bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and
In Vivo
Evaluation of a Novel Histatin-5 Bioadhesive Hydrogel Formulation against Oral Candidiasis
Authors: Kong Eric F. , Tsui Christina , Boyce Heather , Ibrahim Ahmed , Hoag Stephen W. , Karlsson Amy J. , Meiller Timothy F. , Jabra-Rizk Mary Ann 
Published: November 2015

ABSTRACT

Oral candidiasis (OC), caused by the fungal pathogen
Candida albicans
, is the most common opportunistic infection in HIV
+
individuals and other immunocompromised populations. The dramatic increase in resistance to common antifungals has emphasized the importance of identifying unconventional therapeutic options. Antimicrobial peptides have emerged as promising candidates for therapeutic intervention due to their broad antimicrobial properties and lack of toxicity. Histatin-5 (Hst-5) specifically has exhibited potent anticandidal activity indicating its potential as an antifungal agent. To that end, the goal of this study was to design a biocompatible hydrogel delivery system for Hst-5 application. The bioadhesive hydroxypropyl methylcellulose (HPMC) hydrogel formulation was developed for topical oral application against OC. The new formulation was evaluated
in vitro
for gel viscosity, Hst-5 release rate from the gel, and killing potency and, more importantly, was tested
in vivo
in our mouse model of OC. The findings demonstrated a controlled sustained release of Hst-5 from the polymer and rapid killing ability. Based on viable
C. albicans
counts recovered from tongues of treated and untreated mice, three daily applications of the formulation beginning 1 day postinfection with
C. albicans
were effective in protection against development of OC. Interestingly, in some cases, Hst-5 was able to clear existing lesions as well as associated tissue inflammation. These findings were confirmed by histopathology analysis of tongue tissue. Coupled with the lack of toxicity as well as anti-inflammatory and wound-healing properties of Hst-5, the findings from this study support the progression and commercial feasibility of using this compound as a novel therapeutic agent.
Susceptibility of Meningococcal Strains Responsible for Two Serogroup B Outbreaks on U.S. University Campuses to Serum Bactericidal Activity Elicited by the MenB-4C Vaccine
Authors: Rossi Raffaella , Beernink Peter T. , Giuntini Serena , Granoff Dan M. 
Published: November 2015

ABSTRACTIn 2013 and 2014, two U.S. universities had meningococcal serogroup B outbreaks (a total of 14 cases) caused by strains from two different clonal complexes. To control the outbreaks, students were immunized with a serogroup B meningococcal vaccine (Novartis) that was not yet licensed in the United States. The vaccine (referred to as MenB-4C) contains four components capable of eliciting bactericidal activity. Both outbreak strains had high expression levels of two of the vaccine antigens (subfamily B factor H binding protein [FHbp] and neisserial heparin binding antigen [NHba]); the university B outbreak strain also had moderate expression of a third antigen, NadA. We investigated the bactericidal activity of sera from mice immunized with FHbp, NHba, or NadA and sera from MenB-4C-immunized infant macaques and an adult human. The postimmunization bactericidal activity of the macaque or human serum against isolates from university B with FHbp identification (ID) 1 that exactly matched the vaccine FHbp sequence variant was 8- to 21-fold higher than that against isolates from university A with FHbp ID 276 (96% identity to the vaccine antigen). Based on the bactericidal activity of mouse antisera to FHbp, NadA, or NHba and macaque or human postimmunization serum that had been depleted of anti-FHbp antibody, the bactericidal activity against both outbreak strains largely or entirely resulted from antibodies to FHbp. Thus, despite the high level of strain expression of FHbp from a subfamily that matched the vaccine antigen, there can be large differences in anti-FHbp bactericidal activity induced by MenB-4C vaccination. Further, strains with moderate to high NadA and/or NHba expression can be resistant to anti-NadA or anti-NHba bactericidal activity elicited by MenB-4C vaccination.
The Vaccine Candidate Substrate Binding Protein SBP2 Plays a Key Role in Arginine Uptake, Which Is Required for Growth of Moraxella catarrhalis
Authors: Otsuka Taketo , Kirkham Charmaine , Brauer Aimee , Koszelak-Rosenblum Mary , Malkowski Michael G. , Murphy Timothy F. 
Published: November 2015

ABSTRACT

Moraxella catarrhalis
is an exclusively human pathogen that is an important cause of otitis media in children and lower respiratory tract infections in adults with chronic obstructive pulmonary disease. A vaccine to prevent
M. catarrhalis
infections would have an enormous global impact in reducing morbidity resulting from these infections. Substrate binding protein 2 (SBP2) of an ABC transporter system has recently been identified as a promising vaccine candidate antigen on the bacterial surface of
M. catarrhalis
. In this study, we showed that SBP1, -2, and -3 individually bind different basic amino acids with exquisite specificity. We engineered mutants that each expressed a single SBP from this gene cluster and showed in growth experiments that SBP1, -2, and -3 serve a nutritional function through acquisition of amino acids for the bacterium. SBP2 mediates uptake of arginine, a strict growth requirement of
M. catarrhalis
. Adherence and invasion assays demonstrated that SBP1 and SBP3 play a role in invasion of human respiratory epithelial cells, consistent with a nutritional role in intracellular survival in the human respiratory tract. This work demonstrates that the SBPs of an ABC transporter system function in the uptake of basic amino acids to support growth of
M. catarrhalis
. The critical role of SBP2 in arginine uptake may contribute to its potential as a vaccine antigen.
The Chromosome-Encoded Hypothetical Protein TC0668 Is an Upper Genital Tract Pathogenicity Factor of Chlamydia muridarum
Authors: Conrad Turner Allen , Gong Siqi , Yang Zhangsheng , Matulich Patrick , Keck Jonathon , Beltrami Noah , Chen Chaoqun , Zhou Zhou , Dai Jin , Zhong Guangming 
Published: November 2015

ABSTRACT

We previously associated a missense mutation of the
tc0668
gene of serial
in vitro
-passaged
Chlamydia muridarum
, a murine model of human urogenital
C. trachomatis
, with severely attenuated disease development in the upper genital tract of female mice. Since these mutants also contained a TC0237 Q117E missense mutation that enhances their
in vitro
infectivity, an effort was made here to isolate and characterize a
tc0668
single mutant to determine its individual contribution to urogenital pathogenicity. Detailed genetic analysis of
C. muridarum
passages revealed a truncated variant with a G216* nonsense mutation of the 408-amino-acid TC0668 protein that does not produce a detectable product. Intracellular growth and infectivity of
C. muridarum in vitro
remain unaffected in the absence of TC0668. Intravaginal inoculation of the TC0668 null mutant into C3H/HeJ mice results in a typical course of lower genital tract infection but, unlike a pathogenic isogenic control, is unable to elicit significant chronic inflammation of the oviduct and fails to induce hydrosalpinx. Thus, TC0668 is demonstrated as an important chromosome-encoded urogenital pathogenicity factor of
C. muridarum
and the first with these characteristics to be discovered for a
Chlamydia
pathogen.
Enhanced Direct Major Histocompatibility Complex Class I Self-Antigen Presentation Induced by Chlamydia Infection
Authors: Cram Erik D. , Simmons Ryan S. , Palmer Amy L. , Hildebrand William H. , Rockey Daniel D. , Dolan Brian P. 
Published: November 2015

ABSTRACTThe direct major histocompatibility complex (MHC) class I antigen presentation pathway ensures intracellular peptides are displayed at the cellular surface for recognition of infected or transformed cells by CD8+cytotoxic T lymphocytes.Chlamydiaspp. are obligate intracellular bacteria and, as such, should be targeted by CD8+T cells. It is likely thatChlamydiaspp. have evolved mechanisms to avoid the CD8+killer T cell responses by interfering with MHC class I antigen presentation. Using a model system of self-peptide presentation which allows for posttranslational control of the model protein's stability, we tested the ability of variousChlamydiaspecies to alter direct MHC class I antigen presentation. Infection of the JY lymphoblastoid cell line limited the accumulation of a model host protein and increased presentation of the model-protein-derived peptides. Enhanced self-peptide presentation was detected only when presentation was restricted todefectiveribosomalproducts, or DRiPs, and total MHC class I levels remained unaltered. Skewed antigen presentation was dependent on a bacterial synthesized component, as evidenced by reversal of the observed phenotype upon preventing bacterial transcription, translation, and the inhibition of bacterial lipooligosaccharide synthesis. These data suggest thatChlamydiaspp. have evolved to alter the host antigen presentation machinery to favor presentation of defective and rapidly degraded forms of self-antigen, possibly as a mechanism to diminish the presentation of peptides derived from bacterial proteins.
Regulation of a Protein Acetyltransferase in Myxococcus xanthus by the Coenzyme NADP
+
Authors: Liu Xin-Xin , Liu Wei-bing , Ye Bang-Ce 
Published: November 2015

ABSTRACT

NADP
+
is a vital cofactor involved in a wide variety of activities, such as redox potential and cell death. Here, we show that NADP
+
negatively regulates an acetyltransferase from
Myxococcus xanthus
, Mxan_3215 (
Mx
Kat), at physiologic concentrations.
Mx
Kat possesses an NAD(P)-binding domain fused to the Gcn5-type
N
-acetyltransferase (GNAT) domain. We used isothermal titration calorimetry (ITC) and a coupled enzyme assay to show that NADP
+
bound to
Mx
Kat and that the binding had strong effects on enzyme activity. The Gly11 residue of
Mx
Kat was confirmed to play an important role in NADP
+
binding using site-directed mutagenesis and circular dichroism spectrometry. In addition, using mass spectrometry, site-directed mutagenesis, and a coupling enzymatic assay, we demonstrated that
Mx
Kat acetylates acetyl coenzyme A (acetyl-CoA) synthetase (Mxan_2570) at Lys622 in response to changes in NADP
+
concentration. Collectively, our results uncovered a mechanism of protein acetyltransferase regulation by the coenzyme NADP
+
at physiological concentrations, suggesting a novel signaling pathway for the regulation of cellular protein acetylation.

IMPORTANCE
Microorganisms have developed various protein posttranslational modifications (PTMs), which enable cells to respond quickly to changes in the intracellular and extracellular milieus. This work provides the first biochemical characterization of a protein acetyltransferase (
Mx
Kat) that contains a fusion between a GNAT domain and NADP
+
-binding domain with Rossmann folds, and it demonstrates a novel signaling pathway for regulating cellular protein acetylation in
M. xanthus
. We found that NADP
+
specifically binds to the Rossmann fold of
Mx
Kat and negatively regulates its acetyltransferase activity. This finding provides novel insight for connecting cellular metabolic status (NADP
+
metabolism) with levels of protein acetylation, and it extends our understanding of the regulatory mechanisms underlying PTMs.
Biased Gene Conversion in Rhizobium etli Is Caused by Preferential Double-Strand Breaks on One of the Recombining Homologs
Authors: Yáñez-Cuna Fares Osam , Castellanos Mildred , Romero David 
Published: November 2015

ABSTRACT

Gene conversion, the nonreciprocal transfer of information during homologous recombination, is the main process that maintains identity between members of multigene families. Gene conversion in the nitrogenase (
nifH
) multigene family of
Rhizobium etli
was analyzed by using a two-plasmid system, where each plasmid carried a copy of
nifH
. One of the
nifH
copies was modified, creating restriction fragment length polymorphisms (RFLPs) spaced along the gene. Once the modified plasmid was introduced into
R. etli
, selection was done for cointegration with a resident plasmid lacking the RFLPs. Most of the cointegrate molecules harbor gene conversion events, biased toward a gain of RFLPs. This bias may be explained under the double-strand break repair model by proposing that the
nifH
gene lacking the RFLPs suffers a DNA double-strand break, so the incoming plasmid functions as a template for repairing the homolog on the resident plasmid. To support this proposal, we cloned an SceI site into the
nifH
homolog that had the RFLPs used for scoring gene conversion.
In vivo
expression of the meganuclease I-SceI allowed the generation of a double-strand break on this homolog. Upon introduction of this modified plasmid into an
R. etli
strain lacking I-SceI, biased gene conversion still favored the retention of markers on the incoming plasmid. In contrast, when the recipient strain ectopically expressed I-SceI, a dramatic reversal in gene conversion bias was seen, favoring the preservation of resident sequences. These results show that biased gene conversion is caused by preferential double-strand breaks on one of the recombining homologs.

IMPORTANCE
In this work, we analyzed gene conversion by using a system that entails horizontal gene transfer followed by homologous recombination in the recipient cell. Most gene conversion events are biased toward the acquisition of the incoming sequences, ranging in size from 120 bp to 800 bp. This bias is due to preferential cutting of resident DNA and can be reversed upon introduction of a double-strand break on the incoming sequence. Since conditions used in this work are similar to those in horizontal gene transfer, it provides evidence that, upon transfer, the resident DNA preferentially acquires gene variants.
Walnut ingestion in adults at risk for diabetes: effects on body composition, diet quality, and cardiac risk measures
Authors: Njike Valentine Yanchou , Ayettey Rockiy , Petraro Paul , Treu Judith A , Katz David L 
Published: November 2015

BackgroundDespite their energy density, walnuts can be included in the diet without adverse effects on weight or body composition. The effect of habitual walnut intake on total calorie intake is not well studied. Effects on overall diet quality have not been reported.MethodsRandomized, controlled, modified Latin square parallel design study with 2 treatment arms. The 112 participants were randomly assigned to a diet with or without dietary counseling to adjust calorie intake. Within each treatment arm, participants were further randomized to 1 of the 2 possible sequence permutations to receive a walnut-included diet with 56 g (providing 366 kcal) of walnuts per day and a walnut-excluded diet. Participants were assessed for diet quality, body composition, and cardiac risk measures.ResultsWhen compared with a walnut-excluded diet, a walnut-included diet for 6 months, with or without dietary counseling to adjust caloric intake, significantly improved diet quality as measured by the Healthy Eating Index 2010 (9.14±17.71 vs 0.40±15.13; p=0.02 and 7.02±15.89 vs -5.92±21.84; p=0.001, respectively). Endothelial function, total and low-density lipoprotein (LDL) cholesterol improved significantly from baseline in the walnut-included diet. Body mass index, percent body fat, visceral fat, fasting glucose, glycated hemoglobin, and blood pressure did not change significantly.ConclusionsThe inclusion of walnuts in an ad libitum diet for 6 months, with or without dietary counseling to adjust calorie intake, significantly improved diet quality, endothelial function, total and LDL cholesterol, but had no effects on anthropometric measures, blood glucose level, and blood pressure.Trial registration number:NCT02330848
Prevalence of foot disease and risk factors in general inpatient populations: a systematic review and meta-analysis
Authors: Lazzarini Peter A , Hurn Sheree E , Fernando Malindu E , Jen Scott D , Kuys Suzanne S , Kamp Maarten C , Reed Lloyd F 
Published: November 2015

ObjectiveTo systematically review studies reporting the prevalence in general adult inpatient populations of foot disease disorders (foot wounds, foot infections, collective ‘foot disease’) and risk factors (peripheral arterial disease (PAD), peripheral neuropathy (PN), foot deformity).MethodsA systematic review of studies published between 1980 and 2013 was undertaken using electronic databases (MEDLINE, EMBASE and CINAHL). Keywords and synonyms relating to prevalence, inpatients, foot disease disorders and risk factors were used. Studies reporting foot disease or risk factor prevalence data in general inpatient populations were included. Included study's reference lists and citations were searched and experts consulted to identify additional relevant studies. 2 authors, blinded to each other, assessed the methodological quality of included studies. Applicable data were extracted by 1 author and checked by a second author. Prevalence proportions and SEs were calculated for all included studies. Pooled prevalence estimates were calculated using random-effects models where 3 eligible studies were available.ResultsOf the 4972 studies initially identified, 78 studies reporting 84 different cohorts (total 60 231 517 participants) were included. Foot disease prevalence included: foot wounds 0.01–13.5% (70 cohorts), foot infections 0.05–6.4% (7 cohorts), collective foot disease 0.2–11.9% (12 cohorts). Risk factor prevalence included: PAD 0.01–36.0% (10 cohorts), PN 0.003–2.8% (6 cohorts), foot deformity was not reported. Pooled prevalence estimates were only able to be calculated for pressure ulcer-related foot wounds 4.6% (95% CI 3.7% to 5.4%)), diabetes-related foot wounds 2.4% (1.5% to 3.4%), diabetes-related foot infections 3.4% (0.2% to 6.5%), diabetes-related foot disease 4.7% (0.3% to 9.2%). Heterogeneity was high in all pooled estimates (I2=94.2–97.8%, p<0.001).ConclusionsThis review found high heterogeneity, yet suggests foot disease was present in 1 in every 20 inpatients and a major risk factor in 1 in 3 inpatients. These findings are likely an underestimate and more robust studies are required to provide more precise estimates.
Diffusion of anti-VEGF injections in the Portuguese National Health System
Authors: Marques Ana Patrícia , Macedo António Filipe , Perelman Julian , Aguiar Pedro , Rocha-Sousa Amândio , Santana Rui 
Published: November 2015

ObjectivesTo analyse the temporal and geographical diffusion of antivascular endothelial growth factor (anti-VEGF) interventions, and its determinants in a National Health System (NHS).SettingNHS Portuguese hospitals.ParticipantsAll inpatient and day cases related to eye diseases at all Portuguese public hospitals for the period 2002–2012 were selected on the basis of four International Classification of Diseases 9th revision, Clinical Modification (ICD-9-CM) codes for procedures: 1474, 1475, 1479 and 149.Primary and secondary outcome measuresWe measured anti-VEGF treatment rates by year and county. The determinants of the geographical diffusion were investigated using generalised linear modelling.ResultsWe analysed all hospital discharges from all NHS hospitals in Portugal (98 408 hospital discharges corresponding to 57 984 patients). National rates of hospitals episodes for the codes for procedures used were low before anti-VEGF approval in 2007 (less than 12% of hospital discharges). Between 2007 and 2012, the rates of hospital episodes related to the introduction of anti-VEGF injections increased by 27% per year. Patients from areas without ophthalmology departments received fewer treatments than those from areas with ophthalmology departments. The availability of an ophthalmology department in the county increased the rates of hospital episodes by 243%, and a 100-persons greater density per km2raised the rates by 11%.ConclusionsOur study shows a large but unequal diffusion of anti-VEGF treatments despite the universal coverage and very low copayments. The technological innovation in ophthalmology may thus produce unexpected inequalities related to financial constraints unless the implementation of innovative techniques is planned and regulated.
Resuscitative endovascular balloon occlusion of the aorta (REBOA): a population based gap analysis of trauma patients in England and Wales
Authors: Barnard Edward Benjamin Graham , Morrison Jonathan James , Madureira Ricardo Mondoni , Lendrum Robbie , Fragoso-Iñiguez Marisol , Edwards Antoinette , Lecky Fiona , Bouamra Omar , Lawrence Thomas , Jansen Jan Olaf 
Published: November 2015

IntroductionNon-compressible torso haemorrhage (NCTH) carries a high mortality in trauma as many patients exsanguinate prior to definitive haemorrhage control. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an adjunct that has the potential to bridge patients to definitive haemostasis. However, the proportion of trauma patients in whom REBOA may be utilised is unknown.MethodsWe conducted a population based analysis of 2012–2013 Trauma Audit and Research Network (TARN) data. We identified the number of patients in whom REBOA may have been utilised, defined by an Abbreviated Injury Scale score ≥3 to abdominal solid organs, abdominal or pelvic vasculature, pelvic fracture with ring disruption or proximal traumatic lower limb amputation, together with a systolic blood pressure <90 mm Hg. Patients with non-compressible haemorrhage in the mediastinum, axilla, face or neck were excluded.ResultsDuring 2012–2013, 72 677 adult trauma patients admitted to hospitals in England and Wales were identified. 397 patients had an indication(s) and no contraindications for REBOA with evidence of haemorrhagic shock: 69% men, median age 43 years and median Injury Severity Score 32. Overall mortality was 32%. Major trauma centres (MTCs) received the highest concentration of potential REBOA patients, and would be anticipated to receive a patient in whom REBOA may be utilised every 95 days, increasing to every 46 days in the 10 MTCs with the highest attendance of this injury type.ConclusionsThis TARN database analysis has identified a small group of severely injured, resource intensive patients with a highly lethal injury that is theoretically amenable to REBOA. The highest density of these patients is seen at MTCs, and as such a planned evaluation of REBOA should be further considered in these hospitals.