bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of VT-1161 for Treatment of Coccidioidomycosis in Murine Infection Models
Authors: Shubitz Lisa F. , Trinh Hien T. , Galgiani John N. , Lewis Maria L. , Fothergill Annette W. , Wiederhold Nathan P. , Barker Bridget M. , Lewis Eric R. G. , Doyle Adina L. , Hoekstra William J. , Schotzinger Robert J. , Garvey Edward P. 
Published: September 2015

ABSTRACT

Coccidioidomycosis, or valley fever, is a growing health concern endemic to the southwestern United States. Safer, more effective, and more easily administered drugs are needed especially for severe, chronic, or unresponsive infections. The novel fungal CYP51 inhibitor VT-1161 demonstrated
in vitro
antifungal activity, with MIC
50
and MIC
90
values of 1 and 2 μg/ml, respectively, against 52
Coccidioides
clinical isolates. In the initial animal study, oral doses of 10 and 50 mg/kg VT-1161 significantly reduced fungal burdens and increased survival time in a lethal respiratory model in comparison with treatment with a placebo (
P
< 0.001). Oral doses of 25 and 50 mg/kg VT-1161 were similarly efficacious in the murine central nervous system (CNS) model compared to placebo treatment (
P
< 0.001). All comparisons with the positive-control drug, fluconazole at 50 mg/kg per day, demonstrated either statistical equivalence or superiority of VT-1161. VT-1161 treatment also prevented dissemination of infection from the original inoculation site to a greater extent than fluconazole. Many of these
in vivo
results can be explained by the long half-life of VT-1161 leading to sustained high plasma levels. Thus, the efficacy and pharmacokinetics of VT-1161 are attractive characteristics for long-term treatment of this serious fungal infection.
Antibiotic Selection Pressure Determination through Sequence-Based Metagenomics
Authors: Willmann Matthias , El-Hadidi Mohamed , Huson Daniel H. , Schütz Monika , Weidenmaier Christopher , Autenrieth Ingo B. , Peter Silke 
Published: September 2015

ABSTRACT

The human gut forms a dynamic reservoir of antibiotic resistance genes (ARGs). Treatment with antimicrobial agents has a significant impact on the intestinal resistome and leads to enhanced horizontal transfer and selection of resistance. We have monitored the development of intestinal ARGs over a 6-day course of ciprofloxacin (Cp) treatment in two healthy individuals by using sequenced-based metagenomics and different ARG quantification methods. Fixed- and random-effect models were applied to determine the change in ARG abundance per defined daily dose of Cp as an expression of the respective selection pressure. Among various shifts in the composition of the intestinal resistome, we found in one individual a strong positive selection for class D beta-lactamases which were partly located on a mobile genetic element. Furthermore, a trend to a negative selection has been observed with class A beta-lactamases (−2.66 hits per million sample reads/defined daily dose;
P
= 0.06). By 4 weeks after the end of treatment, the composition of ARGs returned toward their initial state but to a different degree in both subjects. We present here a novel analysis algorithm for the determination of antibiotic selection pressure which can be applied in clinical settings to compare therapeutic regimens regarding their effect on the intestinal resistome. This information is of critical importance for clinicians to choose antimicrobial agents with a low selective force on their patients' intestinal ARGs, likely resulting in a diminished spread of resistance and a reduced burden of hospital-acquired infections with multidrug-resistant pathogens.
Treatment of Experimental Candida Sepsis with a Janus Kinase Inhibitor Controls Inflammation and Prolongs Survival
Authors: Tsirigotis P. , Papanikolaou N. , Elefanti A. , Konstantinou P. , Gkirkas K. , Rontogianni D. , Siafakas N. , Karakitsos P. , Roilides E. , Dimitriadis G. , Zerva L. , Meletiadis J. 
Published: September 2015

ABSTRACT

Janus kinases (JAK) are intracellular tyrosine kinases that transduce cytokine-mediated signals to the nucleus, promoting gene expression. Cytokines play a major role in microbial sepsis, which is often associated with uncontrolled inflammation leading to death. JAK inhibitors have been used for the treatment of several autoimmune diseases by modulating immune response, but they have never been tested against microbial sepsis. Ruxolitinib is a small-molecule inhibitor of JAK1/2 proteins, which are involved in the downstream signaling pathway of the vast majority of proinflammatory and anti-inflammatory cytokines. We therefore studied the effect of ruxolitinib in a mouse model of sepsis due to
Candida albicans
. When ruxolitinib therapy (50 mg/kg [of body weight]/day) was started 1 day before infection, the median survival time was reduced by 3 days, the fungal loads in all organs were higher, the inflammation was significantly less, and serum tumor necrosis factor alpha (TNF-α) and interleukin 10 (IL-10) levels and IL-10/TNF-α ratios were higher than in controls. When ruxolitinib therapy (50 to 1.5 mg/kg/day) was started 1 day after infection, an inverted-U relationship was found, with 6.25 mg/kg/day prolonging median survival time by 6 days, resulting in similar fungal loads, less inflammation, and similar cytokine levels but higher IL-10/TNF-α ratios than the controls. The optimal dose of ruxolitinib controlled infection and prolonged survival with less inflammation than in control animals. Administration of JAK inhibitors may be a promising therapeutic adjunct that needs further investigation.
Elucidating the Role of Residue 67 in IMP-Type Metallo-β-Lactamase Evolution
Authors: LaCuran Alecander E. , Pegg Kevin M. , Liu Eleanor M. , Bethel Christopher R. , Ai Ni , Welsh William J. , Bonomo Robert A. , Oelschlaeger Peter 
Published: September 2015

ABSTRACT

Antibiotic resistance in bacteria is ever changing and adapting, as once-novel β-lactam antibiotics are losing their efficacy, primarily due to the production of β-lactamases. Metallo-β-lactamases (MBLs) efficiently inactivate a broad range of β-lactam antibiotics, including carbapenems, and are often coexpressed with other antibacterial resistance factors. The rapid dissemination of MBLs and lack of novel antibacterials pose an imminent threat to global health. In an effort to better counter these resistance-conferring β-lactamases, an investigation of their natural evolution and resulting substrate specificity was employed. In this study, we elucidated the effects of different amino acid substitutions at position 67 in IMP-type MBLs on the ability to hydrolyze and confer resistance to a range of β-lactam antibiotics. Wild-type β-lactamases IMP-1 and IMP-10 and mutants IMP-1-V67A and IMP-1-V67I were characterized biophysically and biochemically, and MICs for
Escherichia coli
cells expressing these enzymes were determined. We found that all variants exhibited catalytic efficiencies (
k
cat
/

K
m

) equal to or higher than that of IMP-1 against all tested β-lactams except penicillins, against which IMP-1 and IMP-1-V67I showed the highest
k
cat
/

K
m

values. The substrate-specific effects of the different amino acid substitutions at position 67 are discussed in light of their side chain structures and possible interactions with the substrates. Docking calculations were employed to investigate interactions between different side chains and an inhibitor used as a β-lactam surrogate. The differences in binding affinities determined experimentally and computationally seem to be governed by hydrophobic interactions between residue 67 and the inhibitor and, by inference, the β-lactam substrates.
Griffithsin and Carrageenan Combination To Target Herpes Simplex Virus 2 and Human Papillomavirus
Authors: Levendosky Keith , Mizenina Olga , Martinelli Elena , Jean-Pierre Ninochka , Kizima Larisa , Rodriguez Aixa , Kleinbeck Kyle , Bonnaire Thierry , Robbiani Melissa , Zydowsky Thomas M. , O'Keefe Barry R. , Fernández-Romero José A. 
Published: September 2015

ABSTRACT

Extensive preclinical evaluation of griffithsin (GRFT) has identified this lectin to be a promising broad-spectrum microbicide. We set out to explore the antiviral properties of a GRFT and carrageenan (CG) combination product against herpes simplex virus 2 (HSV-2) and human papillomavirus (HPV) as well as determine the mechanism of action (MOA) of GRFT against both viruses. We performed the experiments in different cell lines, using time-of-addition and temperature dependence experiments to differentiate inhibition of viral attachment from entry and viral receptor internalization. Surface plasmon resonance (SPR) was used to assess GRFT binding to viral glycoproteins, and immunoprecipitation and immunohistochemistry were used to identify the specific glycoprotein involved. We determined the antiviral activity of GRFT against HSV-2 to be a 50% effective concentration (EC
50
) of 230 nM and provide the first evidence that GRFT has moderate anti-HPV activity (EC
50
= 0.429 to 1.39 μM). GRFT blocks the entry of HSV-2 and HPV into target cells but not the adsorption of HSV-2 and HPV onto target cells. The results of the SPR, immunoprecipitation, and immunohistochemistry analyses of HSV-2 combined suggest that GRFT may block viral entry by binding to HSV-2 glycoprotein D. Cell-based assays suggest anti-HPV activity through α
6
integrin internalization. The GRFT-CG combination product but not GRFT or CG alone reduced HSV-2 vaginal infection in mice when given an hour before challenge (
P
= 0.0352). While GRFT significantly protected mice against vaginal HPV infection when dosed during and after HPV16 pseudovirus challenge (
P
< 0.026), greater CG-mediated protection was afforded by the GRFT-CG combination for up to 8 h (
P
< 0.0022). These findings support the development of the GRFT-CG combination as a broad-spectrum microbicide.
Assessment of Antiviral Properties of Peramivir against H7N9 Avian Influenza Virus in an Experimental Mouse Model
Authors: Farooqui Amber , Huang Linxi , Wu Suwu , Cai Yingmu , Su Min , Lin Pengzhou , Chen Weihong , Fang Xibin , Zhang Li , Liu Yisu , Zeng Tiansheng , Paquette Stephane G. , Khan Adnan , Kelvin Alyson A. , Kelvin David J. 
Published: September 2015

ABSTRACTThe H7N9 influenza virus causes a severe form of disease in humans. Neuraminidase inhibitors, including oral oseltamivir and injectable peramivir, are the first choices of antiviral treatment for such cases; however, the clinical efficacy of these drugs is questionable. Animal experimental models are essential for understanding the viral replication kinetics under the selective pressure of antiviral agents. This study demonstrates the antiviral activity of peramivir in a mouse model of H7N9 avian influenza virus infection. The data show that repeated administration of peramivir at 30 mg/kg of body weight successfully eradicated the virus from the respiratory tract and extrapulmonary tissues during the acute response, prevented clinical signs of the disease, including neuropathy, and eventually protected mice against lethal H7N9 influenza virus infection. Early treatment with peramivir was found to be associated with better disease outcomes.
Nanoscale Plasma Coating Inhibits Formation of Staphylococcus aureus Biofilm
Authors: Xu Yuanxi , Jones John E. , Yu Haiqing , Yu Qingsong , Christensen Gordon D. , Chen Meng , Sun Hongmin 
Published: September 2015

ABSTRACT

Staphylococcus aureus
commonly infects medical implants or devices, with devastating consequences for the patient. The infection begins with bacterial attachment to the device, followed by bacterial multiplication over the surface of the device, generating an adherent sheet of bacteria known as a biofilm. Biofilms resist antimicrobial therapy and promote persistent infection, making management difficult to futile. Infections might be prevented by engineering the surface of the device to discourage bacterial attachment and multiplication; however, progress in this area has been limited. We have developed a novel nanoscale plasma coating technology to inhibit the formation of
Staphylococcus aureus
biofilms. We used monomeric trimethylsilane (TMS) and oxygen to coat the surfaces of silicone rubber, a material often used in the fabrication of implantable medical devices. By quantitative and qualitative analysis, the TMS/O
2
coating significantly decreased the
in vitro
formation of
S. aureus
biofilms; it also significantly decreased
in vivo
biofilm formation in a mouse model of foreign-body infection. Further analysis demonstrated TMS/O
2
coating significantly changed the protein adsorption, which could lead to reduced bacterial adhesion and biofilm formation. These results suggest that TMS/O
2
coating can be used to effectively prevent medical implant-related infections.
Neither Classical nor Alternative Macrophage Activation Is Required for Pneumocystis Clearance during Immune Reconstitution Inflammatory Syndrome
Authors: Zhang Zhuo-Qian , Wang Jing , Hoy Zachary , Keegan Achsah , Bhagwat Samir , Gigliotti Francis , Wright Terry W. 
Published: September 2015

ABSTRACTPneumocystisis a respiratory fungal pathogen that causes pneumonia (Pneumocystispneumonia [PcP]) in immunocompromised patients. Alveolar macrophages are critical effectors for CD4+T cell-dependent clearance ofPneumocystis, and previous studies found that alternative macrophage activation accelerates fungal clearance during PcP-related immune reconstitution inflammatory syndrome (IRIS). However, the requirement for either classically or alternatively activated macrophages forPneumocystisclearance has not been determined. Therefore, RAG2−/−mice lacking either the interferon gamma (IFN-γ) receptor (IFN-γR) or interleukin 4 receptor alpha (IL-4Rα) were infected withPneumocystis. These mice were then immune reconstituted with wild-type lymphocytes to preserve the normal T helper response while preventing downstream effects of Th1 or Th2 effector cytokines on macrophage polarization. As expected, RAG2−/−mice developed severe disease but effectively clearedPneumocystisand resolved IRIS. Neither RAG/IFN-γR−/−nor RAG/IL-4Rα−/−mice displayed impairedPneumocystisclearance. However, RAG/IFN-γR−/−mice developed a dysregulated immune response, with exacerbated IRIS and greater pulmonary function deficits than those in RAG2 and RAG/IL-4Rα−/−mice. RAG/IFN-γR−/−mice had elevated numbers of lung CD4+T cells, neutrophils, eosinophils, and NK cells but severely depressed numbers of lung CD8+T suppressor cells. Impaired lung CD8+T cell responses in RAG/IFN-γR−/−mice were associated with elevated lung IFN-γ levels, and neutralization of IFN-γ restored the CD8 response. These data demonstrate that restricting the ability of macrophages to polarize in response to Th1 or Th2 cytokines does not impairPneumocystisclearance. However, a cell type-specific IFN-γ/IFN-γR-dependent mechanism regulates CD8+T suppressor cell recruitment, limits immunopathogenesis, preserves lung function, and enhances the resolution of PcP-related IRIS.
Host Contributions to Construction of Three Device-Associated Candida albicans Biofilms
Authors: Nett Jeniel E. , Zarnowski Robert , Cabezas-Olcoz Jonathan , Brooks Erin G. , Bernhardt Jörg , Marchillo Karen , Mosher Deane F. , Andes David R. 
Published: September 2015

ABSTRACT

Among the most fascinating virulence attributes of
Candida
is the ability to transition to a biofilm lifestyle. As a biofilm,
Candida
cells adhere to a surface, such as a vascular catheter, and become encased in an extracellular matrix. During this mode of growth,
Candida
resists the normal immune response, often causing devastating disease. Based on scanning electron microscopy images, we hypothesized that host cells and proteins become incorporated into clinical biofilms. As a means to gain an understanding of these host-biofilm interactions, we explored biofilm-associated host components by using microscopy and liquid chromatography-mass spectrometry. Here we characterize the host proteins associated with several
in vivo
rat
Candida albicans
biofilms, including those from vascular catheter, denture, and urinary catheter models as well as uninfected devices. A conserved group of 14 host proteins were found to be more abundant during infection at each of the niches. The host proteins were leukocyte and erythrocyte associated and included proteins involved in inflammation, such as C-reactive protein, myeloperoxidase, and alarmin S100-A9. A group of 59 proteins were associated with both infected and uninfected devices, and these included matricellular and inflammatory proteins. In addition, site-specific proteins were identified, such as amylase in association with the denture device. Cellular analysis revealed neutrophils as the predominant leukocytes associating with biofilms. These experiments demonstrate that host cells and proteins are key components of
in vivo
Candida
biofilms, likely with one subset associating with the device and another being recruited by the proliferating biofilm.
Periodontal Pathogens Invade Gingiva and Aortic Adventitia and Elicit Inflammasome Activation in αvβ6 Integrin-Deficient Mice
Authors: Velsko Irina M. , Chukkapalli Sasanka S. , Rivera-Kweh Mercedes F. , Zheng Donghang , Aukhil Ikramuddin , Lucas Alexandra R. , Larjava Hannu , Kesavalu Lakshmyya 
Published: September 2015

ABSTRACT

The American Heart Association supports an association between periodontal diseases and atherosclerosis but not a causal association. This study explores the use of the integrin β6
−/−
mouse model to study the causality. We investigated the ability of a polymicrobial consortium of
Porphyromonas gingivalis
,
Treponema denticola
,
Tannerella forsythia
, and
Fusobacterium nucleatum
to colonize the periodontium and induce local and systemic inflammatory responses. Polymicrobially infected
Itgβ6
−/−
mice demonstrate greater susceptibility to gingival colonization/infection, with severe gingival inflammation, apical migration of the junctional epithelium, periodontal pocket formation, alveolar bone resorption, osteoclast activation, bacterial invasion of the gingiva, a greater propensity for the bacteria to disseminate hematogenously, and a strong splenic T cell cytokine response. Levels of atherosclerosis risk factors, including serum nitric oxide, oxidized low-density lipoprotein, serum amyloid A, and lipid peroxidation, were significantly altered by polybacterial infection, demonstrating an enhanced potential for atherosclerotic plaque progression. Aortic gene expression revealed significant alterations in specific Toll-like receptor (TLR) and nucleotide-binding domain- and leucine-rich-repeat-containing receptor (NLR) pathway genes in response to periodontal bacterial infection. Histomorphometry of the aorta demonstrated larger atherosclerotic plaques in
Itgβ6
−/−
mice than in wild-type (WT) mice but no significant difference in atherosclerotic plaque size between mice with polybacterial infection and mice with sham infection. Fluorescence
in situ
hybridization demonstrated active invasion of the aortic adventitial layer by
P. gingivalis
. Our observations suggest that polybacterial infection elicits distinct aortic TLR and inflammasome signaling and significantly increases local aortic oxidative stress. These results are the first to demonstrate the mechanism of the host aortic inflammatory response induced by polymicrobial infection with well-characterized periodontal pathogens.
Death by Cystine: an Adverse Emergent Property from a Beneficial Series of Reactions
Authors: Reitzer Larry 
Published: September 2015

ABSTRACT

In this issue of the
Journal of Bacteriology
, Chonoles Imlay et al. (K. R. Chonoles Imlay, S. Korshunov, and J. A. Imlay, J Bacteriol 197:3629–3644, 2015,
http://dx.doi.org/10.1128/JB.00277-15
) show that oxidative stress kills sulfur-restricted
Escherichia coli
grown with sublethal H
2
O
2
when challenged with cystine. Killing requires rapid and seemingly unregulated cystine transport and equally rapid cystine reduction to cysteine. Cysteine export completes an energy-depleting futile cycle. Each reaction of the cycle could be beneficial. Together, a cystine-mediated vulnerability emerges during the transition from a sulfur-restricted to a sulfur-replete environment, perhaps because of complexities of sulfur metabolism.
Does the Finnish intervention prevent obstetric anal sphincter injuries? A systematic review of the literature
Authors: Poulsen Mette Østergaard , Madsen Mia Lund , Skriver-Møller Anne-Cathrine , Overgaard Charlotte 
Published: September 2015

ObjectivesA rise in obstetric anal sphincter injuries (OASIS) has been observed and a preventive approach, originating in Finland, has been introduced in several European hospitals. The aim of this paper was to systematically evaluate the evidence behind the ‘Finnish intervention’.DesignA systematic review of the literature conducted according to the Preferred Reporting for Systematic Reviews and Meta-analyses (PRISMA) guidelines.Outcome measuresThe primary outcome was OASIS. Secondary outcomes were (perinatal): Apgar scores, pH and standard base excess in the umbilical cord, and (maternal): episiotomy, intact perineum, first and second-degree perineal lacerations, duration of second stage, birth position and women's perceptions/birth experiences.MethodsMultiple databases (Cochrane, Embase, Pubmed and SveMed) were systematically searched for studies published up to December 2014. Both randomised controlled trials and observational studies were eligible for inclusion. Studies were excluded if a full-text article was not available. Studies were evaluated by use of international reporting guidelines (eg, STROBE).ResultsOverall, 1042 articles were screened and 65 retrieved for full-text evaluation. Seven studies, all observational and with a level of evidence at 2c or lower, were included and consistently reported a significant reduction in OASIS. All evaluated episiotomy and found a significant increase. Three studies evaluated perinatal outcomes and reported conflicting results. No study reported on other perineal outcomes, duration of the second stage, birth positions or women's perceptions.ConclusionsA reduction in OASIS has been contributed to the Finnish intervention in seven observational studies, all with a low level of evidence. Knowledge about the potential perinatal and maternal side effects and women's perceptions of the intervention is extremely limited and the biological mechanisms underlying the Finnish intervention are not well documented. Studies with a high level of evidence are needed to assess the effects of the intervention before implementation in clinical settings can be recommended.