bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of the prognostic value of MMP‐7 in idiopathic pulmonary fibrosis
Authors: Tzouvelekis Argyris , Herazo‐Maya Jose D. , Slade Martin , Chu Jen‐hwa , Deiuliis Giuseppe , Ryu Changwan , Li Qin , Sakamoto Koji , Ibarra Gabriel , Pan Hongyi , Gulati Mridu , Antin‐Ozerkis Danielle , Herzog Erica L. , Kaminski Naftali 
Published: October 2016

AbstractBackground and objectiveIdiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and variable clinical course. Although matrix metalloproteinase‐7 (MMP‐7) is emerging as an important IPF biomarker, reproducibility across studies is unclear. We aimed to determine whether a previously reported prognostic threshold for MMP‐7 was predictive of mortality in an independent cohort of IPF patients.Methods
MMP‐7 concentrations obtained from heparinized plasma samples were determined by ELISA in 97 patients with IPF and 41 healthy controls. The association of the previously published heparin plasma MMP‐7 threshold of 12.1 ng/mL with all‐cause mortality or transplant‐free survival (TFS) was determined, either as an independent biomarker or as part of the modified personal clinical and molecular mortality index (m‐PCMI).Results
MMP‐7 plasma concentrations were significantly higher in IPF patients compared to healthy controls (14.40 ± 6.55 ng/mL vs 6.03 ± 2.51 ng/mL, P < 0.001). The plasma MMP‐7 threshold of 12.1 ng/mL was significantly associated with both all‐cause mortality and TFS (unadjusted Cox proportional hazard ratio (HR) = 25.85 and 15.49, 95% CI: 10.91–61.23 and 5.41–44.34, respectively, P < 0.001). MMP‐7 concentrations, split by 12.1 ng/mL, were significantly (P < 0.05) predictive of mortality and TFS after adjusting for age, gender, smoking and baseline pulmonary function parameters, in a multivariate Cox proportional hazards model. MMP‐7 concentrations were negatively correlated with diffusing lung capacity of carbon monoxide (DLCO) (r = −0.21, P = 0.02), and positively with a mortality risk scoring system (GAP) that combines age, gender, forced vital capacity (FVC) and DLCO
(r = 0.32, P = 0.001).ConclusionThis study confirms that MMP‐7 concentrations could be used to accurately predict outcomes across cohorts and centres, when similar collection protocols are applied.
Humoral and Cellular Responses to a Single Dose of Fendrix in Renal Transplant Recipients with Non‐response to Previous Hepatitis B Vaccination
Authors: Lindemann M. , Zaslavskaya M. , Fiedler M. , Wilde B. , Heinemann F. M. , Heinold A. , Horn P. A. , Witzke O. 
Published: October 2016

AbstractApproximately 70% of kidney transplant recipients are non‐responders to conventional hepatitis B virus (HBV) vaccines. We examined whether Fendrix™, an HBV vaccine containing 3‐O‐desacyl‐4′‐monophosphoryl lipid A (MPL) as adjuvant, could induce HBV immunity in these patients and compared their vaccination efficacy with healthy controls tested previously by the same assays. We selected 35 kidney transplant recipients who had been vaccinated at least thrice against HBV but had never displayed anti‐HBs antibodies. We re‐assessed their anti‐HBs antibody titres and further determined cellular HBV immunity by proliferation assay and interferon (IFN)‐γ ELISpot. Seventeen recipients did neither display humoral nor cellular immunity and could be tested prior to and at month 1 after vaccination. Of note, HLA antigens associated with non‐response to HBV vaccination (HLA‐DRB1*03 and HLA‐DQB1*02) were over‐represented in these 17 recipients. At month 1 after a single vaccination with Fendrix™, we observed a significant increase in anti‐HBs antibodies (P = 0.02). In seven of 17 recipients, we detected anti‐HBs antibodies ≥10 IU/l (10–264), in four HBV‐specific lymphocyte proliferation (stimulation index of 2.6–8.7) and in one specific IFN‐γ responses (12 spots increment). The vaccination response to Fendrix™ was significantly higher (P = 0.035) than the response to HBVaxPro™ in young healthy controls. In summary, the results show that a single vaccination with Fendrix™ could already induce HBV‐specific humoral and/or cellular responses in ten of 17 kidney transplant patients. Thus, Fendrix™ appears as an efficient vaccine in this patient cohort.
Improved pan‐specific prediction of MHC class I peptide binding using a novel receptor clustering data partitioning strategy
Authors: Mattsson A. H. , Kringelum J. V. , Garde C. , Nielsen M. 
Published: October 2016

AbstractPan‐specific prediction of receptor–ligand interaction is conventionally done using machine‐learning methods that integrates information about both receptor and ligand primary sequences. To achieve optimal performance using machine learning, dealing with overfitting and data redundancy is critical. Most often so‐called ligand clustering methods have been used to deal with these issues in the context of pan‐specific receptor–ligand predictions, and the MHC system the approach has proven highly effective for extrapolating information from a limited set of receptors with well characterized binding motifs, to others with no or very limited experimental characterization. The success of this approach has however proven to depend strongly on the similarity of the query molecule to the molecules with characterized specificity using in the machine‐learning process. Here, we outline an alternative strategy with the aim of altering this and construct data sets optimal for training of pan‐specific receptor–ligand predictions focusing on receptor similarity rather than ligand similarity. We show that this receptor clustering method consistently in benchmarks covering affinity predictions, MHC ligand and MHC epitope identification perform better than the conventional ligand clustering method on the alleles with remote similarity to the training set.
Phenotypic Resistance to Disinfectants and Antibiotics in Methicillin‐Resistant Staphylococcus aureus Strains Isolated from Pigs
Authors: Espigares E. , Moreno Roldan E. , Espigares M. , Abreu R. , Castro B. , Dib A. L. , Arias Á. 
Published: October 2016

SummaryThe aim of this research was to study the phenotypic resistances to disinfectants and antibiotics in strains of methicillin‐resistant Staphylococcus aureus (MRSA) obtained from Canary black pigs. Analyses were performed on 54 strains of MRSA, isolated in Canary black pigs from the province of Tenerife (Spain); all of them carried the mecA gene. The strains were isolated by means of nasal swab samples of healthy pigs, collected under veterinarian supervision. Bactericidal activity of antiseptics and disinfectants was tested by means of the dilution–neutralization method. Susceptibility to the disinfectants glutaraldehyde, peracetic acid and silver nitrate was assessed, as well as to the antiseptics chlorhexidine, benzalkonium chloride and povidone iodine. Susceptibility to a wide array of antibiotics representing the main groups was determined by means of the disc diffusion method. All the strains demonstrated susceptibility to the disinfectants tested at the recommended concentration, and even to dilutions equal to or lesser than 1/16. The most effective antiseptic and disinfectant were, respectively, chlorhexidine and silver nitrate. With regard to the antibiotics, the strains proved to be multiresistant. All presented phenotypic resistance to the β‐lactam antibiotics ampicillin, penicillin and cefoxitin, as well as to numerous aminoglycosides, tetracycline and trimethoprim–sulfamethoxazole. It was also observed that 61.1% of the strains were carriers of plasmids. Our results underline that in the strains such as MRSA, which show multiple resistances to antibiotics, the antiseptics and disinfectants show great efficacy. Moreover, as other authors also suggest, for the treatment and prevention of infections caused by MRSA, the use of β‐lactam and aminoglycoside antibiotics may be less effective.
Serology Enhances Molecular Diagnosis of Respiratory Virus Infections Other than Influenza in Children and Adults Hospitalized with Community-Acquired Pneumonia
Authors: Zhang Yange , Sakthivel Senthilkumar K. , Bramley Anna , Jain Seema , Haynes Amber , Chappell James D. , Hymas Weston , Lenny Noel , Patel Anami , Qi Chao , Ampofo Krow , Arnold Sandra R. , Self Wesley H. , Williams Derek J. , Hillyard David , Anderson Evan J. , Grijalva Carlos G. , Zhu Yuwei , Wunderink Richard G. , Edwards Kathryn M. , Pavia Andrew T. , McCullers Jonathan A. , Erdman Dean D. 
Published: October 2016

ABSTRACT
Both molecular and serological assays have been used previously to determine the etiology of community-acquired pneumonia (CAP). However, the extent to which these methods are correlated and the added diagnostic value of serology for respiratory viruses other than influenza virus have not been fully evaluated. Using data from patients enrolled in the Centers for Disease Control and Prevention (CDC) Etiology of Pneumonia in the Community (EPIC) study, we compared real-time reverse transcription-PCR (RT-PCR) and serology for the diagnosis of respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus 1 to 3 (PIV1, PIV2, and PIV3), and adenovirus (AdV) infections. Of 5,126 patients enrolled, RT-PCR and serology test results were available for 2,023, including 1,087 children below the age of 18 years and 936 adults. For RSV, 287 (14.2%) patients were positive by RT-PCR and 234 (11.6%) were positive by serology; for HMPV, 172 (8.5%) tested positive by RT-PCR and 147 (7.3%) by serology; for the PIVs, 94 (4.6%) tested positive by RT-PCR and 92 (4.6%) by serology; and for AdV, 111 (5.5%) tested positive by RT-PCR and 62 (3.1%) by serology. RT-PCR provided the highest number of positive detections overall, but serology increased diagnostic yield for RSV (by 11.8%), HMPV (by 25.0%), AdV (by 32.4%), and PIV (by 48.9%). The method concordance estimated by Cohen's kappa coefficient (κ) ranged from good (for RSV; κ = 0.73) to fair (for AdV; κ = 0.27). Heterotypic seroresponses observed between PIVs and persistent low-level AdV shedding may account for the higher method discordance observed with each of these viruses. Serology can be a helpful adjunct to RT-PCR for research-based assessment of the etiologic contribution of respiratory viruses other than influenza virus to CAP.
Performance of Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry for Identifying Clinical Malassezia Isolates
Authors: Denis Julie , Machouart Marie , Morio Florent , Sabou Marcela , Kauffmann-LaCroix Catherine , Contet-Audonneau Nelly , Candolfi Ermanno , Letscher-Bru Valérie 
Published: October 2016

ABSTRACT

The genus
Malassezia
comprises commensal yeasts on human skin. These yeasts are involved in superficial infections but are also isolated in deeper infections, such as fungemia, particularly in certain at-risk patients, such as neonates or patients with parenteral nutrition catheters. Very little is known about
Malassezia
epidemiology and virulence. This is due mainly to the difficulty of distinguishing species. Currently, species identification is based on morphological and biochemical characteristics. Only molecular biology techniques identify species with certainty, but they are time-consuming and expensive. The aim of this study was to develop and evaluate a matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) database for identifying
Malassezia
species by mass spectrometry. Eighty-five
Malassezia
isolates from patients in three French university hospitals were investigated. Each strain was identified by internal transcribed spacer sequencing. Forty-five strains of the six species
Malassezia
furfur
,
M. sympodialis
,
M. slooffiae
,
M. globosa
,
M. restricta
, and
M. pachydermatis
allowed the creation of a MALDI-TOF database. Forty other strains were used to test this database. All strains were identified by our
Malassezia
database with log scores of >2.0, according to the manufacturer's criteria. Repeatability and reproducibility tests showed a coefficient of variation of the log score values of <10%. In conclusion, our new
Malassezia
database allows easy, fast, and reliable identification of
Malassezia
species. Implementation of this database will contribute to a better, more rapid identification of
Malassezia
species and will be helpful in gaining a better understanding of their epidemiology.
Potent Inhibition of Human Cytomegalovirus by Modulation of Cellular SNARE Syntaxin 5
Authors: Cruz Linda , Streck Nicholas T. , Ferguson Kevin , Desai Trisha , Desai Dhimant H. , Amin Shantu G. , Buchkovich Nicholas J. 
Published: October 2016

ABSTRACT
Formation of the cytoplasmic viral assembly compartment (cVAC) is an important step for efficient human cytomegalovirus (HCMV) assembly. To do this, the virus must alter and repurpose the normal cellular balance of membrane and protein flux, a process that is not well understood. Although a recent screen identified three viral proteins essential for cVAC formation, less is known about the contribution of cellular factors. We show that HCMV infection increases the protein level of a cellular trafficking factor, syntaxin 5 (STX5), a member of the syntaxin family of SNARE proteins. STX5 is recruited to the cVAC in infected cells and is required for the efficient production of infectious virions. We find that STX5 is important for normal cVAC morphology and the proper localization of viral proteins. A previously identified inhibitor of trafficking, Retro94, causes the mislocalization of STX5, an altered cVAC morphology, and dispersal of viral proteins. The presence of Retro94 results in severely impaired production of infectious virions, with a decrease as great as 5 logs. We show that this inhibition is conserved among different strains of HCMV and the various cell types that support infection, as well as for murine CMV. Thus, our data identify a key cellular trafficking factor important for supporting HCMV infection.

IMPORTANCE
Human cytomegalovirus (HCMV) infection causes severe disease and mortality in immunocompromised individuals, including organ transplant and AIDS patients. In addition, infection of a developing fetus may result in lifelong complications such as deafness and learning disabilities. Understanding in detail the processes involved in HCMV replication is important for developing novel treatments. One of these essential processes, assembly of infectious virions, takes places in the cytoplasmic viral assembly compartment. We identify a cellular protein, syntaxin 5, important for generating this compartment, and show that it is required for the efficient production of infectious virions. We also show that a small molecule that disrupts this protein also significantly reduces the amount of infectious virions that are generated. Thus, by pinpointing a cellular protein that is important in the replication cycle of HCMV, we identified a novel target that can be pursued for therapeutic intervention.
Host Cellular Protein TRAPPC6AΔ Interacts with Influenza A Virus M2 Protein and Regulates Viral Propagation by Modulating M2 Trafficking
Authors: Zhu Pengyang , Liang Libin , Shao Xinyuan , Luo Weiyu , Jiang Shuitao , Zhao Qingqing , Sun Nan , Zhao Yuhui , Li Junping , Wang Jinguang , Zhou Yuan , Zhang Jie , Wang Guangwen , Jiang Li , Chen Hualan , Li Chengjun 
Published: October 2016

ABSTRACT

Influenza A virus (IAV) matrix protein 2 (M2) plays multiple roles in the early and late phases of viral infection. Once synthesized, M2 is translocated to the endoplasmic reticulum (ER), travels to the Golgi apparatus, and is sorted at the
trans
-Golgi network (TGN) for transport to the apical plasma membrane, where it functions in virus budding. We hypothesized that M2 trafficking along with its secretory pathway must be finely regulated, and host factors could be involved in this process. However, no studies examining the role of host factors in M2 posttranslational transport have been reported. Here, we used a yeast two-hybrid (Y2H) system to screen for host proteins that interact with the M2 protein and identified transport protein particle complex 6A (TRAPPC6A) as a potential binding partner. We found that both TRAPPC6A and its N-terminal internal-deletion isoform, TRAPPC6A delta (TRAPPC6AΔ), interact with M2. Truncation and mutation analyses showed that the highly conserved leucine residue at position 96 of M2 is critical for mediating this interaction. The role of TRAPPC6AΔ in the viral life cycle was investigated by the knockdown of endogenous TRAPPC6AΔ with small interfering RNA (siRNA) and by generating a recombinant virus that was unable to interact with TRAPPC6A/TRAPPC6AΔ. The results indicated that TRAPPC6AΔ, through its interaction with M2, slows M2 trafficking to the apical plasma membrane, favors viral replication
in vitro
, and positively modulates virus virulence in mice.

IMPORTANCE
The influenza A virus M2 protein regulates the trafficking of not only other proteins but also itself along the secretory pathway. However, the host factors involved in the regulation of the posttranslational transport of M2 are largely unknown. In this study, we identified TRAPPC6A and its N-terminal internal-deletion isoform, TRAPPC6AΔ, as interacting partners of M2. We found that the leucine (L) residue at position 96 of M2 is critical for mediating this interaction, which leads us to propose that the high level of conservation of 96L is a consequence of M2 adaptation to its interacting host factor TRAPPC6A/TRAPPC6AΔ. Importantly, we discovered that TRAPPC6AΔ can positively regulate viral replication
in vitro
by modulating M2 trafficking to the plasma membrane.
HIV-1 Tat Recruits HDM2 E3 Ligase To Target IRF-1 for Ubiquitination and Proteasomal Degradation
Authors: Remoli Anna Lisa , Marsili Giulia , Perrotti Edvige , Acchioni Chiara , Sgarbanti Marco , Borsetti Alessandra , Hiscott John , Battistini Angela 
Published: October 2016

ABSTRACTIn addition to its ability to regulate HIV-1 promoter activation, the viral transactivator Tat also functions as a determinant of pathogenesis and disease progression by directly and indirectly modulating the host anti-HIV response, largely through the capacity of Tat to interact with and modulate the activities of multiple host proteins. We previously demonstrated that Tat modulated both viral and host transcriptional machinery by interacting with the cellular transcription factor interferon regulatory factor 1 (IRF-1). In the present study, we investigated the mechanistic basis and functional significance of Tat−IRF-1 interaction and demonstrate that Tat dramatically decreased IRF-1 protein stability. To accomplish this, Tat exploited the cellular HDM2 (human double minute 2 protein) ubiquitin ligase to accelerate IRF-1 proteasome-mediated degradation, resulting in a quenching of IRF-1 transcriptional activity during HIV-1 infection. These data identify IRF-1 as a new target of Tat-induced modulation of the cellular protein machinery and reveal a new strategy developed by HIV-1 to evade host immune responses.IMPORTANCECurrent therapies have dramatically reduced morbidity and mortality associated with HIV infection and have converted infection from a fatal pathology to a chronic disease that is manageable via antiretroviral therapy. Nevertheless, HIV-1 infection remains a challenge, and the identification of useful cellular targets for therapeutic intervention remains a major goal. The cellular transcription factor IRF-1 impacts various physiological functions, including the immune response to viral infection. In this study, we have identified a unique mechanism by which HIV-1 evades IRF-1-mediated host immune responses and show that the viral protein Tat accelerates IRF-1 proteasome-mediated degradation and inactivates IRF-1 function. Restoration of IRF-1 functionality may thus be regarded as a potential strategy to reinstate both a direct antiviral response and a more broadly acting immune regulatory circuit.
Identification of Residues in the Lipopolysaccharide ABC Transporter That Coordinate ATPase Activity with Extractor Function
Authors: Simpson Brent W. , Owens Tristan W. , Orabella Matthew J. , Davis Rebecca M. , May Janine M. , Trauger Sunia A. , Kahne Daniel , Ruiz Natividad 
Published: October 2016

ABSTRACT

The surface of most Gram-negative bacteria is covered with lipopolysaccharide (LPS), creating a permeability barrier against toxic molecules, including many antimicrobials. To assemble LPS on their surface, Gram-negative bacteria must extract newly synthesized LPS from the inner membrane, transport it across the aqueous periplasm, and translocate it across the outer membrane. The LptA to -G proteins assemble into a transenvelope complex that transports LPS from the inner membrane to the cell surface. The Lpt system powers LPS transport from the inner membrane by using a poorly characterized ATP-binding cassette system composed of the ATPase LptB and the transmembrane domains LptFG. Here, we characterize a cluster of residues in the groove region of LptB that is important for controlling LPS transport. We also provide the first functional characterization of LptFG and identify their coupling helices that interact with the LptB groove. Substitutions at conserved residues in these coupling helices compromise both the assembly and function of the LptB
2
FG complex. Defects in LPS transport conferred by alterations in the LptFG coupling helices can be rescued by changing a residue in LptB that is adjacent to functionally important residues in the groove region. This suppression is achieved by increasing the ATPase activity of the LptB
2
FG complex. Taken together, these data identify a specific binding site in LptB for the coupling helices of LptFG that is responsible for coupling of ATP hydrolysis by LptB with LptFG function to achieve LPS extraction.

IMPORTANCE
Lipopolysaccharide (LPS) is synthesized at the cytoplasmic membrane of Gram-negative bacteria and transported across several compartments to the cell surface, where it forms a barrier that protects these organisms from antibiotics. The LptB
2
FG proteins form an ATP-binding cassette (ABC) transporter that uses energy from ATP hydrolysis in the cytoplasm to facilitate extraction of LPS from the outer face of the cytoplasmic membrane prior to transport to the cell surface. How ATP hydrolysis is coupled with LPS release from the membrane is not understood. We have identified residues at the interface between the ATPase and the transmembrane domains of this heteromeric ABC complex that are important for LPS transport, some of which coordinate ATPase activity with LPS release.