptions regarding mean and standard deviation of incubation period and regarding the existence of sub-clinically infected cattle. These results indicate that LSD virus spread within the affected herd could hardly be attributed to direct contact between cattle or contact through the milking procedure. It is therefore concluded that transmission mostly occurs by indirect contact, probably by flying, blood-sucking insects. This has important implications for control of LSD.
Triacylglycerol synthesis by PDAT1 in the absence of DGAT1 activity is dependent on re-acylation of LPC by LPCAT2
Authors: Xu Jingyu , Carlsson Anders S , Francis Tammy , Zhang Meng , Hoffman Travis , Giblin Michael E , Taylor David C 
Published: January 2012

Abstract

Background
The Arabidopsis thaliana dgat1 mutant, AS11, has an oil content which is decreased by 30%, and a strongly increased ratio of 18:3/20:1, compared to wild type. Despite lacking a functional DGAT1, AS11 still manages to make 70% of WT seed oil levels. Recently, it was demonstrated that in the absence of DGAT1, PDAT1 was essential for normal seed development, and is a dominant determinant in Arabidopsis TAG biosynthesis.

Methods
Biochemical, metabolic and gene expression studies combined with genetic crossing of selected Arabidopsis mutants have been carried out to demonstrate the contribution of Arabidopsis PDAT1 and LPCAT2 in the absence of DGAT1 activity.

Results
Through microarray and RT-PCR gene expression analyses of AS11 vs. WT mid-developing siliques, we observed consistent trends between the two methods. FAD2 and FAD3 were up-regulated and FAE1 down-regulated, consistent with the AS11 acyl phenotype. PDAT1 expression was up-regulated by ca 65% while PDAT2 expression was up-regulated only 15%, reinforcing the dominant role of PDAT1 in AS11 TAG biosynthesis. The expression of LPCAT2 was up-regulated by 50-75%, while LPCAT1 expression was not significantly affected. In vitro LPCAT activity was enhanced by 75-125% in microsomal protein preparations from mid-developing AS11 seed vs WT. Co-incident homozygous knockout lines of dgat1/lpcat2 exhibited severe penalties on TAG biosynthesis, delayed plant development and seed set, even with a functional PDAT1; the double mutant dgat1/lpcat1 showed only marginally lower oil content than AS11.

Conclusions
Collectively, the data strongly support that in AS11 it is LPCAT2 up-regulation which is primarily responsible for assisting in PDAT1-catalyzed TAG biosynthesis, maintaining a supply of PC as co-substrate to transfer sn-2 moieties to the sn-3 position of the enlarged AS11 DAG pool.
The evil circle of poverty: a qualitative study of malaria and disability
Authors: Ingstad Benedicte , Munthali Alister C , Braathen Stine H , Grut Lisbet 
Published: January 2012

Abstract

Background
This article discusses the link between disability and malaria in a poor rural setting. Global malaria programmes and rehabilitation programmes are organized as vertical and separate programmes, and as such they focus on prevention, cure and control, and disability respectively. When looking at specific conditions and illnesses, the impairing long-term consequences of illness incidents during childhood are not questioned.

Methods
The study design was ethnographic with an open, exploratory approach. Data were collected in Mangochi District in Malawi through qualitative in-depth interviews and participant observation.

Results
Despite a local-based health service system, people living in poor rural areas are confronted with a multitude of barriers when accessing malaria prevention and treatment. Lack of skilled health personnel and equipment add to the general burden of poverty: insufficient knowledge about health care, problems connected to accessing the health facility in time, insufficient initiatives to prevent malaria attacks, and a general lack of attention to the long term disabling effects of a malaria attack.

Conclusions
This study points to the importance of building malaria programmes, research and statistics that take into consideration the consequences of permanent impairment after a malaria attack, as well as the context of poverty in which they often occur. In order to do so, one needs to develop methods for detecting people whose disabilities are a direct result of not having received health services after a malaria episode. This may be done through qualitative approaches in local communities and should also be supplemented by suitable surveys in order to estimate the problem on a larger scale.
Nutritional status and growth of indigenous Xavante children, Central Brazil
Authors: Ferreira Aline A , Welch James R , Santos Ricardo V , Gugelmin Silvia A , Coimbra Carlos EA 
Published: January 2012

Abstract

Background
The aim of this study was to characterize the nutritional status of Xavante Indian children less than 10 years of age in Central Brazil and to evaluate the hypothesis of an association between child nutrition and socioeconomic differentiation in this population.

Methods
A cross-sectional study was conducted in July 2006 that included all children under the age of 10 from the Xavante village Pimentel Barbosa in Mato Grosso, Brazil. The data collected included weight, height, and sociodemographic information. Sociodemographic data were used to generate two indices ("income" and "wealth") and to determine the proportion of adults in each household. Descriptive analyses were performed for weight-for-age (W/A), height-for-age (H/A), and weight-for-height (W/H) using the NCHS and the WHO growth references. Univariate and multivariate analyses were conducted using H/A and W/A as a response variables.

Results
Of a total of 246 children under the age of ten residing in the village, 232 (94.3%) were evaluated. Following the NCHS reference, 5.6% of children under the age of ten presented low W/A and 14.7% presented low H/A. Among children under the age of five, deficit percentages for weight and height were 4.5% and 29.9%, respectively, following the WHO curves. Among children < 2 years of age, H/A index variability was found to be directly related to child's age and inversely related to the proportion of adults in the household. Maternal BMI was positively associated with growth for children from 2 to 4 years of age, explaining 11.5% of the z-score variability for the H/A index. For children 5 years of age and older, the wealth index and maternal height were positively associated with H/A. No significant associations were found using W/A as the dependent variable.

Conclusion
This study demonstrated that undernutrition, in particular linear growth deficit, is a notable health issue for Xavante children. These findings contrast with the nutritional profile observed among Brazilian children nationally, which is characterized by a sharp decline in child undernutrition in recent decades, even in the poorest regions of the country. This discrepancy calls attention to the persistent health disparities that exist between indigenous and non-indigenous people in Brazil.
A negative screen for mutations in calstabin 1 and 2 genes in patients with dilated cardiomyopathy
Authors: Biagi Diogo G , Mill José G , Mansur Alfredo J , Krieger José E , Pereira Alexandre C 
Published: January 2012

Abstract

Background
Calstabins 1 and 2 bind to Ryanodine receptors regulating muscle excitation-contraction coupling. Mutations in Ryanodine receptors affecting their interaction with calstabins lead to different cardiac pathologies. Animal studies suggest the involvement of calstabins with dilated cardiomyopathy.

Results
We tested the hypothesis that calstabins mutations may cause dilated cardiomyopathy in humans screening 186 patients with idiopathic dilated cardiomyopathy for genetic alterations in calstabins 1 and 2 genes (FKBP12 and FKBP12.6). No missense variant was found. Five no-coding variations were found but not related to the disease.

Conclusions
These data corroborate other studies suggesting that mutations in FKBP12 and FKBP12.6 genes are not commonly related to cardiac diseases.
Imiquimod Enhances Excitability of Dorsal Root Ganglion Neurons by Inhibiting Background (K2P) and Voltage-Gated (Kv1.1 and Kv1.2) Potassium Channels
Authors: Lee Jaekwang , Kim Taekeun , Hong Jinpyo , Woo Junsung , Min Hyunjung , Hwang Eunmi , Lee Sung Joong , Lee C Justin 
Published: January 2012

Background: Imiquimod (IQ) is known as an agonist of Toll-like receptor 7 (TLR7) and is widely used to treat various infectious skin diseases. However, it causes severe itching sensation as its side effect. The precise mechanism of how IQ causes itching sensation is unknown. A recent report suggested a molecular target of IQ as TLR7 expressed in dorsal root ganglion (DRG) neurons. However, we recently proposed a TLR7-independent mechanism, in which the activation of TLR7 is not required for the action of IQ in DRG neurons. To resolve this controversy regarding the involvement of TLR7 and to address the exact molecular identity of itching sensation by IQ, we investigated the possible molecular target of IQ in DRG neurons. Findings: When IQ was applied to DRG neurons, we observed an increase in action potential (AP) duration and membrane resistance both in wild type and TLR7-deficient mice. Based on these results, we tested whether the treatment of IQ has an effect on the activity of K+ channels, Kv1.1 and Kv1.2 (voltage-gated K+ channels) and TREK1 and TRAAK (K2P channels). IQ effectively reduced the currents mediated by both K+ channels in a dose-dependent manner, acting as an antagonist at TREK1 and TRAAK and as a partial antagonist at Kv1.1 and Kv1.2. Conclusions: Our results demonstrate that IQ blocks the voltage-gated K+ channels to increase AP duration and K2P channels to increase membrane resistance, which are critical for the membrane excitability of DRG neurons. Therefore, we propose that IQ enhances the excitability of DRG neurons by blocking multiple potassium channels and causing pruritus.
Acute post-cardiopulmonary bypass left atrial thrombosis after mitral valvuloplasty and left atrial thrombectomy
Authors: Lee Dong-Hyup , Jung Tae-Eun , Park Sang-Jin 
Published: January 2012

Abstract
A patient with mitral stenosis and multiple left atrial thrombi underwent valvuloplasty and thrombectomy. While closing the sternum after completing the cardiopulmonary bypass, a new left atrial thrombus was detected by transesophageal echocardiography. We used heparin for the prevention of new thrombus formation and closed the wound after meticulous bleeding control. Three months later, there was no residual thrombus in the left atrium according to the echocardiographic study.
Aqueductal developmental venous anomaly as an unusual cause of congenital hydrocephalus: a case report and review of the literature
Authors: Paulson David , Hwang Steven W , Whitehead William E , Curry Daniel J , Luerssen Thomas G , Jea Andrew 
Published: January 2012

Abstract

Introduction
Aqueductal stenosis may be caused by a number of etiologies including congenital stenosis, tumor, inflammation, and, very rarely, vascular malformation. However, aqueductal stenosis caused by a developmental venous anomaly presenting as congenital hydrocephalus is even more rare, and, to the best of our knowledge, has not yet been reported in the literature. In this study, we review the literature and report the first case of congenital hydrocephalus associated with aqueductal stenosis from a developmental venous anomaly.

Case presentation
The patient is a three-day-old, African-American baby girl with a prenatal diagnosis of hydrocephalus. She presented with a full fontanelle, splayed sutures, and macrocephaly. Postnatal magnetic resonance imaging showed triventricular hydrocephalus, suggesting aqueductal stenosis. Examination of the T1-weighted sagittal magnetic resonance imaging enhanced with gadolinium revealed a developmental venous anomaly passing through the orifice of the aqueduct. We treated the patient with a ventriculoperitoneal shunt.

Conclusions
Ten cases of aqueductal stenosis due to venous lesions have been reported and, although these venous angiomas and developmental venous anomalies are usually considered congenital lesions, all 10 cases became symptomatic as older children and adults. Our case is the first in which aqueductal stenosis caused by a developmental venous anomaly presents as congenital hydrocephalus. We hope adding to the literature will improve understanding of this very uncommon cause of hydrocephalus and, therefore, will aid in treatment.
A dysflagellar mutant of Leishmania (Viannia) braziliensis isolated from a cutaneous leishmaniasis patient
Authors: Zauli Rogéria C , Yokoyama-Yasunaka Jenicer KU , Miguel Danilo C , Moura Alexandre S , Pereira Ledice IA , da Silva Ildefonso A , Lemes Lucianna GN , Dorta Miriam L , de Oliveira Milton AP , Pitaluga André N , Ishikawa Edna AY , Rodrigues Juliany CF , Traub-Cseko Yara M , Bijovsky A Tania , Ribeiro-Dias Fátima , Uliana Silvia RB 
Published: January 2012

AbstractBackgroundParasites of theLeishmaniagenus alternate between the flagellated extracellular promastigote stage and intracellular amastigotes. Here we report the characterization of aLeishmaniaisolate, obtained from a cutaneous leishmaniasis patient, which presents peculiar morphological features.MethodsThe parasite was culturedin vitroand characterized morphologically using optical and electron microscopy. Identification was performed based on monoclonal antibodies and internal ribosomal spacer typing.In vitromacrophage cultures, murine experimental models and sand fly infections were used to evaluate infectivityin vitroandin vivo.ResultsThe isolate was identified asLeishmania(Viannia)braziliensis. In the atypical promastigotes grown in culture, a short flagellum surrounded or interrupted by a protuberance of disorganized material was observed. A normal axoneme was present close to the basal body but without elongation much further outside the flagellar pocket. A disorganized swelling at the precocious end of the axoneme coincided with the lack of a paraflagellar rod structure. The isolate was able to infect macrophagesin vitro, induce lesions in BALB/c mice and infectLutzomyia longipalpis.ConclusionsNotwithstanding the lack of an extracellular flagellum, this isolate infects macrophagesin vitroand produces lesions when inoculated into mice. Moreover, it is able to colonize phlebotomine sand flies. Considering the importance attributed to the flagellum in the successful infection and survival ofLeishmaniain the insect midgut and in the invasion of macrophages, these findings may bring new light into the infectious mechanisms ofL. (V.)braziliensis.
Membrane Phospholipid Asymmetry Counters the Adverse Effects of Sterol Overloading in the Golgi Membrane of Drosophila
Authors: Ma Zhiguo , Liu Zhonghua , Huang Xun 
Published: January 2012

Abstract
Cholesterol and phospholipids serve as structural and functional components of cellular membranes in all eukaryotes. Heterogeneity in cholesterol and phospholipid content both within and between different organelles is an important characteristic of eukaryotic membranes. How this heterogeneity is achieved and orchestrated to maintain proper cellular physiology remains poorly understood. We previously found that overexpression of the Drosophilaoxysterol-binding protein (OSBP) leads to sterol accumulation in the Golgi apparatus. Here, we show that Osbp overexpression in a set of neuroendocrine neurons compromises the function of the Golgi apparatus. It impairs trafficking of the neuropeptide bursicon and results in post-eclosion behavior defects characterized by unexpanded wings. We performed a genetic screen to identify modifiers that suppress the unexpanded wing phenotype. A putative phospholipid flippase-encoding gene, CG33298, was validated, suggesting that a membrane-asymmetry-directed mechanism balances cholesterol chaos within the Golgi membranes. Since the functional connection between cholesterol metabolism and the activity of phospholipid flippase has been implicated in studies in yeast and worms, our findings here support an evolutionarily conserved causal link between cholesterol homeostasis and phospholipid asymmetry that maintains normal cellular physiology.