bluuebunny/crossref_metadata_2025 huggingface dataset:
Climate change and mosquito-borne diseases in China: a review
Authors: Bai Li , Morton Lindsay Carol , Liu Qiyong
Published: March 2013

China has experienced noticeable changes in climate over the past 100 years and the potential impact climate change has on transmission of mosquito-borne infectious diseases poses a risk to Chinese populations. The aims of this paper are to summarize what is known about the impact of climate change on the incidence and prevalence of malaria, dengue fever and Japanese encephalitis in China and to provide important information and direction for adaptation policy making. Fifty-five papers met the inclusion criteria for this study. Examination of these studies indicates that variability in temperature, precipitation, wind, and extreme weather events is linked to transmission of mosquito-borne diseases in some regions of China. However, study findings are inconsistent across geographical locations and this requires strengthening current evidence for timely development of adaptive options. After synthesis of available information we make several key adaptation recommendations including: improving current surveillance and monitoring systems; concentrating adaptation strategies and policies on vulnerable communities; strengthening adaptive capacity of public health systems; developing multidisciplinary approaches sustained by an new mechanism of inter-sectional coordination; and increasing awareness and mobilization of the general public.
Task-oriented training with computer gaming in people with rheumatoid arthritis or osteoarthritis of the hand: study protocol of a randomized controlled pilot trial
Authors: Srikesavan Cynthiav Swarnalatha , Shay Barbara , Robinson David B , Szturm Tony
Published: March 2013

Background

Significant restriction in the ability to participate in home, work and community life results from pain, fatigue, joint damage, stiffness and reduced joint range of motion and muscle strength in people with rheumatoid arthritis or osteoarthritis of the hand. With modest evidence on the therapeutic effectiveness of conventional hand exercises, a task-oriented training program via real life object manipulations has been developed for people with arthritis. An innovative, computer-based gaming platform that allows a broad range of common objects to be seamlessly transformed into therapeutic input devices through instrumentation with a motion-sense mouse has also been designed. Personalized objects are selected to target specific training goals such as graded finger mobility, strength, endurance or fine/gross dexterous functions. The movements and object manipulation tasks that replicate common situations in everyday living will then be used to control and play any computer game, making practice challenging and engaging.

Methods/Design

The ongoing study is a 6-week, single-center, parallel-group, equally allocated and assessor-blinded pilot randomized controlled trial. Thirty people with rheumatoid arthritis or osteoarthritis affecting the hand will be randomized to receive either conventional hand exercises or the task-oriented training. The purpose is to determine a preliminary estimation of therapeutic effectiveness and feasibility of the task-oriented training program. Performance based and self-reported hand function, and exercise compliance are the study outcomes. Changes in outcomes (pre to post intervention) within each group will be assessed by paired Student t test or Wilcoxon signed-rank test and between groups (control versus experimental) post intervention using unpaired Student t test or Mann–Whitney U test.

Discussion

The study findings will inform decisions on the feasibility, safety and completion rate and will also provide preliminary data on the treatment effects of the task-oriented training compared with conventional hand exercises in people with rheumatoid arthritis or osteoarthritis of the hand.

Trial registration

ClinicalTrials.gov: NCT01635582
Ethnotaxonomical considerations and usage of ichthyofauna in a fishing community in Ceará State, Northeast Brazil
Authors: Pinto Márcia Freire , Mourão José da Silva , Alves Rômulo Romeu Nóbrega
Published: March 2013

Background

Artisanal fishery is one of the most important economic activities for human populations living in coastal areas. The traditional knowledge that fishermen have of fishes is of utmost importance for the establishment of conservation strategies for many species. This study aimed to analyse the knowledge of and utilization of fishes by the artisanal fishermen in a fishing community on the coast of Ceará State (Northeast Brazil).

Methods

In 2011, a number of semi-structured interviews were performed with fishermen with more than 20 years of fishery experience. The interviews were about fisheries (collecting spots, artefacts, etc.) and fish use. The fishes cited by the fishermen were identified scientifically and ethnotaxonomically.

Results

Considered masters of fishery, they cited 162 vernacular names of fishes, which corresponded to 290 different species, also including other animals such as dolphins, porpoises, whales and manatees. The criteria for the classification of the fishes were well known and utilised by the fishermen, and they were based on morphology, behaviour, habitat and the importance of commercial and fishing activities. Four hierarchical categories were identified in their classification system: kingdom, life-form, generic and specific. The fish nomenclature created by the fishermen was mostly composed of generic and monotypic names. The main uses of fish were for food and commercial purposes.

Conclusions

The results stress the richness and complexity of the knowledge of the artisanal fishermen of Redonda Beach, and they provide support for the possibility of future studies and for the development of management plans and the management of wildlife resources.
Resolving spatial inconsistencies in chromosome conformation measurements
Authors: Duggal Geet , Patro Rob , Sefer Emre , Wang Hao , Filippova Darya , Khuller Samir , Kingsford Carl
Published: March 2013

Background

Chromosome structure is closely related to its function and Chromosome Conformation Capture (3C) is a widely used technique for exploring spatial properties of chromosomes. 3C interaction frequencies are usually associated with spatial distances. However, the raw data from 3C experiments is an aggregation of interactions from many cells, and the spatial distances of any given interaction are uncertain.

Results

We introduce a new method for filtering 3C interactions that selects subsets of interactions that obey metric constraints of various strictness. We demonstrate that, although the problem is computationally hard, near-optimal results are often attainable in practice using well-designed heuristics and approximation algorithms. Further, we show that, compared with a standard technique, this metric filtering approach leads to (a) subgraphs with higher statistical significance, (b) lower embedding error, (c) lower sensitivity to initial conditions of the embedding algorithm, and (d) structures with better agreement with light microscopy measurements. Our filtering scheme is applicable for a strict frequency-to-distance mapping and a more relaxed mapping from frequency to a range of distances.

Conclusions

Our filtering method for 3C data considers both metric consistency and statistical confidence simultaneously resulting in lower-error embeddings that are biologically more plausible.
Peritoneal tuberculosis mimicking advanced ovarian carcinoma: an important differential diagnosis to consider
Authors: Gosein Maria A , Narinesingh Dylan , Narayansingh Gordon V , Bhim Nazreen A , Sylvester Pearse A
Published: March 2013

Background

Female patients who present with ascites, adnexal masses and elevated CA125 levels are typically presumed to have advanced ovarian carcinoma. This can lead to radical surgery with its associated morbidity. An important differential diagnosis to consider is tuberculous peritonitis which can present in a similar manner and responds well to medical treatment.

Case presentation

A 44 year old female presented with abdominal distension, weight loss and low grade fever. Her CA125 level was 909 U/ml. Imaging studies revealed an adnexal lesion and ascites. The lungs appeared normal and a Mantoux test was negative. Ovarian malignancy was highly suspected. Cytology of ascites was negative for malignant cells. The patient subsequently developed a large pleural effusion which was drained and negative for malignant cells and acid fast bacilli. Repeat imaging revealed a ‘tree in bud’ appearance of the lung parenchyma and dense ascites. Histology from diagnostic laparotomy revealed caseating granulomas with epithelioid cells and Langhan’s type giant cells. The patient responded well to antituberculosis therapy with normalization of CA125 levels, confirming the diagnosis of peritoneal tuberculosis.

Conclusion

CA125 levels lack specificity, with elevated levels encountered in many benign and malignant conditions, including tuberculosis. There are a few discriminating features that suggest a diagnosis of tuberculous peritonitis rather than ovarian carcinoma. Apart from chest findings which may not always be present, smooth peritoneal thickening and a dirty omentum on CT favours a diagnosis of peritoneal tuberculosis compared with nodular thickening of the peritoneum and omentum in peritoneal carcinomatosis. PCR and ADA testing of ascitic fluid can also be helpful. When these tests are negative or unavailable then diagnostic laparoscopy or laparotomy should be performed with the aid of frozen section to avoid unnecessary radical surgery in cases of peritoneal tuberculosis.
Methylene blue as an early diagnostic marker for oral precancer and cancer
Authors: Riaz Akhtar , Shreedhar Balasundari , Kamboj Mala , Natarajan S
Published: March 2013

Oral cancer is one of the most common neoplasm’s and is ranked eighth in the cancer incidence worldwide. Early detection is of critical importance because survival rates markedly improve. In vivo staining is a simple, inexpensive, and fairly sensitive method. Involved 120 patients (50 with Premalignant Lesion, 50 with OSCC and 20 controls) stained by Methylene Blue (MB). The results of MB uptake were compared with a simultaneous biopsy of these lesions. Pathologically confirmed precancers and cancers were the positive targets of this screening, while hyperkeratosis without dysplasia and no evidence of malignancy were sorted as negative subjects of screening. The results revealed sensitivity of 91.4%, specificity of 66.6%, positive predictive value 97.7% and negative predictive value 33% leading to diagnostic accuracy of MB stain to 90%. We state that MB staining is useful diagnostic tool in community oral cancer screening programmes for high-risk individuals.
Panax ginseng extract rich in ginsenoside protopanaxatriol offers combinatorial effects in nitric oxide production via multiple signaling pathways
Authors: Ahn Hee Yoon , Hong So Young , Kim Ji Yeon , Kwon Oran
Published: March 2013

The root of Panax ginseng C.A. Meyer has been shown to induce nitric oxide (NO) release resulting in a hypotensive effect. However, the main active component contributing to vascular endothelium relaxation remains uncertain. In this study, we hypothesized that multiple components of ginseng extract might have combinatory effects providing greater health benefits than a single ginsenosides. To test this hypothesis, we compared the NO-releasing and endothelial NO synthase (eNOS) activating potency of wide range of ginseng extracts (crude extract, CE; protopanaxatriol-enriched extract, TE; protopanaxadiol-enriched extract, DE) and individual ginsenosides (Rg1, Re and Rb1) in human umbilical vein endothelial cells. We found that TE had the highest potency in NO production, followed by CE, DE, and Rg1. We also observed that TE-treatment resulted in rapid activation of intracellular signaling pathways, immediate linear rise of NO, and increased eNOS activation. TE-induced activation of eNOS was abolished by pretreatment with wortmannin (inhibitor for PI3K-Akt), compound C (inhibitor for AMP activated protein kinase, AMPK) or L-NAME (inhibitor for NOS), whereas Rg1-induced eNOS phosphorylation was only partially attenuated. Further analysis revealed that TE, but not Rg1, results in AMPK phosphorylation at Thr172. These novel finding add evidence that the multiple components of Panax ginseng extract rich in protopanaxatriol offers combinatorial effects in NO production and vascular endothelium relaxation via multiple signaling pathways.
Optimization of monomethoxy poly(ethylene glycol) grafting on Langerhans islets capsule using response surface method
Authors: Aghajani-Lazarjani Hamideh , Vasheghani-Farahani Ebrahim , Hashemi-Najafabadi Sameereh , Shojaosadati Seyed Abbas , Zahediasl Saleh , Tiraihi Taki , Atyabi Fatemeh
Published: March 2013

Langerhans islet transplantation is a much less invasive approach compared with the pancreas transplantation to ‘cure’ diabetes. However, destruction of transplanted islets by the immune system is an impediment for a successful treatment. Chemical grafting of monomethoxy poly(ethylene glycol) onto pancreatic islet capsule is a novel approach in islet immunoisolation. The aim of this study was to determine an optimized condition for grafting of monomethoxy poly(ethylene glycol) succinimidyl propionate (mPEG-SPA) on islets capsule. Independent variables such as reaction time, the percentage of longer mPEG in the mixture, and polymer concentration were optimized using a three-factor, three-level Box-Behnken statistical design. The dependent variable was IL-2 (interleukin-2) secretion of lymphocytes co-cultured with PEGylated or uncoated control islets for 7 days co-culturing. A mathematical relationship is obtained which explained the main and quadratic effects and the interaction of factors which affected IL-2 secretion. Response surface methodology predicted the optimized values of reaction time, the percentage of longer mPEG in the mixture, and polymer concentration of 60 min to be 63.7% mPEG10and 22 mg/mL, respectively, for the minimization of the secreted IL-2 as response. Islets which were PEGylated at this condition were transplanted to diabetic rats. The modified islets could survive for 24 days without the aid of any immunosuppressive drugs and it is the longest survival date reported so far. However, free islets (unmodified islets as control) are completely destroyed within 7 days. These results strongly suggest that this new protocol provides an effective clinical means of decreasing transplanted islet immunogenicity.
Abundant stage-dependent Ly49E expression by liver NK cells is not essential for their differentiation and function
Authors: Filtjens Jessica , Taveirne Sylvie , Van Acker Aline , Van Ammel Els , Vanhees Mandy , Kerre Tessa , Taghon Tom , Vandekerckhove Bart , Plum Jean , Leclercq Georges
Published: March 2013

The Ly49E receptor is abundantly expressed on immature liver NK cells, but not essential in NK cell differentiation and function.

The NKR Ly49E has several unique characteristics. Unlike most NKRs, Ly49E is highly expressed on fetal NK cells, whereas expression is decreased on bone marrow-derived NK cells in adult mice. To investigate a possible role for Ly49E in NK cell differentiation and function, we have generated an Ly49E KO mouse. Our results show that bone marrow and splenic NK cells are present in normal numbers in Ly49E KO mice, expressing an unaltered panel of NKRs and differentiation markers. Furthermore, cytokine production and cytotoxicity by these cells are unaffected. Surprisingly, WT DX5− liver NK cells express high Ly49E levels in fetal and adult mice. Ly49E+DX5− liver NK cells transferred into Rag-2−/−/gc−/− mice maintain high Ly49E expression in the liver and differentiate into DX5+ NK cells in spleen and bone marrow. Ly49E expression is not crucial for liver NK cell differentiation during ontogeny, as the DX5−/DX5+ ratio, the NKR repertoire, and the granzyme B and TRAIL levels are comparable in Ly49E KO versus WT mice, except for lower TRAIL expression on DX5− liver NK cells in 20-day-old mice. The TRAIL-, perforin-, and FasL-mediated cytolysis by liver NK cells is unaffected in Ly49E KO mice. Collectively, we show that in addition to high Ly49E expression on fetal NK cells versus low Ly49E expression on conventional NK cells in adult life, Ly49E remains highly expressed on DX5− liver NK cells. However, Ly49E expression does not have a crucial role in differentiation and/or function of these NK cells.
TLR agonists: our best frenemy in cancer immunotherapy
Authors: Kaczanowska Sabina , Joseph Ann Mary , Davila Eduardo
Published: March 2013

Review on the ability of different TLR agonists to orchestrate antitumor immune responses, or promote tumor growth, underscoring the impact of choosing among TLR agonists when applying these therapies in the clinic.

Various TLR agonists are currently under investigation in clinical trials for their ability to orchestrate antitumor immunity. The antitumor responses are largely attributed to their aptitude to stimulate APCs such as DCs which in turn, activate tumor-specific T cell responses. However, there is a potential for TLR signaling to occur on cells other than professional APCs that could negate antitumor responses or even worse, promote tumor growth. The impetus for this review is twofold. First, there is accumulating data demonstrating that the engagement of TLRs on different T cell subsets and different cancer types could promote tumor growth or conversely, contribute to antitumor responses. Second, the efficacy of TLR agonists as monotherapies to treat cancer patients has been limited. In this review, we discuss how TLR signaling within different T cell subsets and cancer cells can potentially impact the generation of antitumor responses. Based on evidence from preclinical models and clinical trials, we draw attention to several criteria that we believe must be considered when selecting TLR agonists for developing effective immunotherapeutic strategies against cancer.
Localized bacterial infection induces systemic activation of neutrophils through Cxcr2 signaling in zebrafish
Authors: Deng Qing , Sarris Milka , Bennin David A , Green Julie M , Herbomel Philippe , Huttenlocher Anna
Published: March 2013

Direct visualization and characterization of Cxcr2 signaling as a mediator of systemic neutrophil reaction to a local infection.

Neutrophils are the first line of defense against tissue damage and are rapidly mobilized to sites of bacterial infection. However, the signals that regulate neutrophil recruitment are not well defined. Here, using photolabel-enabled fate mapping in zebrafish larvae, we show that localized otic infection with Pseudomonas aeruginosa induces systemic activation and mobilization of neutrophils from the CHT through Cxcr2 signaling. We have cloned the zebrafish Cxcr1 and Cxcr2 receptors and show that Cxcr2 functions as a Cxcl8 receptor in live zebrafish. With the use of morpholino-mediated depletion, we show that infection-induced neutrophil mobilization from the CHT is mediated by Cxcr2 but not Cxcr1. By contrast, Cxcr2 depletion does not affect neutrophil recruitment to the chemoattractant LTB4. Taken together, our findings identify Cxcl8-Cxcr2 signaling as an infection-induced long-range cue that mediates neutrophil motility and mobilization from hematopoietic tissues, positioning Cxcr2 as a critical pathway that mediates infection-induced systemic activation of neutrophils.
Pituitary Stalk Interruption Syndrome and Isolated Pituitary Hypoplasia May Be Caused by Mutations in Holoprosencephaly-Related Genes
Authors: Tatsi Christina , Sertedaki Amalia , Voutetakis Antonis , Valavani Eleni , Magiakou Maria-Alexandra , Kanaka-Gantenbein Christina , Chrousos George P. , Dacou-Voutetakis Catherine
Published: March 2013

Context:

Holoprosencephaly (HPE) is a developmental defect characterized by wide phenotypic variability, ranging from minor midline malformations (eg, single central incisor) to severe deformities. In 10–15% of HPE patients, mutations in specific genes have been identified (eg, SHH, TGIF, SIX3). Pituitary stalk interruption syndrome (PSIS) constitutes a distinct abnormality of unknown pathogenesis, whereas isolated pituitary hypoplasia (IPH) has been linked to various developmental genes.

Objective:

Three of our patients with PSIS had a single central incisor, a malformation encountered in some HPE cases. Based on this observation, we initiated a search for mutations in HPE-associated genes in 30 patients with PSIS or IPH.

Design and Participants:

The entire coding region of the TGIF, SHH, and SIX3 genes was sequenced in patients with combined pituitary hormone deficiency associated with either PSIS or IPH and in healthy controls.

Results:

Two novel mutations in the HPE-related genes were detected (ie, c.799 C>T, p.Q267X in the TGIF gene, and c.1279G>A, p.G427R in the SHH gene) in 2 of our patients. The overall incidence of HPE-related gene mutations in our nonsyndromic and nonchromosomal patients was 6.6%. No molecular defect in the SIX3 gene was detected in our cohort.

Conclusions:

The data suggest that HPE-related gene mutations are implicated in the etiology of isolated pituitary defects (PSIS or IPH). Alternatively, PSIS or IPH may constitute mild forms of an expanded HPE spectrum.
From shape to cells: mouse models reveal mechanisms altering palate development in Apert syndrome
Authors: Martínez-Abadías Neus , Holmes Greg , Pankratz Talia , Wang Yingli , Zhou Xueyan , Jabs Ethylin Wang , Richtsmeier Joan T.
Published: March 2013

Apert syndrome is a congenital disorder characterized by severe skull malformations and caused by one of two missense mutations, S252W and P253R, on fibroblast growth factor receptor 2 (FGFR2). The molecular bases underlying differential Apert syndrome phenotypes are still poorly understood and it is unclear why cleft palate is more frequent in patients carrying the S252W mutation. Taking advantage of Apert syndrome mouse models, we performed a novel combination of morphometric, histological and immunohistochemical analyses to precisely quantify distinct palatal phenotypes in Fgfr2+/S252W and Fgfr2+/P253R mice. We localized regions of differentially altered FGF signaling and assessed local cell patterns to establish a baseline for understanding the differential effects of these two Fgfr2 mutations. Palatal suture scoring and comparative 3D shape analysis from high resolution μCT images of 120 newborn mouse skulls showed that Fgfr2+/S252W mice display relatively more severe palate dysmorphologies, with contracted and more separated palatal shelves, a greater tendency to fuse the maxillary-palatine sutures and aberrant development of the inter-premaxillary suture. These palatal defects are associated with suture-specific patterns of abnormal cellular proliferation, differentiation and apoptosis. The posterior region of the developing palate emerges as a potential target for therapeutic strategies in clinical management of cleft palate in Apert syndrome patients.
piggyBac as a high-capacity transgenesis and gene-therapy vector in human cells and mice
Authors: Li Rongbo , Zhuang Yuan , Han Min , Xu Tian , Wu Xiaohui
Published: March 2013

The stable genomic integration and expression of a large transgene is a major hurdle in gene therapy. We show that the modified piggyBac (PB) transposon system can be used to introduce a 207 kb genomic DNA fragment containing the RORγ/γt locus into human cells and mice. PB-mediated transgenesis results in a single copy of a stably inherited and expressed transgene. These results indicate that PB could serve as an effective high-capacity vector for functional analysis of the mammalian genome and for gene therapy in human cells.
Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease
Authors: Bogdanik Laurent P. , Sleigh James N. , Tian Cong , Samuels Mark E. , Bedard Karen , Seburn Kevin L. , Burgess Robert W.
Published: March 2013

Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous condition characterized by peripheral axon degeneration with subsequent motor and sensory deficits. Several CMT gene products function in endosomal sorting and trafficking to the lysosome, suggesting that defects in this cellular pathway may present a common pathogenic mechanism for these conditions. LRSAM1 is an E3 ubiquitin ligase that is implicated in this process, and mutations in LRSAM1 have recently been shown to cause CMT. We have generated mouse mutations in Lrsam1 to create an animal model of this form of CMT (CMT2P). Mouse Lrsam1 is abundantly expressed in the motor and sensory neurons of the peripheral nervous system. Both homozygous and heterozygous mice have largely normal neuromuscular performance and only a very mild neuropathy phenotype with age. However, Lrsam1 mutant mice are more sensitive to challenge with acrylamide, a neurotoxic agent that causes axon degeneration, indicating the axons in the mutant mice are indeed compromised. In transfected cells, LRSAM1 primarily localizes in a perinuclear compartment immediately beyond the Golgi and shows little colocalization with components of the endosome to lysosome trafficking pathway, suggesting that other cellular mechanisms also merit consideration.
Osteoarticular tissue infection and development of skeletal pathology in murine brucellosis
Authors: Magnani Diogo M. , Lyons Elizabeth T. , Forde Toni S. , Shekhani Mohammed T. , Adarichev Vyacheslav A. , Splitter Gary A.
Published: March 2013

Brucellosis, a frequent bacterial zoonosis, can produce debilitating chronic disease with involvement of multiple organs in human patients. Whereas acute brucellosis is well studied using the murine animal model, long-term complications of host-pathogen interaction remain largely elusive. Human brucellosis frequently results in persistent, chronic osteoarticular system involvement, with complications such as arthritis, spondylitis and sacroiliitis. Here, we focused on identifying infectious sites in the mouse that parallel Brucella melitensis foci observed in patients. In vivo imaging showed rapid bacterial dispersal to multiple sites of the murine axial skeleton. In agreement with these findings, immunohistochemistry revealed the presence of bacteria in bones and limbs, and in the lower spine vertebrae of the axial skeleton where they were preferentially located in the bone marrow. Surprisingly, some animals developed arthritis in paws and spine after infection, but without obvious bacteria in these sites. The identification of Brucella in the bones of mice corroborates the findings in humans that these osteoarticular sites are important niches for the persistence of Brucella in the host, but the mechanisms that mediate pathological manifestations in these sites remain unclear. Future studies addressing the immune responses within osteoarticular tissue foci could elucidate important tissue injury mediators and Brucella survival strategies.
Global regulation of alternative splicing by adenosine deaminase acting on RNA (ADAR)
Authors: Solomon Oz , Oren Shirley , Safran Michal , Deshet-Unger Naamit , Akiva Pinchas , Jacob-Hirsch Jasmine , Cesarkas Karen , Kabesa Reut , Amariglio Ninette , Unger Ron , Rechavi Gideon , Eyal Eran
Published: March 2013

Alternative mRNA splicing is a major mechanism for gene regulation and transcriptome diversity. Despite the extent of the phenomenon, the regulation and specificity of the splicing machinery are only partially understood. Adenosine-to-inosine (A-to-I) RNA editing of pre-mRNA by ADAR enzymes has been linked to splicing regulation in several cases. Here we used bioinformatics approaches, RNA-seq and exon-specific microarray of ADAR knockdown cells to globally examine how ADAR and its A-to-I RNA editing activity influence alternative mRNA splicing. Although A-to-I RNA editing only rarely targets canonical splicing acceptor, donor, and branch sites, it was found to affect splicing regulatory elements (SREs) within exons. Cassette exons were found to be significantly enriched with A-to-I RNA editing sites compared with constitutive exons. RNA-seq and exon-specific microarray revealed that ADAR knockdown in hepatocarcinoma and myelogenous leukemia cell lines leads to global changes in gene expression, with hundreds of genes changing their splicing patterns in both cell lines. This global change in splicing pattern cannot be explained by putative editing sites alone. Genes showing significant changes in their splicing pattern are frequently involved in RNA processing and splicing activity. Analysis of recently published RNA-seq data from glioblastoma cell lines showed similar results. Our global analysis reveals that ADAR plays a major role in splicing regulation. Although direct editing of the splicing motifs does occur, we suggest it is not likely to be the primary mechanism for ADAR-mediated regulation of alternative splicing. Rather, this regulation is achieved by modulating trans-acting factors involved in the splicing machinery.
Interplay between EGR1 and SP1 is critical for 13-cis retinoic acid-mediated transcriptional repression of angiotensin type 1A receptor
Authors: Snyder Russell , Thekkumkara Thomas
Published: March 2013

Recently, we have demonstrated that 13-cisretinoic acid (13cRA) downregulates rat angiotensin type 1A receptor (Agtr1a) gene transcription through a MAP kinase (ERK1/2)-dependent mechanism in rat liver epithelial and aortic smooth muscle cells. However, the exact mechanism remained unknown. In this study, we determined the signaling intermediates activated by ERK1/2 involved in 13cRA-mediatedAgtr1adownregulation. RatAgtr1achloramphenicol acetyltransferase (CAT) promoter construct containing a sequence -2541 and -1836 bp upstream of the start site demonstrated reduced CAT activity; this region possesses a specificity protein 1 (SP1) consensus sequence (5′-TGGGGCGGGGCGGGG-3′). Mobility shift analysis using untreated nuclear extracts in the presence of mithramycin A suggests that thetrans-acting factor binding to thiscis-acting element is SP1. 13cRA significantly reduced specific binding without any change in SP1 protein expression. Studies showed that 13cRA treatment maximally phosphorylates ERK1/2 within 5–10 min, which translocates to the nucleus, activating early growth response protein 1 (Egr1) mRNA expression at 20 min followed byde novoprotein synthesis, leading to an EGR1/SP1 interaction. siRNA silencing ofEgr1restoredAgtr1amRNA and protein expression in 13cRA-treated cells, andSp1silencing results in complete loss ofAgtr1aexpression. Our study suggests that 13cRA-mediated activation of ERK1/2, through EGR1, is capable of disrupting SP1, the requisitetrans-activator forAgtr1aexpression, providing a novel paradigm inAgtr1agene transcription.
Glucose regulates secretion of exogenously expressed insulin from HepG2 cells in vitro and in a mouse model of diabetes mellitus in vivo
Authors: Liu Y Y , Jia W , Wanke I E , Muruve D A , Xiao H P , Wong N C W
Published: March 2013

Glucose-controlled insulin secretion is a key component of its regulation. Here, we examined whether liver cell secretion of insulin derived from an engineered construct can be regulated by glucose. Adenovirus constructs were designed to express proinsulin or mature insulin containing the conditional binding domain (CBD). This motif binds GRP78 (HSPA5), an endoplasmic reticulum (ER) protein that enables the chimeric hormone to enter into and stay within the ER until glucose regulates its release from the organelle. Infected HepG2 cells expressed proinsulin mRNA and the protein containing the CBD. Immunocytochemistry studies suggested that GRP78 and proinsulin appeared together in the ER of the cell. The amount of hormone released from infected cells varied directly with the ambient concentration of glucose in the media. Glucose-regulated release of the hormone from infected cells was rapid and sustained. Removal of glucose from the cells decreased release of the hormone. In streptozotocin-induced diabetic mice, when infected with adenovirus expressing mature insulin, glucose levels declined. Our data show that glucose regulates release of exogenously expressed insulin from the ER of liver cells. This approach may be useful in devising new ways to treat diabetes mellitus.
Kinesin-1 Acts with Netrin and DCC to Maintain Sensory Neuron Position in Caenorhabditis elegans
Authors: Barsi-Rhyne Benjamin J , Miller Kristine M , Vargas Christopher T , Thomas Anthony B , Park Joori , Bremer Martina , Jarecki Jessica L , VanHoven Miri K
Published: March 2013

The organization of neurons and the maintenance of that arrangement are critical to brain function. Failure of these processes in humans can lead to severe birth defects, mental retardation, and epilepsy. Several kinesins have been shown to play important roles in cell migration in vertebrate systems, but few upstream and downstream pathway members have been identified. Here, we utilize the genetic model organism Caenorhabditis elegans to elucidate the pathway by which the C. elegans Kinesin-1 Heavy Chain (KHC)/KIF5 ortholog UNC-116 functions to maintain neuronal cell body position in the PHB sensory neurons. We find that UNC-116/KHC acts in part with the cell and axon migration molecules UNC-6/Netrin and UNC-40/DCC in this process, but in parallel to SAX-3/Robo. We have also identified several potential adaptor, cargo, and regulatory proteins that may provide insight into the mechanism of UNC-116/KHC’s function in this process. These include the cargo receptor UNC-33/CRMP2, the cargo adaptor protein UNC-76/FEZ and its regulator UNC-51/ULK, the cargo molecule UNC-69/SCOCO, and the actin regulators UNC-44/Ankyrin and UNC-34/Enabled. These genes also act in cell migration and axon outgrowth; however, many proteins that function in these processes do not affect PHB position. Our findings suggest an active posterior cell migration mediated by UNC-116/KHC occurs throughout development to maintain proper PHB cell body position and define a new pathway that mediates maintenance of neuronal cell body position.
Systems Genetics of Environmental Response in the Mature Wheat Embryo
Authors: Munkvold Jesse D , Laudencia-Chingcuanco Debbie , Sorrells Mark E
Published: March 2013

Quantitative phenotypic traits are influenced by genetic and environmental variables as well as the interaction between the two. Underlying genetic × environment interaction is the influence that the surrounding environment exerts on gene expression. Perturbation of gene expression by environmental factors manifests itself in alterations to gene co-expression networks and ultimately in phenotypic plasticity. Comparative gene co-expression networks have been used to uncover biological mechanisms that differentiate tissues or other biological factors. In this study, we have extended consensus and differential Weighted Gene Co-Expression Network Analysis to compare the influence of different growing environments on gene co-expression in the mature wheat (Triticum aestivum) embryo. This network approach was combined with mapping of individual gene expression QTL to examine the genetic control of environmentally static and variable gene expression. The approach is useful for gene expression experiments containing multiple environments and allowed for the identification of specific gene co-expression modules responsive to environmental factors. This procedure identified conserved coregulation of gene expression between environments related to basic developmental and cellular functions, including protein localization and catabolism, vesicle composition/trafficking, Golgi transport, and polysaccharide metabolism among others. Environmentally unique modules were found to contain genes with predicted functions in responding to abiotic and biotic environmental variables. These findings represent the first report using consensus and differential Weighted Gene Co-expression Network Analysis to characterize the influence of environment on coordinated transcriptional regulation.
Modelos matemáticos para o crescimento da população do estado de São Paulo e a exploração de diferentes taxas de crescimento
Authors: Leite Maria Beatriz Ferreira , Silva Gabriella Helena Jorge da , Sousa Livia Fernandes de
Published: March 2013

A utilização de modelos matemáticos que descrevem a evolução temporal de populações (crescimento ou decréscimo) pode ser extremamente útil para a escolha de medidas preventivas e/ou de controle. São muitas as ferramentas matemáticas disponíveis, e uma escolha adequada depende tanto do tipo de informações disponíveis quanto dos objetivos almejados. Buscando explorar conteúdos matemáticos do Ensino Médio, neste trabalho são apresentados alguns modelos matemáticos que descrevem o crescimento da população do Estado de São Paulo, a partir da utilização de diferentes funções. Diferentes taxas de crescimento são exploradas, e as características e hipóteses básicas de cada modelo proposto são apresentadas. Uma comparação quantitativa e qualitativa é feita para validar os modelos obtidos.
Cardiac Tolerability of Pertuzumab Plus Trastuzumab Plus Docetaxel in Patients With HER2-Positive Metastatic Breast Cancer in CLEOPATRA: A Randomized, Double-Blind, Placebo-Controlled Phase III Study
Authors: Swain Sandra M. , Ewer Michael S. , Cortés Javier , Amadori Dino , Miles David , Knott Adam , Clark Emma , Benyunes Mark C. , Ross Graham , Baselga José
Published: March 2013

Introduction.

We report cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel observed in the phase III study CLEOPATRA in patients with HER2-positive first-line metastatic breast cancer (MBC).

Patients and Methods.

Left ventricular ejection fraction (LVEF) ≥50% and ECOG performance status of 0 or 1 were required for study entry. During the study, LVEF assessments took place every 9 weeks. Pertuzumab/placebo was given at 840 mg, then 420 mg q3w; trastuzumab was administered at 8 mg/kg, then 6 mg/kg q3w, and docetaxel was initiated at 75 mg/m2 q3w.

Results.

The incidence of cardiac adverse events (all grades) was 16.4% in the placebo arm and 14.5% in the pertuzumab arm, with left ventricular systolic dysfunction (LVSD, all grades) being the most frequently reported event (8.3% versus 4.4% in the placebo and pertuzumab arm). Declines in LVEF by ≥10% points from baseline and to <50% were reported in 6.6% and 3.8% of patients in the placebo and pertuzumab arm, respectively. Seventy-two percent (placebo arm) and 86.7% (pertuzumab arm) of those patients recovered to a value ≥50%. The incidence of symptomatic LVSD was low, occurring in 1.8% (n = 7) versus 1.0% (n = 4) of patients in the placebo and pertuzumab arm. In 8/11 patients, the symptomatic LVSD had resolved at data cutoff.

Conclusion.

The combination of pertuzumab plus trastuzumab plus docetaxel did not increase the incidence of cardiac adverse events, including LVSD, compared with the control arm in HER2-positive MBC. The majority of cardiac adverse events were reversible.
The potential for using geopolymer concrete in the UK
Authors: Heath Andrew , Paine Kevin , Goodhew Steve , Ramage Michael , Lawrence Mike
Published: March 2013

Geopolymers are a novel class of inorganic polymers, which have the potential to replace Portland cement in a number of different applications. Geopolymers can utilise a higher level of industrial by-products than Portland cement blends and numerous studies have concluded geopolymer concretes have significantly lower embodied carbon dioxide than Portland-cement-based concretes. This paper examines the potential for the use of geopolymer binders as a Portland cement replacement in the UK. The quantities of material required, the major sources of these materials, the environmental implications and the barriers to implementation are discussed.
Hygrothermal performance of bio-based insulation materials
Authors: Lawrence Mike , Shea Andy , Walker Pete , De Wilde Pieter
Published: March 2013

Bio-based insulation materials have the potential to make a significant contribution to the reduction in the global warming potential of the construction industry world-wide. They contribute in two ways. First they provide the opportunity to reduce the embodied energy in the fabric of buildings. They do this because they are renewable and recyclable. Plant-based insulation materials also sequester carbon dioxide through photosynthesis, sealing up atmospheric carbon dioxide for the life-time of the building. Second they are able to reduce the in-use energy consumption of buildings in more ways than by simply reducing energy transmission. They have the ability to buffer heat and moisture, which is most evident in dynamic situations. This paper discusses the hygrothermal performance of bio-based insulation materials, examining the hygrothermal effects associated with their vapour activity. The incremental performance offered by these materials is not allowed for in building regulations, nor is it readily accounted for in many commercially available building physics models. The paper discusses the reasons for this and identifies the need for the transient performance of bio-based insulation materials to be taken into account, because this will better reflect their actual contribution to the energy performance of a building.
Rethinking structural masonry: unreinforced, stone-cut shells
Authors: Rippmann Matthias , Block Philippe
Published: March 2013

Recently, the interest of architects and designers in contemporary applications of masonry has increased considerably. Motivated by the elegance of historic masonry structures, mostly decorative stone and brick applications have been developed, driven by new possibilities in fabrication technology and the increasing relevance of sustainable building materials. In contrast, the use and potential of structural masonry has rarely been addressed in these developments. This paper presents novel methods for structural stone masonry, focusing on the possibilities of approaches closely interrelating form-finding and material-driven fabrication. Thanks to newly developed structural form-finding methods for the design of unreinforced masonry shells, new, ‘free-form’ vaulted structures in stone are now imaginable. These new structural design tools have been integrated into a digital process, which is informed by relevant construction and fabrication parameters. The paper focuses on this interrelation, linking expressive structural form to its real-world demands in stone construction by considering appropriate and efficient fabrication technology. The design for the MLK Jr Park Vault in Austin, Texas, USA is used as a proof-of-concept case study for the process, taking full advantage of modern stone-cutting technology and using the compression strength and weight of stone masonry to efficiently combine construction material and structural form.
Energy-based seismic performance of reinforced concrete frame structures
Authors: Guan Minsheng , Du Hongbiao
Published: March 2013

The distribution of structural hysteretic energy is significant in energy-based seismic performance evaluations of reinforced concrete (RC) structures. This research involved the design of a six-storey RC frame and analysis of its dynamic time history for typical ground motions. Based on a comparison of the numerical results of the earthquake input energy and structural hysteretic energy under minor, moderate and major levels of earthquakes of grades 8 and 9, the allocation and distribution of structural hysteretic energy were studied. The results indicate that the ground motion characteristics have a small influence on the ratio of the maximum hysteretic energy to the maximum earthquake input energy, as well as on the distribution pattern of hysteretic energy along the height of the structure. Upper storeys dissipate less energy than lower ones and are little affected by ground motion severity when the plasticity of the structure is sufficiently developed. Beams dissipate most hysteretic energy in the structures, and energy consumption of the columns is almost zero except in the lower columns. Thus, larger plastic deformation is found to be concentrated in the lower storeys, with damage to the structure in the form of a strong column and weak beam.
Non-linear shear analysis of reinforced concrete columns by fixed-angle theory
Authors: Lee Jung-Yoon , Kim Kil-Hee , Kim Sang-Woo
Published: March 2013

This paper predicts the shear response of reinforced concrete columns with bending moment and axial load by a truss model based on the fixed-angle theory. The proposed model has a simple formulation by using average constitutive relationships and can also estimate the shear contribution of concrete at crack surfaces by fixing crack directions. Using the constitutive laws of principal applied stress direction, the model is applicable to reinforced concrete columns that have a large difference in the amounts of longitudinal and transverse reinforcements. In addition, the effects of bending moment and axial force acting on the shear-critical columns are considered in the proposed formulation. To verify the applicability of the proposed formulation to the shear behaviour of reinforced concrete columns, nine reinforced concrete columns with various shear span-to-depth ratios and axial force ratios were cast and tested. Additionally, the experimentally observed shear strengths of 47 columns in the literature were compared with predicted shear strengths obtained from the proposed model and existing models.
A Critical Comparison of Reduced and Conventional EOS Algorithms
Authors: Haugen Kjetil B. , Beckner Bret L.
Published: March 2013

Phase-equilibrium calculations can be a time-consuming part of process simulators and compositional reservoir simulations. Various authors have presented encouraging speed improvements based on reduced methods that can lower the computational cost by reducing the number of independent variables and thus generating a smaller system of equations to solve. This paper presents a careful comparison of conventional and reduced algorithms, showing that they can be expressed as linear transformations of each other. Consequently, the two sets of algorithms exhibit identical convergence behavior, and the performance gain of the reduced methods is entirely caused by reducing the cost of linear-algebra operations. Performance benchmarks show much smaller speed-up numbers than seen in previously published material. Highly optimized linear-algebra operations significantly limit the opportunity for further speed improvement from reduced methods. Only a marginal speed-up potential is observed for mixtures with 15 components or less. This suggests that reduced methods may be less attractive for reservoir simulation than previously thought.