bluuebunny/crossref_metadata_2025_split huggingface dataset:
The MAPK Pathway Is a Predominant Regulator of HLA-A Expression in Esophageal and Gastric Cancer
Authors: Mimura Kousaku , Shiraishi Kensuke , Mueller Anja , Izawa Shinichiro , Kua Ley-Fang , So Jimmy , Yong Wei-Peng , Fujii Hideki , Seliger Barbara , Kiessling Rolf , Kono Koji 
Published: November 2013

Abstract
Downregulation of HLA class I expression may contribute to a poor prognosis in cancer patients. There is limited information about epigenetic and oncogenic regulation of HLA class I, and multiple mechanisms may be involved. In the current study, we examined the relationship between the HER2-signaling pathway (MAPK and PI3K-Akt) and the expression of HLA class I and Ag-processing machinery (APM) components. A panel of gastric and esophageal cancer cell lines was treated with wortmannin as an Akt-signal inhibitor; the MAPK signal inhibitor PD98059; lapatinib, which inhibits both the epidermal growth factor receptor and HER2 tyrosine kinase; or siRNA for MAPK. The levels of HER2-signaling molecules, APM components, and HLA class I were evaluated by Western blot, quantitative PCR, and flow cytometry. Resected gastric tumor tissues (n = 102) were analyzed for p-Erk and HLA class I expression by immunohistochemistry. As a result, inhibition of the MAPK pathway induced upregulation of HLA-A02 and HLA-A24 expression in parallel with an increase in APM components and enhanced target sensitivity to tumor Ag–specific CTL lysis. HLA-A expression was predominantly regulated by the MAPK pathway, but it was also influenced, in part, by the Akt pathway. There was a strong inverse correlation between p-Erk expression and HLA class I expression in clinical tumor samples. In conclusion, HLA-A expression is predominantly regulated by the MAPK pathway in gastric and esophageal cancer.
Optineurin Insufficiency Impairs IRF3 but Not NF-κB Activation in Immune Cells
Authors: Munitic Ivana , Giardino Torchia Maria Letizia , Meena Netra Pal , Zhu Guozhi , Li Caiyi C. , Ashwell Jonathan D. 
Published: November 2013

Abstract
Optineurin is a widely expressed polyubiquitin-binding protein that has been implicated in regulating cell signaling via its NF-κB essential modulator–homologous C-terminal ubiquitin (Ub)-binding region. Its functions are controversial, with in vitro studies finding that optineurin suppressed TNF-mediated NF-κB activation and virus-induced activation of IFN regulatory factor 3 (IRF3), whereas bone marrow–derived macrophages (BMDMs) from mice carrying an optineurin Ub-binding point mutation had normal TLR-mediated NF-κB activation and diminished IRF3 activation. We have generated a mouse model in which the entire Ub-binding C-terminal region is deleted (Optn470T). Akin to C-terminal optineurin mutations found in patients with certain neurodegenerative diseases, Optn470T was expressed at substantially lower levels than the native protein, allowing assessment not only of the lack of Ub binding, but also of protein insufficiency. Embryonic lethality with incomplete penetrance was observed for 129 × C57BL/6 Optn470T/470T mice, but after further backcrossing to C57BL/6, offspring viability was restored. Moreover, the mice that survived were indistinguishable from wild type littermates and had normal immune cell distributions. Activation of NF-κB in Optn470T BMDM and BM-derived dendritic cells with TNF or via TLR4, T cells via the TCR, and B cells with LPS or anti-CD40 was normal. In contrast, optineurin and/or its Ub-binding function was necessary for optimal TANK binding kinase 1 and IRF3 activation, and both Optn470T BMDMs and bone marrow–derived dendritic cells had diminished IFN-β production upon LPS stimulation. Importantly, Optn470T mice produced less IFN-β upon LPS challenge. Therefore, endogenous optineurin is dispensable for NF-κB activation but necessary for optimal IRF3 activation in immune cells.
AID and Caspase 8 Shape the Germinal Center Response through Apoptosis
Authors: Boulianne Bryant , Rojas Olga L. , Haddad Dania , Zaheen Ahmad , Kapelnikov Anat , Nguyen Thanh , Li Conglei , Hakem Razq , Gommerman Jennifer L. , Martin Alberto 
Published: November 2013

Abstract
Germinal centers (GCs) are clusters of activated B cells that form in secondary lymphoid organs during a T-dependent immune response. B cells enter GCs and become rapidly proliferating centroblasts that express the enzyme activation-induced deaminase (AID) to undergo somatic hypermutation and class-switch recombination. Centroblasts then mature into centrocytes to undergo clonal selection. Within the GC, the highest affinity B cell clones are selected to mature into memory or plasma cells while lower affinity clones undergo apoptosis. We reported previously that murine Aicda−/− GC B cells have enhanced viability and accumulate in GCs. We now show that murine Aicda−/− GC B cells accumulate as centrocytes and inefficiently generate plasma cells. The reduced rate of plasma cell formation was not due to an absence of AID-induced DNA lesions. In addition, we show that the deletion of caspase 8 specifically in murine GC-B cells results in larger GCs and a delay in affinity maturation, demonstrating the importance of apoptosis in GC homeostasis and clonal selection.
α2β1 Integrin Regulates Th17 Cell Activity and Its Neutralization Decreases the Severity of Collagen-Induced Arthritis
Authors: El Azreq Mohammed-Amine , Boisvert Marc , Cesaro Annabelle , Pagé Nathalie , Loubaki Lionel , Allaeys Isabelle , Chakir Jamila , Poubelle Patrice E. , Tessier Philippe A. , Aoudjit Fawzi 
Published: November 2013

Abstract
Th17 cells play a critical role in the pathogenesis of rheumatoid arthritis (RA), but the mechanisms by which these cells regulate the development of RA are not fully understood. We have recently shown that α2β1 integrin, the receptor of type I collagen, is the major collagen-binding integrin expressed by human Th17 cells. In this study, we examined the role of α2β1 integrin in Th17-mediated destructive arthritis in the murine model of collagen-induced arthritis (CIA). We found that α2β1 integrin is expressed on synovial Th17 cells from CIA mice and its neutralization with a specific mAb significantly reduced inflammation and cartilage degradation, and protected the mice from bone erosion. Blockade of α2β1 integrin led to a decrease in the number of Th17 cells in the joints and to a reduction of IL-17 levels in CIA mice. This was associated with an inhibition of receptor activator of NF-κB ligand levels and osteoclast numbers, and reduction of bone loss. We further show that α2β1 integrin is expressed on synovial Th17 cells from RA patients, and that its ligation with collagen costimulated the production of IL-17 by polarized human Th17 cells by enhancing the expression of retinoic acid receptor–related orphan receptor C through ERK and PI3K/AKT. Our findings provide the first evidence, to our knowledge, that α2β1 integrin is an important pathway in Th17 cell activation in the pathogenesis of CIA, suggesting that its blockade can be beneficial for the treatment of RA and other Th17-associated autoimmune diseases.
Cutting Edge: Leukotriene C4 Activates Mouse Platelets in Plasma Exclusively through the Type 2 Cysteinyl Leukotriene Receptor
Authors: Cummings Hannah E. , Liu Tao , Feng Chunli , Laidlaw Tanya M. , Conley Pamela B. , Kanaoka Yoshihide , Boyce Joshua A. 
Published: November 2013

Abstract
Leukotriene C4 (LTC4) and its extracellular metabolites, LTD4 and LTE4, mediate airway inflammation. They signal through three specific receptors (type 1 cys-LT receptor [CysLT1R], CysLT2R, and GPR99) with overlapping ligand preferences. In this article, we demonstrate that LTC4, but not LTD4 or LTE4, activates mouse platelets exclusively through CysLT2R. Platelets expressed CysLT1R and CysLT2R proteins. LTC4 induced surface expression of CD62P by wild-type mouse platelets in platelet-rich plasma (PRP) and caused their secretion of thromboxane A2 and CXCL4. LTC4 was fully active on PRP from mice lacking either CysLT1R or GPR99, but completely inactive on PRP from CysLT2R-null (Cysltr2−/−) mice. LTC4/CysLT2R signaling required an autocrine ADP-mediated response through P2Y12 receptors. LTC4 potentiated airway inflammation in a platelet- and CysLT2R-dependent manner. Thus, CysLT2R on platelets recognizes LTC4 with unexpected selectivity. Nascent LTC4 may activate platelets at a synapse with granulocytes before it is converted to LTD4, promoting mediator generation and the formation of leukocyte–platelet complexes that facilitate inflammation.
TAM Receptors Affect Adult Brain Neurogenesis by Negative Regulation of Microglial Cell Activation
Authors: Ji Rui , Tian Shifu , Lu Helen J. , Lu Qingjun , Zheng Yan , Wang Xiaomin , Ding Jixiang , Li Qiutang , Lu Qingxian 
Published: November 2013

AbstractTAM tyrosine kinases play multiple functional roles, including regulation of the target genes important in homeostatic regulation of cytokine receptors or TLR-mediated signal transduction pathways. In this study, we show that TAM receptors affect adult hippocampal neurogenesis and loss of TAM receptors impairs hippocampal neurogenesis, largely attributed to exaggerated inflammatory responses by microglia characterized by increased MAPK and NF-κB activation and elevated production of proinflammatory cytokines that are detrimental to neuron stem cell proliferation and neuronal differentiation. Injection of LPS causes even more severe inhibition of BrdU incorporation in the Tyro3−/−Axl−/−Mertk−/− triple-knockout (TKO) brains, consistent with the LPS-elicited enhanced expression of proinflammatory mediators, for example, IL-1β, IL-6, TNF-α, and inducible NO synthase, and this effect is antagonized by coinjection of the anti-inflammatory drug indomethacin in wild-type but not TKO brains. Conditioned medium from TKO microglia cultures inhibits neuron stem cell proliferation and neuronal differentiation. IL-6 knockout in Axl−/−Mertk−/− double-knockout mice overcomes the inflammatory inhibition of neurogenesis, suggesting that IL-6 is a major downstream neurotoxic mediator under homeostatic regulation by TAM receptors in microglia. Additionally, autonomous trophic function of the TAM receptors on the proliferating neuronal progenitors may also promote progenitor differentiation into immature neurons.
Factors driving mercury variability in the Arctic atmosphere and ocean over the past 30 years
Authors: Fisher Jenny A. , Jacob Daniel J. , Soerensen Anne L. , Amos Helen M. , Corbitt Elizabeth S. , Streets David G. , Wang Qiaoqiao , Yantosca Robert M. , Sunderland Elsie M. 
Published: November 2013

AbstractLong‐term observations at Arctic sites (Alert and Zeppelin) show large interannual variability (IAV) in atmospheric mercury (Hg), implying a strong sensitivity of Hg to environmental factors and potentially to climate change. We use the GEOS‐Chem global biogeochemical Hg model to interpret these observations and identify the principal drivers of spring and summer IAV in the Arctic atmosphere and surface ocean from 1979–2008. The model has moderate skill in simulating the observed atmospheric IAV at the two sites (r ~ 0.4) and successfully reproduces a long‐term shift at Alert in the timing of the spring minimum from May to April (r = 0.7). Principal component analysis indicates that much of the IAV in the model can be explained by a single climate mode with high temperatures, low sea ice fraction, low cloudiness, and shallow boundary layer. This mode drives decreased bromine‐driven deposition in spring and increased ocean evasion in summer. In the Arctic surface ocean, we find that the IAV for modeled total Hg is dominated by the meltwater flux of Hg previously deposited to sea ice, which is largest in years with high solar radiation (clear skies) and cold spring air temperature. Climate change in the Arctic is projected to result in increased cloudiness and strong warming in spring, which may thus lead to decreased Hg inputs to the Arctic Ocean. The effect of climate change on Hg discharges from Arctic rivers remains a major source of uncertainty.
Subtropical‐polar jet interactions in Southern Plains dust storms
Authors: Kaplan Michael L. , Vellore Ramesh K. , Lewis John M. , Underwood S. Jeffrey , Pauley Patricia M. , Martin Jonathan E. , Rabin Robert M. , Krishnan R. 
Published: November 2013

AbstractThe origin of two separate Southern High Plains dust storms, which occurred over a 2 day period in February 2007, is traced to an interaction between the subtropical jet (STJ) and the polar jet (PJ). A large‐scale thermal wind imbalance resulting from the confluence of these two jets led to a series of mesoscale circulations that ultimately produced the dust storms. Understanding the connectivity between the dust storms with differing geometries is central to the present investigation. The study rests on the interpretation of analyses from upper air and surface observations complemented by imagery from satellites, the 32 km gridded data set from the North American Regional Reanalysis, and a fine‐resolution (6 km grid) simulation from the Weather Research and Forecasting model. Principal assertions from the present study are (1) scale interaction is fundamental to the creation of an environment conducive to dust storm development, (2) low to middle tropospheric mass adjustment is the primary response to a large‐scale imbalance, (3) the mesoscale mass adjustment is associated with circulations about a highly accelerative jet streak resulting from the merger of the PJ and STJ, (4) the structure of the jet streak resulting from this merger governs the evolution of the geometry of the dust plumes, with plumes that initially had a straight‐line orientation developing a semicircular geometry, and (5) it is concluded that improvements in dust storm prediction will depend on an augmentation to the upper air network in concert with a flow‐dependent data assimilation strategy.
Nutritional status in parasitized and nonparasitized children from two districts of buenos aires, Argentina
Authors: Orden Alicia B. , Apezteguía María C. , Ciarmela María L. , Molina Nora B. , Pezzani Betina C. , Rosa Diana , Minvielle Marta C. 
Published: November 2013

ABSTRACTThe Program for the Control of Intestinal Parasites and Nutrition was designed to intervene in small communities to prevent and control the effects of parasitic infections on children's health. Objectives: To analyze the association between nutritional status and parasitic infection in suburban and rural children from Buenos Aires, Argentina. Methods: Nutritional status was assessed by anthropometric (weight, height, BMI, skinfolds, upper arm circumference, muscle, and fat upper arm areas) and biochemical (Hb, Ca, Mg, Zn, and Cu) indicators. Parasitological analysis were made on both serial stool and perianal swab samples. A total of 708 children aged 3–11 were measured. The biochemical analysis included 217 blood samples and the parasitological study included 284 samples. Results: Anthropometric status was similar in both settings with low rates of underweight and stunting (<6%), and high rates of overweight (∼17%) and obesity (∼12%). Ca deficiency was significantly higher in suburban children where 80% of them were hypocalcemic. Around 70% of fecal samples contained parasites. Among infected children, the most prevalent species were Blastocystis hominis and Enterobius vermicularis (∼43%) followed by Giardia lamblia (∼17%). Differences in parasitological status between districts were not significant. In the suburban district parasitized children were lighter, shorter, and had a lower upper arm circumference than their non‐infected peers. No differences in anthropometric status were seen among infected and uninfected rural children. Conclusions: The results suggest an association between intestinal parasites and physical growth in suburban children. Rural children seem to be protected against the effects of parasitic infection. Am. J. Hum. Biol. 26:73–79, 2014. © 2013 Wiley Periodicals, Inc.
The association of the original OSHA chemical hazard communication standard with reductions in acute work injuries/illnesses in private industry and the industrial releases of chemical carcinogens
Authors: Oleinick Arthur 
Published: November 2013

AbstractBackgroundOSHA predicted the original chemical Hazard Communication Standard (HCS) would cumulatively reduce the lost workday acute injury/illness rate for exposure events by 20% over 20 years and reduce exposure to chemical carcinogens.MethodsJoinPoint trend software identified changes in the rate of change of BLS rates for days away from work for acute injuries/illnesses during 1992–2009 for manufacturing and nonmanufacturing industries for both chemical, noxious or allergenic injury exposure events and All other exposure events. The annual percent change in the rates was used to adjust observed numbers of cases to estimate their association with the standard. A case‐control study of EPA's Toxic Release Inventory 1988–2009 data compared carcinogen and non‐carcinogens' releases.ResultsThe study estimates that the HCS was associated with a reduction in the number of acute injuries/illnesses due to chemical injury exposure events over the background rate in the range 107,569–459,395 (Hudson method/modified BIC model) depending on whether the HCS is treated as a marginal or sole factor in the decrease. Carcinogen releases have declined at a substantially faster rate than control non‐carcinogens.DiscussionThe previous HCS standard was associated with significant reductions in chemical event acute injuries/illnesses and chemical carcinogen exposures. Am. J. Ind. Med. 57:138–152, 2014. © 2013 Wiley Periodicals, Inc.
Novel hypoglycemic injury mechanism: N‐methyl‐D‐aspartate receptor–mediated white matter damage
Authors: Yang Xin , Hamner Margaret A. , Brown Angus M. , Evans Richard D. , Ye Zu‐Cheng , Chen Shengdi , Ransom Bruce R. 
Published: November 2013

ObjectiveHypoglycemia is a common adverse event and can injure central nervous system (CNS) white matter (WM). We determined whether glutamate receptors were involved in hypoglycemic WM injury.MethodsMouse optic nerves (MON), CNS WM tracts, were maintained at 37°C with oxygenated artificial cerebrospinal fluid (ACSF) containing 10mM glucose. Aglycemia was produced by switching to 0 glucose ACSF. Supramaximal compound action potentials (CAPs) were elicited using suction electrodes, and axon function was quantified as the area under the CAP. Amino acid release was measured using high‐performance liquid chromatography. Extracellular lactate concentration ([lactate−]o) was measured using an enzyme electrode.ResultsAbout 50% of MON axons were injured after 60 minutes of aglycemia (90% after 90 minutes); injury extent was not affected by animal age. Blockade of N‐methyl‐D‐aspartate (NMDA)‐type glutamate receptors improved recovery after 90 minutes of aglycemia by 250%. Aglycemic injury was increased by reducing [Mg2+]o or increasing [glycine]o, and decreased by lowering pHo, expected results for NMDA receptor‐mediated injury. pHo increased during aglycemia due to a drop in [lactate−]o. Aglycemic injury was dramatically reduced in the absence of [Ca2+]o. Extracellular aspartate, a selective NMDA receptor agonist, increased during aglycemia ([glutamate]o fell).InterpretationAglycemia injured WM by a unique excitotoxic mechanism involving NMDA receptors (located primarily on oligodendrocytes). During WM aglycemia, the selective NMDA agonist aspartate is released, probably from astrocytes. Injury is mediated by Ca2+ influx through aspartate‐activated NMDA receptors made permeable by an accompanying alkaline shift in pHo caused by a fall in [lactate−]o. These insights have important clinical implications. Ann Neurol 2014;75:492–507
Metallothioneins as dynamic markers for brain disease in lysosomal disorders
Authors: Cesani Martina , Cavalca Eleonora , Macco Romina , Leoncini Giuseppe , Terreni Maria Rosa , Lorioli Laura , Furlan Roberto , Comi Giancarlo , Doglioni Claudio , Zacchetti Daniele , Sessa Maria , Scherzer Clemens R. , Biffi Alessandra 
Published: November 2013

ObjectiveTo facilitate development of novel disease‐modifying therapies for lysosomal storage disorder (LSDs) characterized by nervous system involvement such as metachromatic leukodystrophy (MLD), molecular markers for monitoring disease progression and therapeutic response are needed. To this end, we sought to identify blood transcripts associated with the progression of MLD.MethodsGenome‐wide expression analysis was performed in primary T lymphocytes of 24 patients with MLD compared to 24 age‐ and sex‐matched healthy controls. Genes associated with MLD were identified, confirmed on a quantitative polymerase chain reaction platform, and replicated in an independent patient cohort. mRNA and protein expression of the prioritized gene family of metallothioneins was evaluated in postmortem patient brains and in mouse models representing 6 other LSDs. Metallothionein expression during disease progression and in response to specific treatment was evaluated in 1 of the tested LSD mouse models. Finally, a set of in vitro studies was planned to dissect the biological functions exerted by this class of molecules.ResultsMetallothionein genes were significantly overexpressed in T lymphocytes and brain of patients with MLD and generally marked nervous tissue damage in the LSDs here evaluated. Overexpression of metallothioneins correlated with measures of disease progression in mice and patients, whereas their levels decreased in mice upon therapeutic treatment. In vitro studies indicated that metallothionein expression is regulated in response to oxidative stress and inflammation, which are biochemical hallmarks of lysosomal storage diseases.InterpretationMetallothioneins are potential markers of neurologic disease processes and treatment response in LSDs.Ann Neurol 2014;75:127–137
Self‐welding 1‐butene/ethylene copolymers from metallocene catalysts: Structure, morphology, and mechanical properties
Authors: Marega Carla , Spataro Stefano , Fassone Elisa , Camurati Isabella , Marigo Antonio 
Published: November 2013

AbstractSamples of random copolymers consisting of 1‐butene modified with a low ethylene content (4, 5, 8% by weight) produced with metallocene catalysts were studied to elucidate the polymorphic behavior of this new class of materials and to characterize them from a structural, morphological, and mechanical point of view. The samples cooled down from the melt are in amorphous phase and crystallize in a mixture of form I and I′ or in pure form I′ with aging time, according to the C2 content. Infrared and nuclear magnetic resonance spectroscopy, X‐ray diffraction and microscopic techniques were used to follow the changes of the material with aging time and to correlate the structural and morphological behavior with the peculiar mechanical properties that differentiate the samples with increasing C2 content. The presence, in the aged samples with higher C2 content, of the pure form I′ induces the peculiar ability to self‐welding and these copolymers combine high flexibility with good elasticity and ductility and can be processed directly or used as modifying agents in polymers. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 40119.