bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced Control of Cucumber Wilt Disease by Bacillus amyloliquefaciens SQR9 by Altering the Regulation of Its DegU Phosphorylation
Authors: Xu Zhihui , Zhang Ruifu , Wang Dandan , Qiu Meihua , Feng Haichao , Zhang Nan , Shen Qirong 
Published: March 2014

ABSTRACT

Bacillus amyloliquefaciens
strain SQR9, isolated from the cucumber rhizosphere, suppresses the growth of
Fusarium oxysporum
in the cucumber rhizosphere and protects the host plant from pathogen invasion through efficient root colonization. In the Gram-positive bacterium
Bacillus
, the response regulator DegU regulates genetic competence, swarming motility, biofilm formation, complex colony architecture, and protease production. In this study, we report that stepwise phosphorylation of DegU in
B. amyloliquefaciens
SQR9 can influence biocontrol activity by coordinating multicellular behavior and regulating the synthesis of antibiotics. Results from
in vitro
and
in situ
experiments and quantitative PCR (qPCR) studies demonstrate the following: (i) that the lowest level of phosphorylated DegU (DegU∼P) (the
degQ
mutation) impairs complex colony architecture, biofilm formation, colonization activities, and biocontrol efficiency of
Fusarium
wilt disease but increases the production of macrolactin and bacillaene, and (ii) that increasing the level of DegU∼P by
degQ
and
degSU
overexpression significantly improves complex colony architecture, biofilm formation, colonization activities, production of the antibiotics bacillomycin D and difficidin, and efficiency of biocontrol of
Fusarium
wilt disease. The results offer a new strategy to enhance the biocontrol efficacy of
Bacillus amyloliquefaciens
SQR9.
Randomized Controlled Study of the Safety and Immunogenicity of Pneumococcal Vaccine Formulations Containing PhtD and Detoxified Pneumolysin with Alum or Adjuvant System AS02
V
in Elderly Adults
Authors: Pauksens Karlis , Nilsson Anna C. , Caubet Magalie , Pascal Thierry G. , Van Belle Pascale , Poolman Jan T. , Vandepapelière Pierre G. , Verlant Vincent , Vink Peter E. 
Published: March 2014

ABSTRACT

Six vaccine formulations containing AS02
V
or alum (aluminum phosphate [AlPO
4
]) adjuvant with pneumococcal proteins, pneumococcal histidine triad D (PhtD), and/or detoxified pneumolysin (dPly), either as a polysaccharide carrier in an 8-valent pneumococcal conjugate vaccine (8PCV) or as free (unconjugated) proteins, were evaluated in adults -65 to 85 years of age. In this phase I observer-blind study, 167 healthy subjects were randomized to receive two doses (days 0 and 60) of 10 or 30 μg PhtD-dPly plus AS02
V
or alum, 8PCV plus AS02
V
or alum, or one dose (day 0) of 23-valent polysaccharide pneumococcal vaccine (23PPV) as a control (placebo on day 60). The safety, reactogenicity, and antibody-specific responses to these vaccines were evaluated. No vaccine-related serious adverse events were reported. The incidences of solicited local and specific general (fatigue and myalgia) symptoms tended to be higher in the AS02
V
groups than in other groups. Anti-PhtD and anti-Ply antibody responses were observed in all groups except the control group. One month post-dose 2, the anti-PhtD and anti-Ply antibody geometric mean concentrations tended to be higher with AS02
V
than with alum, higher with a dose of 30 μg than with 10 μg for PhtD-dPly and higher with 30-μg PhtD-dPly formulations than with conjugated PhtD and dPly (8PCV) formulations. Functional antibody responses, measured by an opsonophagocytic activity assay, tended to be higher with 8PCV than with 23PPV. In conclusion, vaccine formulations containing free or conjugated PhtD and dPly had acceptable reactogenicity and safety profiles in elderly adults. Immune responses were enhanced with an AS02
V
-adjuvanted formulation containing free 30-μg PhtD-dPly compared to those with alum adjuvant and conjugated proteins. (This study has been registered at
ClinicalTrials.gov
under registration no. NCT00756067.)
The Path to Triacylglyceride Obesity in the
sta6
Strain of Chlamydomonas reinhardtii
Authors: Goodenough Ursula , Blaby Ian , Casero David , Gallaher Sean D. , Goodson Carrie , Johnson Shannon , Lee Jae-Hyeok , Merchant Sabeeha S. , Pellegrini Matteo , Roth Robyn , Rusch Jannette , Singh Manmilan , Umen James G. , Weiss Taylor L. , Wulan Tuya 
Published: March 2014

ABSTRACT

When the
sta6
(starch-null) strain of the green microalga
Chlamydomonas reinhardtii
is nitrogen starved in acetate and then “boosted” after 2 days with additional acetate, the cells become “obese” after 8 days, with triacylglyceride (TAG)-filled lipid bodies filling their cytoplasm and chloroplasts. To assess the transcriptional correlates of this response, the
sta6
strain and the starch-forming
cw15
strain were subjected to RNA-Seq analysis during the 2 days prior and 2 days after the boost, and the data were compared with published reports using other strains and growth conditions. During the 2 h after the boost, ∼425 genes are upregulated ≥2-fold and ∼875 genes are downregulated ≥2-fold in each strain. Expression of a small subset of “sensitive” genes, encoding enzymes involved in the glyoxylate and Calvin-Benson cycles, gluconeogenesis, and the pentose phosphate pathway, is responsive to culture conditions and genetic background as well as to boosting. Four genes—encoding a diacylglycerol acyltransferase (
DGTT2
), a glycerol-3-P dehydrogenase (
GPD3
), and two candidate lipases (Cre03.g155250 and Cre17.g735600)—are selectively upregulated in the
sta6
strain. Although the bulk rate of acetate depletion from the medium is not boost enhanced, three candidate acetate permease-encoding genes in the
GPR1/FUN34/YaaH
superfamily are boost upregulated, and 13 of the “sensitive” genes are strongly responsive to the cell's acetate status. A cohort of 64 autophagy-related genes is downregulated by the boost. Our results indicate that the boost serves both to avert an autophagy program and to prolong the operation of key pathways that shuttle carbon from acetate into storage lipid, the combined outcome being enhanced TAG accumulation, notably in the
sta6
strain.
Pbx Proteins in Cryptococcus neoformans Cell Wall Remodeling and Capsule Assembly
Authors: Kumar Pardeep , Heiss Christian , Santiago-Tirado Felipe H. , Black Ian , Azadi Parastoo , Doering Tamara L. 
Published: March 2014

ABSTRACT

The cryptococcal capsule is a critical virulence factor of an important pathogen, but little is known about how it is associated with the cell or released into the environment. Two mutants lacking
PBX1
and
PBX2
were found to shed reduced amounts of the capsule polysaccharide glucuronoxylomannan (GXM). Nuclear magnetic resonance, composition, and physical analyses showed that the shed material was of normal mass but was slightly enriched in xylose. In contrast to previous reports, this material contained no glucose. Notably, the capsule fibers of
pbx
Δ mutant cells grown under capsule-inducing conditions were present at a lower than usual density and were loosely attached to the cell wall. Mutant cell walls were also defective, as indicated by phenotypes including abnormal cell morphology, reduced mating filamentation, and altered cell integrity. All observed phenotypes were shared between the two mutants and exacerbated in a double mutant. Consistent with a role in surface glycan synthesis, the Pbx proteins localized to detergent-resistant membrane domains. These results, together with the sequence motifs in the Pbx proteins, suggest that Pbx1 and Pbx2 are redundant proteins that act in remodeling the cell wall to maintain normal cell morphology and precursor availability for other glycan synthetic processes. Their absence results in aberrant cell wall growth and metabolic imbalance, which together impact cell wall and capsule synthesis, cell morphology, and capsule association. The surface changes also lead to increased engulfment by host phagocytes, consistent with the lack of virulence of
pbx
mutants in animal models.
Inhibition and Structure of Toxoplasma gondii Purine Nucleoside Phosphorylase
Authors: Donaldson Teraya M. , Cassera María B. , Ho Meng-Chiao , Zhan Chenyang , Merino Emilio F. , Evans Gary B. , Tyler Peter C. , Almo Steven C. , Schramm Vern L. , Kim Kami 
Published: March 2014

ABSTRACT

The intracellular pathogen
Toxoplasma gondii
is a purine auxotroph that relies on purine salvage for proliferation. We have optimized
T. gondii
purine nucleoside phosphorylase (
Tg
PNP) stability and crystallized
Tg
PNP with phosphate and immucillin-H, a transition-state analogue that has high affinity for the enzyme. Immucillin-H bound to
Tg
PNP with a dissociation constant of 370 pM, the highest affinity of 11 immucillins selected to probe the catalytic site. The specificity for transition-state analogues indicated an early dissociative transition state for
Tg
PNP. Compared to
Plasmodium falciparum
PNP, large substituents surrounding the 5′-hydroxyl group of inhibitors demonstrate reduced capacity for
Tg
PNP inhibition. Catalytic discrimination against large 5′ groups is consistent with the inability of
Tg
PNP to catalyze the phosphorolysis of 5′-methylthioinosine to hypoxanthine. In contrast to mammalian PNP, the 2′-hydroxyl group is crucial for inhibitor binding in the catalytic site of
Tg
PNP. This first crystal structure of TgPNP describes the basis for discrimination against 5′-methylthioinosine and similarly 5′-hydroxy-substituted immucillins; structural differences reflect the unique adaptations of purine salvage pathways of
Apicomplexa
.
The Haemophilus Cryptic Genospecies Cha Adhesin Has at Least Two Variants That Differ in Host Cell Binding, Bacterial Aggregation, and Biofilm Formation Properties
Authors: McCann Jessica R. , Sheets Amanda J. , Grass Susan , St. Geme Joseph W. 
Published: March 2014

ABSTRACT

The
Haemophilus
cryptic genospecies (HCG) causes genital tract infections in pregnant and postpartum women and respiratory infections in neonates. The major surface adhesin in HCG is called Cha, which mediates bacterial adherence to cultured human epithelial cells. In this study, we report that there are two antigenically distinct variants of Cha, dubbed Cha1 and Cha2. These variants are encoded by the same genetic locus in diverse strains and have nearly identical N-terminal export and C-terminal surface anchoring domains but significantly different internal adhesive domains. Based on the comparison of derivatives of a laboratory strain of
Haemophilus influenzae
expressing either surface-associated Cha1 or surface-associated Cha2, Cha1 mediates a higher level of adherence to cultured human epithelial cells and Cha2 mediates a higher level of adherence to abiotic surfaces. We hypothesize that variation in the Cha1 and Cha2 internal region results in changes in binding specificity or binding affinity and may be associated with adaptation to different host environments during colonization and disease.
Scientific publications in respiratory journals from Chinese authors in various parts of North Asia: a 10-year survey of literature
Authors: Ye Bo , Du Ting-Ting , Xie Ting , Ji Jun-Tao , Zheng Zhao-Hong , Liao Zhuan , Hu Liang-Hao , Li Zhao-Shen 
Published: March 2014

ObjectivesRespiratory disease remains one of the leading causes of morbidity and mortality in China. However, little is known about the research status of respirology in three major regions of China—Mainland (ML), Hong Kong (HK) and Taiwan (TW). A 10-year survey of literature was conducted to compare the three regions’ outputs in the research of respirology.DesignA bibliometric study.SettingChina.Participants and outcome measuresA literature search in PubMed database, updated as of September 2012, led to the identification of the related articles from 2000 to 2009. The number of total articles, randomised controlled trials, case reports, meta-analysis, impact factors (IF), citations and articles published in top general medicine journals was collected for quantity and quality comparisons.Results2208 articles were collected, 814 from ML, 909 from TW and 485 from HK. The total number of articles from the three regions has increased significantly from 2000 to 2009. The number of articles published per year from ML has exceeded that from HK in 2005 and TW in 2008. The accumulated IF of articles from TW (3192.417) was much higher than that from ML (2409.956) and HK (1898.312). HK got the highest average IF of respirology articles and the majority of articles were published in top general medicine journals.ConclusionsThe total number of published articles from the three major regions of China has increased notably from 2000 to 2009. The annual number of publications by ML researchers exceeded those from TW and HK. However, the quality of articles from TW and HK is better than that from ML.
A longitudinal, multicentre, cohort study of community rehabilitation service delivery in long-term neurological conditions
Authors: Siegert Richard J , Jackson Diana M , Playford E Diane , Fleminger Simon , Turner-Stokes Lynne 
Published: March 2014

ObjectivesPart A: To pilot the use of a register to identify and monitor patients with complex needs arising from long-term neurological conditions.Part B: To determine the extent to which patients’ needs for health and social services are met following discharge to the community after inpatient rehabilitation; to identify which factors predict unmet needs and to explore the relationship between service provision and outcomes at 12 months.DesignA multicentre, prospective, cohort study surveying participants at 1, 6 and 12 months using postal/online questionnaires and telephone interview.SettingConsecutive discharges to the community from all nine tertiary, specialist, inpatient neurorehabilitation services in London over 18 months in 2010–2011.ParticipantsOf 576 admissions 428 patients were recruited at discharge: 256 responded at 4 weeks, 212 at 6 months and 190 at 12 months.MeasuresNeurological Impairment Scale, The Needs and Provision Complexity Scale, The Northwick Park Dependency Scale, Community Integration Questionnaire, Zarit Burden Inventory.Resultsn=322 (75%) expressed willingness to be registered, but in practice less than half responded to questionnaires at 6 and 12 months (49% and 44%, respectively), despite extensive efforts to contact them, with no significant differences between responders and non-responders. Significant unmet needs were identified within the first year following discharge, particularly in rehabilitation, social work support and provision of specialist equipment. Dependency for basic care and motor and cognitive impairment predicted services received, together accounting for 40% of the variance. Contra to expectation, patients whose rehabilitation needs were met were more dependent and less well integrated at 12 months post discharge than those with unmet needs.ConclusionsRegistration is acceptable to most patients, but questionnaires/telephone interviews may not be the most efficient way to reach them. When community resources are limited, service provision tends to be focused on the most dependent patients.RegistrationThe study was registered with the NIHR Comprehensive Local Research Network: ID number 7503
Molecular Pathways: Molecular Basis for Sensitivity and Resistance to JAK Kinase Inhibitors
Authors: Meyer Sara C. , Levine Ross L. 
Published: March 2014

Abstract
Janus-activated kinases (JAK) are the mediators of a variety of cytokine signals via their cognate receptors that result in activation of intracellular signaling pathways. Alterations in JAK1, JAK2, JAK3, and TYK2 signaling contribute to different disease states, and dysregulated JAK–STAT signaling is associated with hematologic malignancies, autoimmune disorders, and immune-deficient conditions. Genetic alterations of JAK2 occur in the majority of patients with myeloproliferative neoplasms and occur in a subset of patients with acute leukemias. JAK-mediated signaling critically relies on STAT transcription factors, and on activation of the MAPK and PI3K/Akt signaling axes. Hyperactive JAK at the apex of these potent oncogenic signaling pathways therefore represents an important target for small-molecule kinase inhibitors in different disease states. The JAK1/2 inhibitor ruxolitinib and the JAK3 inhibitor tofacitinib were recently approved for the treatment of myelofibrosis and rheumatoid arthritis, respectively, and additional ATP-competitive JAK inhibitors are in clinical development. Although these agents show clinical activity, the ability of these JAK inhibitors to induce clinical/molecular remissions in hematologic malignancies seems limited and resistance upon chronic drug exposure is seen. Alternative modes of targeting JAK2 such as allosteric kinase inhibition or HSP90 inhibition are under evaluation, as is the use of histone deacetylase inhibitors. Combination therapy approaches integrating inhibition of STAT, PI3K/Akt, and MAPK pathways with JAK kinase inhibitors might be critical to overcome malignancies characterized by dysregulated JAK signaling. Clin Cancer Res; 20(8); 2051–9. ©2014 AACR.
Dabrafenib and Trametinib, Alone and in Combination for BRAF-Mutant Metastatic Melanoma
Authors: Menzies Alexander M. , Long Georgina V. 
Published: March 2014

Abstract
Dabrafenib and trametinib were approved for use as monotherapies in BRAF-mutant metastatic melanoma by the U.S. Food and Drug Administration (FDA) in 2013, and most recently, their use in combination has received accelerated FDA approval. Both drugs target the mitogen-activated protein kinase (MAPK) pathway: dabrafenib selectively inhibits mutant BRAF that constitutively activates the pathway, and trametinib selectively inhibits MEK1 and MEK2 proteins activated by RAF kinases. The phase III study of dabrafenib in BRAFV600E metastatic melanoma reported rapid tumor regression in most patients and a 59% objective RECIST response rate. The median progression-free survival (PFS) and overall survival (OS) were improved compared with dacarbazine. Toxicities were well tolerated and different from those reported for vemurafenib, the first FDA-approved BRAF inhibitor. Efficacy has been demonstrated in other BRAF-mutant genotypes. The phase III study of trametinib in BRAF inhibitor–naïve patients with BRAFV600E or BRAFV600K also showed benefit with a prolonged median PFS and OS compared with chemotherapy. Trametinib is ineffective in patients who have progressed on BRAF inhibitors. A phase II trial of combined dabrafenib and trametinib demonstrated higher response rates and longer median PFS than dabrafenib monotherapy, with less cutaneous toxicity. Here, we review the clinical development of both drugs as monotherapies and in combination, and discuss their role in the management of BRAF-mutant melanoma. Clin Cancer Res; 20(8); 2035–43. ©2014 AACR.
CTLA4 Blockade Broadens the Peripheral T-Cell Receptor Repertoire
Authors: Robert Lidia , Tsoi Jennifer , Wang Xiaoyan , Emerson Ryan , Homet Blanca , Chodon Thinle , Mok Stephen , Huang Rong Rong , Cochran Alistair J. , Comin-Anduix Begoña , Koya Richard C. , Graeber Thomas G. , Robins Harlan , Ribas Antoni 
Published: March 2014

Abstract
Purpose: To evaluate the immunomodulatory effects of cytotoxic T–lymphocyte-associated protein 4 (CTLA4) blockade with tremelimumab in peripheral blood mononuclear cells (PBMC).
Experimental Design: We used next-generation sequencing to study the complementarity-determining region 3 (CDR3) from the rearranged T-cell receptor (TCR) variable beta (V-beta) in PBMCs of 21 patients, at baseline and 30 to 60 days after receiving tremelimumab.
Results: After receiving tremelimumab, there was a median of 30% increase in unique productive sequences of TCR V-beta CDR3 in 19 out of 21 patients, and a median decrease of 30% in only 2 out of 21 patients. These changes were significant for richness (P = 0.01) and for Shannon index diversity (P = 0.04). In comparison, serially collected PBMCs from four healthy donors did not show a significant change in TCR V-beta CDR3 diversity over 1 year. There was a significant difference in the total unique productive TCR V-beta CDR3 sequences between patients experiencing toxicity with tremelimumab compared with patients without toxicity (P = 0.05). No relevant differences were noted between clinical responders and nonresponders.
Conclusions: CTLA4 blockade with tremelimumab diversifies the peripheral T-cell pool, representing a pharmacodynamic effect of how this class of antibodies modulates the human immune system. Clin Cancer Res; 20(9); 2424–32. ©2014 AACR.
c-Cbl Inhibition Improves Cardiac Function and Survival in Response to Myocardial Ischemia
Authors: Rafiq Khadija , Kolpakov Mikhail A. , Seqqat Rachid , Guo Jianfen , Guo Xinji , Qi Zhao , Yu Daohai , Mohapatra Bhopal , Zutshi Neha , An Wei , Band Hamid , Sanjay Archana , Houser Steven R. , Sabri Abdelkarim 
Published: March 2014

Background—
The proto-oncogene Casitas b-lineage lymphoma (c-Cbl) is an adaptor protein with an intrinsic E3 ubiquitin ligase activity that targets receptor and nonreceptor tyrosine kinases, resulting in their ubiquitination and downregulation. However, the function of c-Cbl in the control of cardiac function is currently unknown. In this study, we examined the role of c-Cbl in myocyte death and cardiac function after myocardial ischemia.

Methods and Results—

We show increased c-Cbl expression in human ischemic and dilated cardiomyopathy hearts and in response to pathological stress stimuli in mice. c-Cbl–deficient mice demonstrated a more robust functional recovery after myocardial ischemia/reperfusion injury and significantly reduced myocyte apoptosis and improved cardiac function. Ubiquitination and downregulation of key survival c-Cbl targets, epidermal growth factor receptors and focal adhesion kinase, were significantly reduced in c-Cbl knockout mice. Inhibition of c-Cbl expression or its ubiquitin ligase activity in cardiac myocytes offered protection against H
2
O
2
stress. Interestingly, c-Cbl deletion reduced the risk of death and increased cardiac functional recovery after chronic myocardial ischemia. This beneficial effect of c-Cbl deletion was associated with enhanced neoangiogenesis and increased expression of vascular endothelial growth factor-a and vascular endothelial growth factor receptor type 2 in the infarcted region.

Conclusions—
c-Cbl activation promotes myocyte apoptosis, inhibits angiogenesis, and causes adverse cardiac remodeling after myocardial infarction. These findings point to c-Cbl as a potential therapeutic target for the maintenance of cardiac function and remodeling after myocardial ischemia.