bluuebunny/crossref_metadata_2025 huggingface dataset:
A Multicenter, Prospective, Randomized, Double-blind Study to Evaluate the Safety and Efficacy of Saroglitazar 2 and 4 mg Compared to Pioglitazone 45 mg in Diabetic Dyslipidemia (PRESS V)
Authors: Pai Vikas , Paneerselvam A , Mukhopadhyay Satinath , Bhansali Anil , Kamath Dinesh , Shankar V , Gambhire Dhiraj , Jani Rajendrakumar H. , Joshi Shashank , Patel Pankaj
Published: January 2014

Background:

Dual PPARα/γ can improve both metabolic effects and minimized the side effects caused by either PPARα or PPARγ agonist. The PRESS V study was aimed to evaluate the safety, tolerability, and efficacy of saroglitazar 2 mg and 4 mg capsules (Lipaglyn™; Zydus Code: ZYH1) as compared to high dose pioglitazone in patients with diabetic dyslipidemia.

Methods:

In this 26-week double-blind, parallel arm, phase 3 study patients with hypertriglyceridemia with type 2 diabetes mellitus (BMI > 23 kg/m2; hypertriglyceridemia: TG > 200 to 400 mg/dL; glycosylated hemoglobin [HbA1c] >7 to 9%) were enrolled from 14 sites in India. After 2 weeks of lifestyle modification, 122 patients were randomized double-blind to 24-week treatment with the study drugs (saroglitazar 2 mg or 4 mg or pioglitazone 45 mg once daily) in a 1:1:1 ratio. The primary end point was change in plasma triglyceride level at week 24. The secondary end points were change in lipid profile and fasting plasma glucose at week 24. Patients who received study medication and had undergone at least 1 postbaseline efficacy evaluation were included in the efficacy analysis. All randomized patients who received at least a single dose were included for safety evaluation.

Results:

The efficacy analysis included 109 patients (n = 37 in saroglitazar 2 mg; n = 39 in saroglitazar 4 mg; n = 33 in pioglitazone). Saroglitazar 2 mg and 4 mg significantly reduced ( P < .001) plasma triglyceride from baseline by 26.4% (absolute change ± SD: −78.2 ± 81.98 mg/dL) and 45% (absolute change ± SD −115.4 ± 68.11 mg/dL), respectively, as compared to pioglitazone -15.5% (absolute change ± SD: −33.3 ± 162.41 mg/dL) at week 24. Saroglitazar 4 mg treatment also demonstrated marked decrease in low-density lipoprotein (5%), very-low-density lipoprotein (45.5%), total cholesterol (7.7%), and apolipoprotein-B (10.9%). Saroglitazar treatment was generally safe and well tolerated. No serious adverse events were reported in saroglitazar treatment arm and no persistent change in laboratory parameters.

Conclusions:

Saroglitazar appeared to be an effective and safe therapeutic option for improving hypertriglyceridemia in patients with type 2 diabetes mellitus.
Correlates of Cyberbullying and How School Nurses Can Respond
Authors: Van Ouytsel Joris , Walrave Michel , Vandebosch Heidi
Published: January 2014

Cyberbullying is one of many online risks that affect an increasing number of children and teenagers. This form of abuse often occurs under the radar of adults as it usually takes place outside of school and away from adult supervision. Moreover, bystanders and victims are often reluctant to report what they have experienced. School nurses might be among the first to witness the real-life consequences of this virtual behavior, as involvement in cyberbullying is often correlated with psychological and behavioral problems. For this reason, school nurses should know how to recognize the warning signs so that they can respond and intervene appropriately. This article provides a discussion of what cyberbullying is and a summary of research on factors associated with cyberbullying, in terms of both victimization and perpetration. It also provides school nurses with evidence-based strategies for responding effectively.
The Role and Status of English in Spanish-Speaking Argentina and Its Education System
Authors: Porto Melina
Published: January 2014

There is a lot of controversy nowadays in the field of English Language Teaching (ELT) in the context of Teaching English to Speakers of Other Languages (TESOL) regarding the status and role of English in non-English speaking countries, in particular in developing countries, as well as in English-speaking countries with a history of colonialism. In these settings, the discourse of English as a form of imperialism requires a reconsideration of the role and status of English in the national school curriculum in primary and secondary school contexts. It also requires the exploration of the connections with nationalism and national identity, for within this discourse of imperialism, English tends to be seen as detrimental to the national identity, which education explicitly aims to form and develop through formal schooling.
Physician Barriers to Successful Implementation of US Preventive Services Task Force Routine HIV Testing Recommendations
Authors: Zheng Micha Yin , Suneja Amit , Chou Ann Love , Arya Monisha
Published: January 2014

In 2006, the US Centers for Disease Control and Prevention issued recommendations supporting routine HIV testing in health care settings for all persons aged 13 to 64 years. Despite these recommendations, physicians are not offering HIV testing routinely. We apply a model that has previously identified 3 central, inter-related factors (knowledge-, attitude-, and behavior-related barriers) for why physicians do not follow practice guidelines in order to better understand why physicians are not offering HIV testing routinely. This model frames our review of the existing literature on physician barriers to routine HIV testing. Within the model, knowledge barriers include lack of familiarity or awareness of clinical recommendations, attitude barriers include lack of agreement with guidelines, while behavioral barriers include external barriers related to the guidelines themselves, to patients, or to environmental factors. Our review reveals that many physicians face these barriers with regards to implementing routine HIV testing. Several factors underscore the importance of determining how to best address physician barriers to HIV testing, including: provisions of the Affordable Care Act that are likely to require or incentivize major payers to cover HIV testing, evidence which suggests that a physician's recommendation to test for HIV is a strong predictor of patient testing behavior, and data which reveals that nearly 20% of HIV-positive individuals may be unaware of their status. In April 2013, the US Preventive Services Task Force released a recommendation supporting routine HIV testing; strategies are needed to help address ongoing physician barriers to testing.
Mutations in Krüppel-like factor 1 cause transfusion-dependent hemolytic anemia and persistence of embryonic globin gene expression
Authors: Viprakasit Vip , Ekwattanakit Supachai , Riolueang Suchada , Chalaow Nipon , Fisher Chris , Lower Karen , Kanno Hitoshi , Tachavanich Kalaya , Bejrachandra Sasithorn , Saipin Jariya , Juntharaniyom Monthana , Sanpakit Kleebsabai , Tanphaichitr Voravarn S. , Songdej Duantida , Babbs Christian , Gibbons Richard J. , Philipsen Sjaak , Higgs Douglas R.
Published: January 2014

Key Points

KLF1 mutations cause severe congenital hemolytic anemia associated with a deficiency of red cell pyruvate kinase. A severe KLF1 deficiency causes hereditary persistence of embryonic globin synthesis.
Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-2 cohorts
Authors: Passamonti Francesco , Maffioli Margherita , Cervantes Francisco , Vannucchi Alessandro Maria , Morra Enrica , Barbui Tiziano , Caramazza Domenica , Pieri Lisa , Rumi Elisa , Gisslinger Heinz , Knoops Laurent , Kiladjian Jean Jaques , Mora Barbara , Hollaender Norbert , Pascutto Cristiana , Harrison Claire , Cazzola Mario
Published: January 2014

Key Points

Patients with primary myelofibrosis and intermediate-2 or high IPSS risk have a median life expectancy of 4 years or less. PMF patients with higher IPSS risks who receive ruxolitinib treatment have longer survival than those who receive conventional therapy.
MMP-2 and TIMP-1 predict healing of WTC-lung injury in New York City firefighters
Authors: Nolan Anna , Kwon Sophia , Cho Soo Jung , Naveed Bushra , Comfort Ashley L , Prezant David J , Rom William N , Weiden Michael D
Published: January 2014

Rationale

After 9/11/2001, most FDNY workers had persistent lung function decline but some exposed workers recovered. We hypothesized that the protease/anti-protease balance in serum soon after exposure predicts subsequent recovery.

Methods

We performed a nested case–control study measuring biomarkers in serum drawn before 3/2002 and subsequent forced expiratory volume at one second (FEV1) on repeat spirometry before 3/2008. Serum was assayed for matrix metalloproteinases (MMP-1,2,3,7,8,9,12 and 13) and tissue inhibitors of metalloproteinases (TIMP-1,2,3,4). The representative sub-cohort defined analyte distribution and a concentration above 75th percentile defined elevated biomarker expression. An FEV1 one standard deviation above the mean defined resistance to airway injury. Logistic regression was adjusted for pre-9/11 FEV1, BMI, age and exposure intensity modeled the association between elevated biomarker expression and above average FEV1.

Results

FEV1 in cases and controls declined 10% of after 9/11/2001. Cases subsequently returned to 99% of their pre-exposure FEV1 while decline persisted in controls. Elevated TIMP-1 and MMP-2 increased the odds of resistance by 5.4 and 4.2 fold while elevated MMP-1 decreased it by 0.27 fold.

Conclusions

Resistant cases displayed healing, returning to 99% of pre-exposure values. High TIMP-1 and MMP-2 predict healing. MMP/TIMP balance reflects independent pathways to airway injury and repair after WTC exposure.
Comparison of different assembly and annotation tools on analysis of simulated viral metagenomic communities in the gut
Authors: Vázquez-Castellanos Jorge F , García-López Rodrigo , Pérez-Brocal Vicente , Pignatelli Miguel , Moya Andrés
Published: January 2014

Background

The main limitations in the analysis of viral metagenomes are perhaps the high genetic variability and the lack of information in extant databases. To address these issues, several bioinformatic tools have been specifically designed or adapted for metagenomics by improving read assembly and creating more sensitive methods for homology detection. This study compares the performance of different available assemblers and taxonomic annotation software using simulated viral-metagenomic data.

Results

We simulated two 454 viral metagenomes using genomes from NCBI's RefSeq database based on the list of actual viruses found in previously published metagenomes. Three different assembly strategies, spanning six assemblers, were tested for performance: overlap-layout-consensus algorithms Newbler, Celera and Minimo; de Bruijn graphs algorithms Velvet and MetaVelvet; and read probabilistic model Genovo. The performance of the assemblies was measured by the length of resulting contigs (using N50), the percentage of reads assembled and the overall accuracy when comparing against corresponding reference genomes. Additionally, the number of chimeras per contig and the lowest common ancestor were estimated in order to assess the effect of assembling on taxonomic and functional annotation. The functional classification of the reads was evaluated by counting the reads that correctly matched the functional data previously reported for the original genomes and calculating the number of over-represented functional categories in chimeric contigs. The sensitivity and specificity of tBLASTx, PhymmBL and the k-mer frequencies were measured by accurate predictions when comparing simulated reads against the NCBI Virus genomes RefSeq database.

Conclusions

Assembling improves functional annotation by increasing accurate assignations and decreasing ambiguous hits between viruses and bacteria. However, the success is limited by the chimeric contigs occurring at all taxonomic levels. The assembler and its parameters should be selected based on the focus of each study. Minimo's non-chimeric contigs and Genovo's long contigs excelled in taxonomy assignation and functional annotation, respectively.

tBLASTx stood out as the best approach for taxonomic annotation for virus identification. PhymmBL proved useful in datasets in which no related sequences are present as it uses genomic features that may help identify distant taxa. The k-frequencies underperformed in all viral datasets.
Transcriptome profiling of granulosa cells from bovine ovarian follicles during atresia
Authors: Hatzirodos Nicholas , Hummitzsch Katja , Irving-Rodgers Helen F , Harland Margaret L , Morris Stephanie E , Rodgers Raymond J
Published: January 2014

Background

The major function of the ovary is to produce oocytes for fertilisation. Oocytes mature in follicles surrounded by nurturing granulosa cells and all are enclosed by a basal lamina. During growth, granulosa cells replicate and a large fluid-filled cavity (the antrum) develops in the centre. Only follicles that have enlarged to over 10 mm can ovulate in cows. In mammals, the number of primordial follicles far exceeds the numbers that ever ovulate and atresia or regression of follicles is a mechanism to regulate the number of oocytes ovulated and to contribute to the timing of ovulation. To better understand the molecular basis of follicular atresia, we undertook transcriptome profiling of granulosa cells from healthy (n = 10) and atretic (n = 5) bovine follicles at early antral stages (< 5 mm).

Results

Principal Component Analysis (PCA) and hierarchical classification of the signal intensity plots for the arrays showed primary clustering into two groups, healthy and atretic. These analyses and size-frequency plots of coefficients of variation of signal intensities revealed that the healthy follicles were more heterogeneous. Examining the differentially-expressed genes the most significantly affected functions in atretic follicles were cell death, organ development, tissue development and embryonic development. The overall processes influenced by transcription factor gene TP53 were predicted to be activated, whereas those of MYC were inhibited on the basis of known interactions with the genes in our dataset. The top ranked canonical pathway contained signalling molecules common to various inflammatory/fibrotic pathways such as the transforming growth factor-β and tumour necrosis factor-α pathways. The two most significant networks also reflect this pattern of tissue remodelling/fibrosis gene expression. These networks also contain molecules which are present in the canonical pathways of hepatic fibrosis/hepatic stellate cell activation and transforming growth factor-β signalling and were up regulated.

Conclusions

Small healthy antral follicles, which have a number of growth outcomes, exhibit greater variability in gene expression, particularly in genes associated with cell division and other growth-related functions. Atresia, on the other hand, not only involves cell death but clearly is an active process similar to wound healing.
Coverage, quality of and barriers to postnatal care in rural Hebei, China: a mixed method study
Authors: Chen Li , Qiong Wu , van Velthoven Michelle Helena , Yanfeng Zhang , Shuyi Zhang , Ye Li , Wei Wang , Xiaozhen Du , Ting Zhang
Published: January 2014

Background

Postnatal care is an important link in the continuum of care for maternal and child health. However, coverage and quality of postnatal care are poor in low- and middle-income countries. In 2009, the Chinese government set a policy providing free postnatal care services to all mothers and their newborns in China. Our study aimed at exploring coverage, quality of care, reasons for not receiving and barriers to providing postnatal care after introduction of this new policy.

Methods

We carried out a mixed method study in Zhao County, Hebei Province, China from July to August 2011. To quantify the coverage, quality of care and reasons for not using postnatal care, we conducted a household survey with 1601 caregivers of children younger than two years of age. We also conducted semi-structured interviews with 24 township maternal and child healthcare workers to evaluate their views on workload, in-service training and barriers to postnatal home visits.

Results

Of 1442 (90% of surveyed caregivers) women who completed the postnatal care survey module, 8% received a timely postnatal home visit (within one week after delivery) and 24% of women received postnatal care within 42 days after delivery. Among women who received postnatal care, 37% received counseling or guidance on infant feeding and 32% on cord care. 24% of women reported that the service provider checked jaundice of their newborns and 18% were consulted on danger signs and thermal care of their newborns. Of 991 mothers who did not seek postnatal care within 42 days after birth, 65% of them said that they did not knew about postnatal care and 24% of them thought it was unnecessary. Qualitative findings revealed that staff shortages and inconvenient transportation limited maternal and child healthcare workers in reaching out to women at home. In addition, maternal and child healthcare workers said that in-service training was inadequate and more training on postnatal care, hands-on practice, and supervision were needed.

Conclusions

Coverage and quality of postnatal care were low in rural Hebei Province and far below the targets set by Chinese government. We identified barriers both from the supply and demand side.
Systemic treatment with CAR-engineered T cells against PSCA delays subcutaneous tumor growth and prolongs survival of mice
Authors: Hillerdal Victoria , Ramachandran Mohanraj , Leja Justyna , Essand Magnus
Published: January 2014

Background

Adoptive transfer of T cells genetically engineered with a chimeric antigen receptor (CAR) has successfully been used to treat both chronic and acute lymphocytic leukemia as well as other hematological cancers. Experimental therapy with CAR-engineered T cells has also shown promising results on solid tumors. The prostate stem cell antigen (PSCA) is a protein expressed on the surface of prostate epithelial cells as well as in primary and metastatic prostate cancer cells and therefore a promising target for immunotherapy of prostate cancer.

Methods

We developed a third-generation CAR against PSCA including the CD28, OX-40 and CD3 ζ signaling domains. T cells were transduced with a lentivirus encoding the PSCA-CAR and evaluated for cytokine production (paired Student’s t-test), proliferation (paired Student’s t-test), CD107a expression (paired Student’s t-test) and target cell killing in vitro and tumor growth and survival in vivo (Log-rank test comparing Kaplan-Meier survival curves).

Results

PSCA-CAR T cells exhibit specific interferon (IFN)-γ and interleukin (IL)-2 secretion and specific proliferation in response to PSCA-expressing target cells. Furthermore, the PSCA-CAR-engineered T cells efficiently kill PSCA-expressing tumor cells in vitro and systemic treatment with PSCA-CAR-engineered T cells significantly delays subcutaneous tumor growth and prolongs survival of mice.

Conclusions

Our data confirms that PSCA-CAR T cells may be developed for treatment of prostate cancer.
Economic evaluation of access to musculoskeletal care: the case of waiting for total knee arthroplasty
Authors: Mather Richard C , Hug Kevin T , Orlando Lori A , Watters Tyler Steven , Koenig Lane , Nunley Ryan M , Bolognesi Michael P
Published: January 2014

Background

The projected demand for total knee arthroplasty is staggering. At its root, the solution involves increasing supply or decreasing demand. Other developed nations have used rationing and wait times to distribute this service. However, economic impact and cost-effectiveness of waiting for TKA is unknown.

Methods

A Markov decision model was constructed for a cost-utility analysis of three treatment strategies for end-stage knee osteoarthritis: 1) TKA without delay, 2) a waiting period with no non-operative treatment and 3) a non-operative treatment bridge during that waiting period in a cohort of 60 year-old patients. Outcome probabilities and effectiveness were derived from the literature. Costs were estimated from the societal perspective with national average Medicare reimbursement. Effectiveness was expressed in quality-adjusted life years (QALYs) gained. Principal outcome measures were average incremental costs, effectiveness, and quality-adjusted life years; and net health benefits.

Results

In the base case, a 2-year wait-time both with and without a non-operative treatment bridge resulted in a lower number of average QALYs gained (11.57 (no bridge) and 11.95 (bridge) vs. 12.14 (no delay). The average cost was $1,660 higher for TKA without delay than wait-time with no bridge, but $1,810 less than wait-time with non-operative bridge. The incremental cost-effectiveness ratio comparing wait-time with no bridge to TKA without delay was $2,901/QALY. When comparing TKA without delay to waiting with non-operative bridge, TKA without delay produced greater utility at a lower cost to society.

Conclusions

TKA without delay is the preferred cost-effective treatment strategy when compared to a waiting for TKA without non-operative bridge. TKA without delay is cost saving when a non-operative bridge is used during the waiting period. As it is unlikely that patients waiting for TKA would not receive non-operative treatment, TKA without delay may be an overall cost-saving health care delivery strategy. Policies aimed at increasing the supply of TKA should be considered as savings exist that could indirectly fund those strategies.
Decision-making factors affecting different family members regarding the placement of relatives in long-term care facilities
Authors: Huang Ying-Chia , Chu Chiao-Lee , Ho Ching-Sung , Lan Shou-Jen , Hsieh Chen-Hsi , Hsieh Yen-Ping
Published: January 2014

Background

The aim of this research was to investigate factors affecting different family members’ decisions regarding the placement of relatives in long-term car (LTC) facilities in Taiwan. The objective was to investigate the correlations between family members’ personal traits, the living conditions of residents in the LTC facilities, and family members’ experiences with LTC facilities.

Methods

This study selected family members visiting residents in LTC facilities as research subjects and used a structured questionnaire to perform face-to-face interviews. This study used nonlinear canonical correlation analysis (OVERALS) to categorize the decision-making factors affecting family members’ choices of LTC facilities.

Results

The results showed that when making decisions about the placement of family members, spouses chose facilities according to their own life experiences, children considered medical treatment convenience, grandchildren preferred to collect relevant information on facilities, and other relatives preferred to decide based on introductions from government departments.

Conclusions

These results help clarify how different family roles affect decision-making processes regarding the choice of LTC facilities. In particular, spouses and female relatives require an interventional service mechanism that provides consultation or referral information.
Safety and efficacy of bevacizumab combined with R-CHOP regimen in seven Chinese patients with untreated diffuse large B-cell lymphoma
Authors: Fu Zhiying , Zhu Jun , Zheng Wen , Liu Weiping , Ying Zhitao , Xie Yan , Wang Xiaopei , Lin Ningjing , Tu Meifeng , Ping Lingyan , Deng Lijuan , Zhang Chen , Ding Ning , Song Yuqin
Published: January 2014

Background

Rituximab plus CHOP (R-CHOP) significantly improved the outcome of diffuse large B cell lymphoma (DLBCL), a common sub-type of non-Hodgkin lymphoma. But 40% – 50% of DLBCL patients cannot be cured by this regimen. Some clinical trials showed that bevacizumab might be useful in the treatment of DLBCL. This study evaluated the safety and efficacy of bevacizumab combined with the R-CHOP (A-R-CHOP) regimen in Chinese patients with previously untreated DLBCL.

Methods

Patients with previously untreated DLBCL received A-R-CHOP regimen therapy. All patients with complete response (CR)/ unconfirmed complete response(CRu) after 8 cycles of A-R-CHOP received the bevacizumab maintenance therapy once every 3 weeks. The remained bulky disease was treated with radiotherapy.

Results

Seven Chinese patients were treated. All of them had bulky diseases. One patient had progressive disease after 4 cycles of A-R-CHOP therapy. The rest six patients completed 8 cycles of A-R-CHOP treatment. All of these six patients reached CR/CRu (5 CR, 1 CRu). Bevacizumab maintenance therapy was given to 4 CR patients. All 7 patients experienced Grade 3/4 hematologic adverse events; additionally, one had Grade 3 gastrointestinal toxicity and one had Grade 1 epistaxis. During bevacizumab maintenance therapy, one patient had Grade 1 gingival bleeding, another experienced Grade 1 proteinuria and then Grade 3 congestive heart failure 4 months after completion of maintenance therapy. At the end of July 2013, the patient who had progressive disease after 4 cycles of A-R-CHOP died of progressive disease, the other six remained CR response.

Conclusions

The A-R-CHOP regimen is effective for untreated DLBCL, but may cause bevacizumab-specific toxicities, which should be monitored.
Metastasis of prostate cancer and melanoma cells in a preclinical in vivo mouse model is enhanced by L-plastin expression and phosphorylation
Authors: Riplinger Selina M , Wabnitz Guido H , Kirchgessner Henning , Jahraus Beate , Lasitschka Felix , Schulte Bianca , van der Pluijm Gabri , van der Horst Geertje , Hämmerling Günter J , Nakchbandi Inaam , Samstag Yvonne
Published: January 2014

Background

Tumor cell migration and metastasis require dynamic rearrangements of the actin cytoskeleton. Interestingly, the F-actin cross-linking and stabilizing protein L-plastin, originally described as a leukocyte specific protein, is aberrantly expressed in several non-hematopoietic malignant tumors. Therefore, it has been discussed as a tumor marker. However, systematicin vivoanalyses of the functional relevance of L-plastin for tumor cell metastasis were so far lacking.

Methods

We investigated the relevance of L-plastin expression and phosphorylation by ectopical expression of L-plastin in human melanoma cells (MV3) and knock-down of endogenous L-plastin in prostate cancer (PC3M). The growth and metastatic potential of tumor cells expressing no L-plastin, phosphorylatable or non-phosphorylatable L-plastin was analyzed in a preclinical mouse model after subcutaneous and intracardial injection of the tumor cells.

Results

Knock-down of endogenous L-plastin in human prostate carcinoma cells led to reduced tumor cell growth and metastasis. Vice versa, and in line with these findings, ectopic expression of L-plastin in L-plastin negative melanoma cells significantly increased the number of metastases. Strikingly, the metastasis promoting effect of L-plastin was not observed if a non-phosphorylatable L-plastin mutant was expressed.

Conclusions

Our data provide the firstin vivoevidence that expression of L-plastin promotes tumor metastasis and, importantly, that this effect depends on an additionally required phosphorylation of L-plastin. In conclusion, these findings imply that for determining the importance of tumor-associated proteins like L-plastin a characterization of posttranslational modifications is indispensable.
High Mg effective incorporation in Al-rich Al
x
Ga1 - xN by periodic repetition of ultimate V/III ratio conditions
Authors: Zheng Tongchang , Lin Wei , Cai Duanjun , Yang Weihuang , Jiang Wei , Chen Hangyang , Li Jinchai , Li Shuping , Kang Junyong
Published: January 2014

According to first-principles calculations, the solubility of Mg as a substitute for Ga or Al in Al
x
Ga1 – x
N bulk is limited by large, positive formation enthalpies. In contrast to the bulk case, the formation enthalpies become negative on Al
x
Ga1 – x
N surface. In addition, the N-rich growth atmosphere can also be favorable to Mg incorporation on the surface by changing the chemical potentials. On the basis of these special features, we proposed a modified surface engineering technique that applies periodical interruptions under an ultimate V/III ratio condition (extremely N-rich), to enhance Mg effective incorporation. By optimizing the interruption conditions (2 nm interruption interval with 2 s interruption time), the enhancement ratio can be up to about 5 in the Al0.99Ga0.01N epilayer.
B-Type Natriuretic Peptide is Neither Itch-Specific Nor Functions Upstream of the GRP-GRPR Signaling Pathway
Authors: Liu Xian-Yu , Wan Li , Huo Fu-Quan , Barry Devin M , Li Hui , Zhao Zhong-Qiu , Chen Zhou-Feng
Published: January 2014

Background:

A recent study by Mishra and Hoon identified B-type natriuretic peptide (BNP) as an important peptide for itch transmission and proposed that BNP activates spinal natriuretic peptide receptor-A (NPRA) expressing neurons, which release gastrin releasing peptide (GRP) to activate GRP receptor (GRPR) expressing neurons to relay itch information from the periphery to the brain ( Science 340:968–971, 2013). A central premise for the validity of this novel pathway is the absence of GRP in the dorsal root ganglion (DRG) neurons. To this end, they showed that Grp mRNA in DRG neurons is either absent or barely detectable and claimed that BNP but not GRP is a major neurotransmitter for itch in pruriceptors. They showed that NPRA immunostaining is perfectly co-localized with Grp-eGFP in the spinal cord, and a few acute pain behaviors in Nppb−/− mice were tested. They claimed that BNP is an itch-selective peptide that acts as the first station of a dedicated neuronal pathway comprising a GRP-GRPR cascade for itch. However, our studies, along with the others, do not support their claims.

Findings:

We were unable to reproduce the immunostaining of BNP and NPRA as shown by Mishra and Hoon. By contrast, we were able to detect Grp mRNA in DRGs using in situ hybridization and real time RT-PCR. We show that the expression pattern of Grp mRNA is comparable to that of GRP protein in DRGs. Pharmacological and genetic blockade of GRP-GRPR signaling does not significantly affect intrathecal BNP-induced scratching behavior. We show that BNP inhibits inflammatory pain and morphine analgesia.

Conclusions:

Accumulating evidence demonstrates that GRP is a key neurotransmitter in pruriceptors for mediating histamine-independent itch. BNP-NPRA signaling is involved in both itch and pain and does not function upstream of the GRP-GRPR dedicated neuronal pathway. The site of BNP action in itch and pain and its relationship with GRP remain to be clarified.
Can a combined screening/treatment programme prevent premature failure of renal transplants due to chronic rejection in patients with HLA antibodies: study protocol for the multicentre randomised controlled OuTSMART trial
Authors: Dorling Anthony , Rebollo-Mesa Irene , Hilton Rachel , Peacock Janet L , Vaughan Robert , Gardner Leanne , Danzi Guilherme , Baker Richard , Clark Brendan , Thuraisingham Raj C , Buckland Matthew , Picton Michael , Martin Susan , Borrows Richard , Briggs David , Horne Robert , McCrone Paul , Kelly Joanna , Murphy Caroline
Published: January 2014

Background

Renal transplantation is the best treatment for kidney failure, in terms of length and quality of life and cost-effectiveness. However, most transplants fail after 10 to 12 years, consigning patients back onto dialysis. Damage by the immune system accounts for approximately 50% of failing transplants and it is possible to identify patients at risk by screening for the presence of antibodies against human leukocyte antigens. However, it is not clear how best to treat patients with antibodies. This trial will test a combined screening and treatment protocol in renal transplant recipients.

Methods/Design

Recipients >1 year post-transplantation, aged 18 to 70 with an estimated glomerular filtration rate >30 mL/min will be randomly allocated to blinded or unblinded screening arms, before being screened for the presence of antibodies. In the unblinded arm, test results will be revealed. Those with antibodies will have biomarker-led care, consisting of a change in their anti-rejection drugs to prednisone, tacrolimus and mycophenolate mofetil. In the blinded arm, screening results will be double blinded and all recruits will remain on current therapy (standard care). In both arms, those without antibodies will be retested every 8 months for 3 years. The primary outcome is the 3-year kidney failure rate for the antibody-positive recruits, as measured by initiation of long-term dialysis or re-transplantation, predicted to be approximately 20% in the standard care group but <10% in biomarker-led care. The secondary outcomes include the rate of transplant dysfunction, incidence of infection, cancer and diabetes mellitus, an analysis of adherence with medication and a health economic analysis of the combined screening and treatment protocol. Blood samples will be collected and stored every 4 months and will form the basis of separately funded studies to identify new biomarkers associated with the outcomes.

Discussion

We have evidence that the biomarker-led care regime will be effective at preventing graft dysfunction and expect this to feed through to graft survival. This trial will confirm the benefit of routine screening and lead to a greater understanding of how to keep kidney transplants working longer.

Trial registration

Current Controlled TrialsISRCTN46157828.
Effect of polyols on thermostability of xylanase from a tropical isolate of Aureobasidium pullulans and its application in prebleaching of rice straw pulp
Authors: Bankeeree Wichanee , Lotrakul Pongtharin , Prasongsuk Sehanat , Chaiareekij Somporn , Eveleigh Douglas E , Kim Seung Wook , Punnapayak Hunsa
Published: January 2014

In an attempt to find a thermostable xylanase enzyme for potential application in the pretreatment prior to H2O2bleaching of paper pulp for industry, an extracellular xylanase fromAureobasidium pullulansCBS 135684 was purified 17.3-fold to apparent homogeneity with a recovery yield of 13.7%. Its molecular mass was approximately 72 kDa as determined by SDS-PAGE. The optimal pH and temperature for activity of the purified enzyme were pH 6.0 and 70°C, respectively. The enzyme was relatively stable at 50°C, retaining more than half of its original activity after 3-h incubation. The thermostability of the enzyme was improved by the addition of 0.75 mM sorbitol prolonging the enzyme’s activity up to 10-fold at 70°C. When the potential of using the enzyme in pretreatment of rice straw pulp prior to bleaching was evaluated, the greatest efficiency was obtained in a mixture containing xylanase and sorbitol. Treatment of the rice straw pulp with xylanase prior to treatment with 10% (v/v) H2O2and production of hand sheets increased the ISO sheet brightness by 13.5% and increased the tensile and tear strengths of the pulp by up to 1.16 and 1.71-fold, respectively, compared with pulps treated with H2O2alone. The results suggested the potential application of the enzyme before the bleaching process of paper pulp when the maintenance of high temperature and enzyme stability are desirable.
A novel immunomodulatory function of PHLPP1: inhibition of iNOS via attenuation of STAT1 ser727 phosphorylation in mouse macrophages
Authors: Alamuru Neeraja P , Behera Soma , Butchar Jonathan P , Tridandapani Susheela , Kaimal Suraj Sasidhara , Babu P Prakash , Hasnain Seyed E , Ehtesham Nasreen Z , Parsa Kishore V L
Published: January 2014

PHLPP1 is a novel tumor suppressor, but its role in the regulation of innate immune responses, which are frequently dysregulated in cancer, is unexplored. Here, we report that LPS attenuated PHLPP1 expression at mRNA and protein levels in immune cells, suggesting its involvement in immune responses. To test this, we overexpressed PHLPP1 in RAW 264.7 macrophages and observed a dramatic reduction in LPS/IFN-γ-induced iNOS expression. Conversely, silencing of PHLPP1 by siRNA or by shRNA robustly augmented LPS/IFN-γ-induced iNOS expression. qPCR and iNOS promoter reporter experiments showed that PHLPP1 inhibited iNOS transcription. Mechanistic analysis revealed that PHLPP1 suppressed LPS/IFN-γ-induced phosphorylation of ser727 STAT1; however, the underlying mechanisms differed. PHLPP1 reduced IFN-γ-stimulated but not LPS-induced ERK1/2 phosphorylation, and inhibition of ERK1/2 abolished IFN-γ-induced ser727 STAT1 phosphorylation and iNOS expression. In contrast, PHLPP1 knockdown augmented LPS-induced but not IFN-γ-elicited p38 phosphorylation. Blockade of p38 abolished LPS-stimulated phosphorylation of ser727 STAT1 and iNOS expression. Furthermore, PHLPP1 suppressed LPS-induced phosphorylation of tyr701 STAT1 by dampening p38-dependent IFN-β feedback. Collectively, our data demonstrate for the first time that PHLPP1 plays a vital role in restricting innate immune responses of macrophages, and further studies may show it to be a potential therapeutic target within the context of dysregulated macrophage activity.
Tumult in the Land of Managed Democracy: An Introduction
Authors: Penzin Alexei
Published: January 2014

The article provides an introduction and context for this section of Against the Day, which analyzes the ongoing protests in Russia. The mainstream interpretations of Russian events create a stereotypical picture formed by liberal narratives as a struggle with an authoritarian regime waged by a rising urban middle class. The goal of the essays here is to challenge this view and demonstrate a different and radical perspective on the process. This introduction stresses several points important for understanding the protests: the prolonged effects of privatization and neoliberal “shock therapy,” the manipulative and managerial approach to politics in the ruling elites, and the highly specific and heterogeneous constitution of the emergent subject of struggle. It also gives further insight into the global meaning of the Russian protests as the result of an “overdetermination” of electoral procedures under the conditions of the regime of managed democracy and as an expression of the limits of any “really existing democracy” in the age of biopolitical governmentality. This introduction also highlights the engaged positions of the authors, who have been active participants in the protest movement.
Hoxb1b controls oriented cell division, cell shape and microtubule dynamics in neural tube morphogenesis
Authors: Žigman Mihaela , Laumann-Lipp Nico , Titus Tom , Postlethwait John , Moens Cecilia B.
Published: January 2014

Hox genes are classically ascribed to function in patterning the anterior-posterior axis of bilaterian animals; however, their role in directing molecular mechanisms underlying morphogenesis at the cellular level remains largely unstudied. We unveil a non-classical role for the zebrafish hoxb1b gene, which shares ancestral functions with mammalian Hoxa1, in controlling progenitor cell shape and oriented cell division during zebrafish anterior hindbrain neural tube morphogenesis. This is likely distinct from its role in cell fate acquisition and segment boundary formation. We show that, without affecting major components of apico-basal or planar cell polarity, Hoxb1b regulates mitotic spindle rotation during the oriented neural keel symmetric mitoses that are required for normal neural tube lumen formation in the zebrafish. This function correlates with a non-cell-autonomous requirement for Hoxb1b in regulating microtubule plus-end dynamics in progenitor cells in interphase. We propose that Hox genes can influence global tissue morphogenesis by control of microtubule dynamics in individual cells in vivo.
tRNA anticodon shifts in eukaryotic genomes
Authors: Rogers Hubert H. , Griffiths-Jones Sam
Published: January 2014

Embedded in the sequence of each transfer RNA are elements that promote specific interactions with its cognate aminoacyl tRNA-synthetase. Although many such “identity elements” are known, their detection is difficult since they rely on unique structural signatures and the combinatorial action of multiple elements spread throughout the tRNA molecule. Since the anticodon is often a major identity determinant itself, it is possible to switch between certain tRNA functional types by means of anticodon substitutions. This has been shown to have occurred during the evolution of some genomes; however, the scale and relevance of “anticodon shifts” to the evolution of the tRNA multigene family is unclear. Using a synteny-conservation–based method, we detected tRNA anticodon shifts in groups of closely related species: five primates, 12 Drosophila, six nematodes, 11 Saccharomycetes, and 61 Enterobacteriaceae. We found a total of 75 anticodon shifts: 31 involving switches of identity (alloacceptor shifts) and 44 between isoacceptors that code for the same amino acid (isoacceptor shifts). The relative numbers of shifts in each taxa suggest that tRNA gene redundancy is likely the driving factor, with greater constraint on changes of identity. Sites that frequently covary with alloacceptor shifts are located at the extreme ends of the molecule, in common with most known identity determinants. Isoacceptor shifts are associated with changes in the midsections of the tRNA sequence. However, the mutation patterns of anticodon shifts involving the same identities are often dissimilar, suggesting that alternate sets of mutation may achieve the same functional compensation.
The N-terminal extension of S12 influences small ribosomal subunit assembly in Escherichia coli
Authors: Calidas Deepika , Lyon Hiram , Culver Gloria M.
Published: January 2014

The small subunit (SSU) of the ribosome of E. coli consists of a core of ribosomal RNA (rRNA) surrounded peripherally by ribosomal proteins (r-proteins). Ten of the 15 universally conserved SSU r-proteins possess nonglobular regions called extensions. The N-terminal noncanonically structured extension of S12 traverses from the solvent to intersubunit surface of the SSU and is followed by a more C-terminal globular region that is adjacent to the decoding center of the SSU. The role of the globular region in maintaining translational fidelity is well characterized, but a role for the S12 extension in SSU structure and function is unknown. We examined the effect of stepwise truncation of the extension of S12 in SSU assembly and function in vitro and in vivo. Examination of in vitro assembly in the presence of sequential N-terminal truncated variants of S12 reveals that N-terminal deletions of greater than nine amino acids exhibit decreased tRNA-binding activity and altered 16S rRNA architecture particularly in the platform of the SSU. While wild-type S12 expressed from a plasmid can rescue a genomic deletion of the essential gene for S12, rpsl; N-terminal deletions of S12 exhibit deleterious phenotypic consequences. Partial N-terminal deletions of S12 are slow growing and cold sensitive. Strains bearing these truncations as the sole copy of S12 have increased levels of free SSUs and immature 16S rRNA as compared with the wild-type S12. These differences are hallmarks of SSU biogenesis defects, indicating that the extension of S12 plays an important role in SSU assembly.
The DExD/H-box ATPase Prp2p destabilizes and proofreads the catalytic RNA core of the spliceosome
Authors: Wlodaver Alissa M. , Staley Jonathan P.
Published: January 2014

After undergoing massive RNA and protein rearrangements during assembly, the spliceosome undergoes a final, more subtle, ATP-dependent rearrangement that is essential for catalysis. This rearrangement requires the DEAH-box protein Prp2p, an RNA-dependent ATPase. Prp2p has been implicated in destabilizing interactions between the spliceosome and the protein complexes SF3 and RES, but a role for Prp2p in destabilizing RNA–RNA interactions has not been explored. Using directed molecular genetics in budding yeast, we have found that a cold-sensitive prp2 mutation is suppressed not only by mutations in SF3 and RES components but also by a range of mutations that disrupt the spliceosomal catalytic core element U2/U6 helix I, which is implicated in juxtaposing the 5′ splice site and branch site and in positioning metal ions for catalysis within the context of a putative catalytic triplex; indeed, mutations in this putative catalytic triplex also suppressed a prp2 mutation. Remarkably, we also found that prp2 mutations rescue lethal mutations in U2/U6 helix I. These data provide evidence that RNA elements that comprise the catalytic core are already formed at the Prp2p stage and that Prp2p destabilizes these elements, directly or indirectly, both to proofread spliceosome activation and to promote reconfiguration of the spliceosome to a fully competent, catalytic conformation.
Molecular crowders and cosolutes promote folding cooperativity of RNA under physiological ionic conditions
Authors: Strulson Christopher A. , Boyer Joshua A. , Whitman Elisabeth E. , Bevilacqua Philip C.
Published: January 2014

Folding mechanisms of functional RNAs under idealized in vitro conditions of dilute solution and high ionic strength have been well studied. Comparatively little is known, however, about mechanisms for folding of RNA in vivo where Mg2+ ion concentrations are low, K+ concentrations are modest, and concentrations of macromolecular crowders and low-molecular-weight cosolutes are high. Herein, we apply a combination of biophysical and structure mapping techniques to tRNA to elucidate thermodynamic and functional principles that govern RNA folding under in vivo–like conditions. We show by thermal denaturation and SHAPE studies that tRNA folding cooperativity increases in physiologically low concentrations of Mg2+ (0.5–2 mM) and K+ (140 mM) if the solution is supplemented with physiological amounts (∼20%) of a water-soluble neutral macromolecular crowding agent such as PEG or dextran. Low-molecular-weight cosolutes show varying effects on tRNA folding cooperativity, increasing or decreasing it based on the identity of the cosolute. For those additives that increase folding cooperativity, the gain is manifested in sharpened two-state-like folding transitions for full-length tRNA over its secondary structural elements. Temperature-dependent SHAPE experiments in the absence and presence of crowders and cosolutes reveal extent of cooperative folding of tRNA on a nucleotide basis and are consistent with the melting studies. Mechanistically, crowding agents appear to promote cooperativity by stabilizing tertiary structure, while those low molecular cosolutes that promote cooperativity stabilize tertiary structure and/or destabilize secondary structure. Cooperative folding of functional RNA under physiological-like conditions parallels the behavior of many proteins and has implications for cellular RNA folding kinetics and evolution.
The determinations of values ​​of reduce of forest recreation resources due to anthropogenic influence
Authors: Сериков  , Serikov Mikhail , Водолажский  , Vodolazhskiy Aleksey
Published: January 2014

This article discusses the two main factors of anthropogenic impacts on forest ecosystems: recreation and anthropogenic air pollution. Degree of impact of these factors on tree species is compared via corresponding reduction in growth of Scots pine shoots, due to their separate and joint action. Growth of pine shoots was measured on sections of four categories: 1) areas subjected only to technogenic impact, 2) areas subjected only to the recreational exposure, 3) areas experiencing complex (anthropogenic and recreational) effects, 4) control (without anthropogenic influence).
Dynamic analysis technique for bodies of forest motor roads
Authors: Михеевская  , Mikheevskaya Marina , Сушков  , Sushkov Sergey , Бурмистрова  , Burmistrova Olga
Published: January 2014

The article describes a method of dynamic analysis of pavement bodies of timber road Ukhta – Troitsky-Pechorsk, a forecast of full sinkage and consolidation time of the subsoil. Reinforcing gravel with geogrids increases the overall (equivalent) elastic modulus of structure for 6…15 %, reduces the magnitude of the tangential stress in the layer, underlying the geogrid by 25…80 %, increases the modulus of defor-mation with significant precipitation more than in 2 times.