bluuebunny/crossref_metadata_2025 huggingface dataset:
MicroRNA‐205 inhibits cancer cell migration and invasion via modulation of centromere protein F regulating pathways in prostate cancer
Authors: Nishikawa Rika , Goto Yusuke , Kurozumi Akira , Matsushita Ryosuke , Enokida Hideki , Kojima Satoko , Naya Yukio , Nakagawa Masayuki , Ichikawa Tomohiko , Seki Naohiko
Published: June 2015

Objectives

To investigate the functional roles of microRNA‐205 in the modulation of novel cancer pathways in prostate cancer cells.

Methods

Functional studies of microRNA‐205 were carried out to investigate cell proliferation, migration and invasion in prostate cancer cell lines (PC3 and DU145) by restoration of mature microRNA. In silico database and genome‐wide gene expression analyses were carried out to identify molecular targets and pathways mediated by microRNA‐205. Loss‐of‐function studies were applied to microRNA‐205 target genes.

Results

Restoration of microRNA‐205 in cancer cell lines significantly inhibited cancer cell migration and invasion. Our data showed that the centromere protein F gene was overexpressed in prostate cancer clinical specimens and was a direct target of microRNA‐205 regulation. Silencing of centromere protein F significantly inhibited cancer cell migration and invasion. Furthermore, MCM7, an oncogenic gene functioning downstream of centromere protein F, was identified by si‐centromere protein F transfectants in prostate cancer cells.

Conclusions

Loss of tumor‐suppressive microRNA‐205 seems to enhance cancer cell migration and invasion in prostate cancer through direct regulation of centromere protein F. Our data describing pathways regulated by tumor‐suppressive microRNA‐205 provide new insights into the potential mechanisms of prostate cancer oncogenesis and metastasis.
Telocytes in regenerative medicine
Authors: Bei Yihua , Wang Fei , Yang Changqing , Xiao Junjie
Published: June 2015

Telocytes (TCs) are a distinct type of interstitial cells characterized by a small cell body and extremely long and thin telopodes (Tps). The presence ofTCs has been documented in many tissues and organs (go tohttp://www.telocytes.com). Functionally,TCs form a three‐dimensional (3D) interstitial network by homocellular and heterocellular communication and are involved in the maintenance of tissue homeostasis. As important interstitial cells to guide or nurse putative stem and progenitor cells in stem cell niches in a spectrum of tissues and organs,TCs contribute to tissue repair and regeneration. This review focuses on the latest progresses regardingTCs in the repair and regeneration of different tissues and organs, including heart, lung, skeletal muscle, skin, meninges and choroid plexus, eye, liver, uterus and urinary system. By targetingTCs alone or in tandem with stem cells, we might promote regeneration and prevent the evolution to irreversible tissue damage. Exploring pharmacological or non‐pharmacological methods to enhance the growth ofTCs would be a novel therapeutic strategy besides exogenous transplantation for many diseased disorders.
Impact of fibrosis progression on clinical outcome in patients treated for post‐ transplant hepatitis C recurrence
Authors: Dhanasekaran Renumathy , Sanchez William , Mounajjed Taofic , Wiesner Russell H. , Watt Kymberly D. , Charlton Michael R.
Published: June 2015

Background & Aims

Patients who achieve sustained virological response (SVR) following the treatment of post‐liver transplant (LT) recurrence of hepatitis C virus (HCV) infection have improved outcomes. The full impact of eradication of HCV on allograft histology is, however, not clearly known.

Methods

We studied allograft histology in protocol‐based paired liver biopsies in consecutive LT recipients who underwent post‐LT treatment of recurrence of HCV.

Results

A total of 116 patients were treated with interferon‐based therapy for recurrent HCV. Paired pre‐treatment baseline biopsies and post‐treatment biopsies were available in 83.2% of patients. SVR was achieved in 37.9% of patients. Among the patients who achieved SVR, 20.5% had progression of fibrosis on post‐treatment biopsies vs. 65.5% of patients with non‐response/relapse (P < 0.001). The impact of virological response on fibrosis progression was sustained and a similar outcome was observed in the subset of patients who had 4–5 year post‐treatment biopsies available. In the SVR group, 12.8% progressed to fibrosis stage ≥3 on post‐treatment biopsies vs. 37.9% in the non‐response/relapse group (P = 0.001). The 5‐year survival in patients with progression of fibrosis 86% vs. 98% among patients who had improvement/stable fibrosis [P = 0.003; HR 3.8 (1.2–11.8)]. A small subset of patients who achieve SVR unfortunately still experience progression of fibrosis, most commonly associated with plasma cell hepatitis.

Conclusions

In post‐transplant patients treated for HCV, SVR is associated with improved graft survival and also with sustained and significant improvement in histological outcome. Importantly, progression of fibrosis still occurred in a small subset of patients who achieved SVR.
Hepatosplenic schistosomiasis is characterised by high blood markers of translocation, inflammation and fibrosis
Authors: Sinkala Edford , Kapulu Melissa C. , Besa Ellen , Zyambo Kanekwa , Chisoso Ng'andu J. , Foster Graham R. , Kelly Paul
Published: June 2015

Background & Aims

Cirrhosis is the main cause of portal hypertension worldwide but schistosomiasis dominates in much of the tropics. The seroprevalence of Schistosoma mansoni is up to 77% in endemic parts of Zambia. Morbidity is attributed to portal hypertension causing variceal bleeding which can be fatal. Bacterial translocation is associated with portal hypertension in cirrhosis but this is almost unexplored in hepatosplenic schistosomiasis. Liver biopsy is usually used to assess fibrosis although it is invasive and prone to sampling error. We aimed to investigate translocation, fibrosis and inflammatory makers in a case‐control study of schistosomiasis at the University Teaching Hospital, Lusaka, Zambia.

Methods

Patients had oesophageal varices, but were negative for human immunodeficiency virus, hepatitis B and C viruses. Plasma lipopolysaccharide binding protein was used as a marker of translocation while hyaluronan and laminin measured liver fibrosis. Inflammatory markers were measured in blood. Controls were patients with non‐specific abdominal pain who had normal endoscopy.

Results

Median (interquartile range) lipopolysaccharide binding protein was elevated in patients [44.3 ng/ml (35.7, 57.1)] compared to controls [30.7 ng/ml (30.4, 35.5), P < 0.0001]. Hyaluronan was higher in patients [111.6 ng/ml (39.1, 240.3)] compared to controls [21.0 ng/ml (12.4, 37.6), P < 0.0001] and so was laminin [2.2 μg/ml (1.0, 3.7)] compared to controls [0.9 μg/ml (0.7, 1.2), P = 0.0015]. Inflammatory markers, except C‐reactive protein, were elevated in patients.

Conclusions

These data suggest that the bacterial translocation contributes to systemic inflammation in hepatosplenic schistosomiasis. Elevated fibrotic markers suggest they may be useful in diagnosing and monitoring periportal fibrosis.
Muslim Mandarins in Chinese Courts: Dispute Resolution, Islamic Law, and the Secular State in Northwest China
Authors: Erie Matthew S.
Published: June 2015

Many sociolegal studies have investigated the relationship between state law and informal law, examining alternativedispute resolutionandpopular justiceas intersections between such types of law. However, such questions have received little attention in East Asian authoritarian states. I use the case of dispute resolution among Chinese Muslim minorities (the Hui) to reexamine the relationship between state law and Islamic law. Based on nineteen months of fieldwork in Northwest China, I argue that the Hui case shows codependence between the types of law. Law is deeply embedded in social relationships between the Hui and the party‐state. An analysis of personalistic relationships shows the ways in which religious and secular authorities access each other, transforming each other's law to augment their own legitimacy, but not without the potential for violence. The China case illuminates dynamics between Muslim communities and states that are prevalent elsewhere in the post‐9/11 period.
‘This little piranha’: a qualitative analysis of the language used by health professionals and mothers to describe infant behaviour during breastfeeding
Authors: Burns Elaine , Fenwick Jenny , Sheehan Athena , Schmied Virginia
Published: June 2015

Exclusive breastfeeding for the first 6 months of life offers the recommended best start in the life for a newborn baby. Yet, in Australia only a small number of babies receive breast milk exclusively for the first 6 months. Reasons for the introduction of formula milk are multi‐factorial including access to appropriate support and the woman's experience of breastfeeding. The language and practices of health professionals can impact upon how a woman feels about breastfeeding and her breastfeeding body. One aspect of breastfeeding support that has had scarce attention in the literature is the language used by health professionals to describe the behaviour of the breastfeeding infant during the early establishment phase of breastfeeding. This paper reveals some of the ways in which midwives, lactation consultants and breastfeeding women describe the newborn baby during the first week after birth. The study was conducted at two maternity units in New South Wales. Interactions between midwives and breastfeeding women were observed and audio recorded on the post‐natal ward and in women's homes, in the first week after birth. The transcribed data were analysed using discourse analysis searching for recurring words, themes and metaphors used in descriptions of the breastfeeding baby. Repeated negative references to infant personality and unfavourable interpretations of infant behaviour influenced how women perceived their infant. The findings revealed that positive language and interpretations of infant breastfeeding behaviour emerged from more relationship‐based communication.
An analysis of England's nursing policy on compassion and the 6Cs: the hidden presence of M. Simone Roach's model of caring
Authors: Bradshaw Ann
Published: June 2015

In 2012, chief nursing officers (CNO) in England published a policy on compassion in response to serious criticisms of patients’ care. Because their objective is fundamentally to shape nursing, this study argues, following Popper, that the policy should be analysed. An appraisal tool, developed from Popper, Gadamer, Jauss and Thiselton, is the framework for this analysis. The CNO policy document identified six values and behaviours, termed ‘6Cs’, required by all nurses, midwives and care staff. The document contains no data, references or acknowledgements, but is similar to the 6Cs defined by the Canadian nursing nun, Sister M. Simone Roach, in her theory of caring published 30 years earlier. Roach considered caring and the components of it, including compassion, to be moral virtues, an inner motivation to care. This study suggests that without explicit reference to Roach's ideas, and her underlying theoretical base, the CNO requirement has the effect of turning virtues into commodities and a form of external control, described by Ritzer as a McDonaldized dehumanization. This study, which has international relevance beyond England and the UK, suggests that the CNO revise their policy by acknowledging Roach's 6Cs and openly discuss the implications of her work for their policy.
The Effect of a Novel form of Extended‐Release Gabapentin on Pain and Sleep in Fibromyalgia Subjects: An Open‐Label Pilot Study
Authors: North James M. , Hong Kyung‐soo J. , Rauck Richard L.
Published: June 2015

Introduction

We assessed the efficacy and safety of extended‐release gabapentin in a 15‐week, open‐label, single‐arm, single‐center study in patients with fibromyalgia (FM).

Methods

Subjects with documented diagnosis of FM were allowed to participate in the study. We opened enrollment to those who have tried and failed gabapentinoids such as gabapentin or pregabalin due to side effects. Subjects with autoimmune conditions, and or taking opioids for management of their FM pain, were excluded from the study. Subjects were given an extended‐release gabapentin starter pack and treated for total of 12 weeks. The primary study endpoint of pain relief was measured using Numeric Pain Rating System (NPRS) scores, and secondary study endpoints were measured with Fibromyalgia Impact Questionnaire (FIQ), Patient's Global Impression of Change (PGIC), and Medical Outcome Sleep questionnaires (MOS).

Results

A total of 34 subjects were enrolled and 29 subjects completed the starter pack (85%). Patients reported significant pain relief on NPRS by end of 4 weeks (P < 0.0001) on NPRS. Subjects also reported similar magnitude of improvements in FM and its impact on daily life by end of 4 weeks on FIQ (P < 0.0001). Survey of MOS showed our subjects reporting improved sleep quantity (on average, 1.2 hours over baseline) with gradual and statistically significant improvement in quality. Improvements in primary and secondary measurements were reflected in PGIC, with significant improvement in patient's impression of FM by week 8.

Limitations

Small sample size, geographical bias, relatively short duration of treatment, and single‐arm study without control group.

Conclusions

Extended‐release gabapentin relieved FM pain symptoms and improved quality‐of‐life for the FM subjects studied. Subjects reported improvements in both quantity and quality of sleep.
Mapping of clubroot (Plasmodiophora brassicae) resistance in canola (Brassica napus)
Authors: Zhang H. , Feng J. , Hwang S.‐F. , Strelkov S. E. , Falak I. , Huang X. , Sun R.
Published: June 2015

Clubroot disease, caused by Plasmodiophora brassicae, has become a major problem in the production of cruciferous crops worldwide. In this study, a population of 121 doubled haploid (DH) lines derived from a crossing between a resistant and a susceptible canola (Brassica napus) genotype was subjected to phenotypic and genotypic studies to determine the inheritance and location of the resistance gene(s). After inoculation with pathotype 3 of P. brassicae, the lines showed a 1:1 segregation ratio for resistance, indicating that resistance in this population is controlled by a single gene. Fifteen PCR‐based markers that were known to be linked to clubroot resistance (CR) genes were screened against genomic DNA from parents and resistant and susceptible bulks. Marker GC1680, linked to the CR gene CRa, exhibited polymorphism between the parents and between the resistant and susceptible bulks. CRa target primers were used to amplify fragments from the two parents and the resultant sequences were compared. A high degree of sequence similarity was found between the parents in the nucleotide binding site domain of CRa. In contrast, sequence polymorphisms were detected in the leucine‐rich repeat (LRR) domain. One pair of primers that amplify a band from the LRR region of the resistant parent but not the susceptible parent was used to screen the DH population. Amplicons were obtained from 60 of the 61 resistant lines and two of the 60 susceptible lines; thus, three recombinants were found. Based on these results, a resistance locus linked to CRa was found.
The (D)evolution of the Prostitute in Russian Beauty
Authors: MATTHEWS EMILY SCHUCKMAN
Published: June 2015

The article explores the post‐modernist representation of the prostitute to look at the ways in which the familiar tropes associated with the character are challenged and retooled. The article offers an in‐depth critique of Victor Erofeev's novel Russian Beauty. Erofeev is one of the most vocal advocates for innovations in Russia's literary style. Through a close examination of his text, the article concludes that despite the challenges to the standard language and tropes associated with the prostitute character, she ultimately retains her potent symbolic power, used in “new” literature in much the same was she was used in “old.”
On the Application of LIDAR Sensors for Track Geometry Monitoring
Authors: Andani Masood Taheri , Ahmadian Mehdi , Munoz Josh , O’Connor Thomas , Ha Dong
Published: June 2015

The applicability of Doppler based, Light Detection and Ranging (LIDAR) sensors for track geometry monitoring is investigated in this article. The optimum configuration of the LIDAR lenses, suitable for effective lateral track geometry measurements, is presented. In the proposed embodiment, two low-elevation LIDAR optics are employed with their beams reflected off of the rail gage face on each side to capture speed signals from both rails individually. A processing technique is developed based on the frequency bandwidth dissimilarities between the vehicle speed and track geometry irregularity to separate the two from each other. LIDAR system is body-mounted to a geometry inspection car and tests are carried out on revenue service track. The results indicate that LIDAR optics can provide a reliable track monitoring instrument for use over substantial track mileage in inclement weather and harsh track conditions with minimal operator supervision.
Hunting Analysis of a Partially-Filled Railway Tank Car
Authors: Hazrati Ashtiani Iman , Rakheja Subhash , Ahmed A. K. W. , Zhang Jimin
Published: June 2015

General purpose railway tank cars similar to road tankers are known to transport liquid cargo in partial-fill state due to variations in liquid cargo density and governing axle load limits. It is widely reported that the cargo movements constitute additional forces and moments that could strongly affect the wheel-rail interactions and coupling forces, and thereby the directional dynamics of the wagon. In this study, the linear slosh theory is used to describe the liquid cargo movement in the roll plane by a simple pendulum, which is integrated into a comprehensive nonlinear multi-body model of a three-piece truck to study the effects of liquid cargo slosh on lateral dynamics of the tank car. The model also incorporates the nonlinear secondary suspension restoring and damping forces, attributed to friction of the wedges, using the non-smooth contact method in addition to the geometric constraints of various components. The wheel/rail contact forces are simulated considering non-elliptical wheel-rail contact using the FASTSIM algorithm. The lateral dynamic responses of the multi-body model of a freight car with partially filled liquid load and an equivalent rigid cargo are evaluated to study the effect of cargo movement on the critical speed and the wheelset hunting oscillations frequency. The results obtained considering different fill ratios of the liquid cargo suggest that the fluid slosh yields additional damping effect on the lateral dynamics of the car. Liquid cargo movement within partly-filled tank car could thus yield a beneficial influence on the wheelset hunting. This was evidenced from the phase relationship between the lateral oscillations of the pendulum and the bogie/wheelset. Consequently, a partially filled tanker resulted in relatively higher critical hunting velocity compared to that of the wagon with equivalent rigid cargo.
Exploration of Alternatives for Prestressed Concrete Monoblock Crosstie Design Based on Flexural Capacity
Authors: Csenge Matthew V. , Wolf Henry E. , Dersch Marcus S. , Edwards J. Riley , Kernes Ryan G. , Romero Mauricio Gutierrez
Published: June 2015

Recent North American railway trends signify a transition to increased axle loads and higher train speeds. The use of concrete crossties is common practice in these applications for a variety of reasons, including higher load-carrying capacity and improved ability to maintain proper track geometry. Currently, prestressed concrete monoblock crossties share many geometric and structural properties regardless of manufacturer. For multiple reasons, some manufacturers are investigating the potential benefits of new geometries for crosstie design. One alternative currently being explored is to modify the length and cross-section of the crosstie in order to increase the flexural capacity while using a similar amount of material. In this paper the benefits and implications of these changes will be explored both through theoretical calculations and laboratory testing. This alternative design will be evaluated and compared to concrete crossties representative of those currently found in North America. Comparison of the designs will be based on structural cracking at critical locations along the crosstie. These results were used to provide guidance on critical design parameters for concrete crossties capable of withstanding future loading and performance demands.
Laboratory Development and Testing of “SmartRock” for Railroad Ballast Using Discrete Element Modeling
Authors: Liu Shushu , Huang Hai , Qiu Tong
Published: June 2015

Ballast aggregate settlement is generally a result of consolidation or rearrangment of ballast particles in the area underneath crossties. Excessive settlement negatively impacts track performance, resulting in increased risk of train derailment. The purpose of this paper is to compare two methods to evaluate ballast aggregate settlement with repeated loading in railroad: discrete element modeling and laboratory tests using “SmartRock”.

In this study, ballast aggregates are considered as uniformly graded, angular shaped with crushed faces. For the discrete element modeling, digital imaging techniques are utilized to create the ballast aggregates. Aggregate settlement in railroad ballast and the effect of aggregate shape on the dynamic response of ballast are evaluated through the discrete element simulations. A wireless device, “SmartRock” is developed to study the relationship between individual ballast particle behavior and overall ballast performance. It has a shell of a typical ballast particle shape with force cells attached on the surface and embedded with a tri-axial gyroscope, a tri-axial accelerometer, and a tri-axial magnetometer. The device can move under train traffic like a real ballast particle and record inter-particle contact forces and particle motion in real time. For the laboratory tests, a model-scale track section is constructed and subjected to repeated loading similar to train traffic. The developed “SmartRock” are embedded below rail seats and in the track shoulders.

The laboratory data using “SmartRock” can be compared with results from the discrete element modeling in the future. These comparisons will validate the discrete element modeling procedure as a means to analyze railroad ballast aggregate behavior and the potential of “SmartRock” in railroad applications.
Developing Safety Performance Functions for Railway Grade Crossings: A Case Study of Canada
Authors: Heydari Shahram , Fu Liping
Published: June 2015

Although accident frequencies at railway grade crossings have shown a decreasing trend over the last two decades (partly due to implemented safety improvements and technological advances), safety at grade crossings is still a major concern since crossing accidents are usually associated with devastating consequences. This paper investigates the effect of various site attributes on railway crossing safety outcomes using recent Canada wide data from a 6-year period (2008–2013). The new data sets allow adjusting previous accident models according to latest circumstances (e.g., vehicles’ improved safety features) affecting safety dynamics at crossings. Employing Bayesian hierarchical models including the non-conventional Poisson-Weibull model, different safety performance functions were separately developed for crossings with the following major warning systems: (1) flashing light and bell (FLB), (2) flashing light, bell, and gate (FLBG), (3) standard reflectorized crossing sign (SRCS), and (4) standard reflectorized crossing sign and stop sign (SRCS & STOP). Among other findings, the results indicated that traffic exposure (product of train and vehicle), number of lanes, whistle prohibition, train speed, and road speed were the most important factors affecting accident frequencies at Canadian railway crossings. It should be also noted that safety performance functions vary, in terms of independent variables and their associated coefficients, between the aforementioned warning devices.
Decreased Circulating mtDNA Levels in Professional Male Volleyball Players
Authors: Nasi Milena , Cristani Alessandro , Pinti Marcello , Lamberti Igor , Gibellini Lara , De Biasi Sara , Guazzaloca Alessandro , Trenti Tommaso , Cossarizza Andrea
Published: June 2015

Purpose:

Exercise exerts various effects on the immune system, and evidence is emerging on its anti-inflammatory effects; the mechanisms on the basis of these modifications are poorly understood. Mitochondrial DNA (mtDNA) released from damaged cells acts as a molecule containing the so-called damage-associated molecular patterns and can trigger sterile inflammation. Indeed, high plasma levels of mtDNA are associated to several inflammatory conditions and physiological aging and longevity. The authors evaluated plasma mtDNA in professional male volleyball players during seasonal training and the possible correlation between mtDNA levels and clinical parameters, body composition, and physical performance.

Methods:

Plasma mtDNA was quantified by real-time PCR every 2 mo in 12 professional volleyball players (PVPs) during 2 consecutive seasons. As comparison, 20 healthy nonathlete male volunteers (NAs) were analyzed.

Results:

The authors found lower levels of mtDNA in plasma of PVPs than in NAs. However, PVPs showed a decrease of circulating mtDNA only in the first season, while no appreciable variations were observed during the second season. No correlation was observed among mtDNA, hematochemical, and anthropometric parameters.

Conclusions:

Regular physical activity appeared associated with lower levels of circulating mtDNA, further confirming the protective, anti-inflammatory effect of exercise.
Pacing Behavior and Tactical Positioning in 1500-m Short-Track Speed Skating
Authors: Konings Marco J. , Noorbergen Olaf S. , Parry David , Hettinga Florentina J.
Published: June 2015

Purpose:

To gain more insight in pacing behavior and tactical positioning in 1500-m short-track speed skating, a sport in which several athletes directly compete in the same race.

Methods:

Lap times and intermediate rankings of elite 1500-m short-track-skating competitors were collected over the season 2012–13 (N = 510, 85 races). Two statistical approaches were used to assess pacing behavior and tactical positioning. First, lap times were analyzed using a MANOVA, and for each lap differences between sex, race type, final rankings, and stage of competition were determined. Second, Kendall tau b correlations were used to assess relationships between intermediate and final rankings. In addition, intermediate rankings of the winner of each race were examined.

Results:

In 1500 m (13.5 laps of 111.12 m), correlations between intermediate and final ranking gradually increased throughout the race (eg, lap 1, r = .05; lap 7, r = .26; lap 13, r = .85). Moreover, the percentage of race winners skating in the leading position was over 50% during the last 3 laps. Top finishers were faster than bottom-place finishers only during the last 5 laps, with on average 0.1- to 1.5-s faster lap times of the race winners compared with the others during the last 5 laps.

Conclusions:

Although a fast start led to faster finishing times, top finishers were faster than bottom-placed finishers only during the last 5 laps. Moreover, tactical positioning at 1 of the foremost positions during the latter phase of the race appeared to be a strong determinant of finishing position.
The Effectiveness of Nonoperative Rehabilitation Programs for Athletes Diagnosed With Osteitis Pubis
Authors: Cheatham Scott W. , Kolber Morey J. , Shimamura Kathryn Kumagai
Published: June 2015

Clinical Scenario:

The differential diagnosis of groin pain can be very challenging due to the many causative pathologies. Osteitis pubis is a pathology that is becoming more recognized in athletes who participate in sports such as soccer, ice hockey, rugby, and football. Conservative nonoperative treatment is often prescribed first before surgical intervention. Of particular interest are the outcomes of nonoperative rehabilitation programs and their effectiveness to return athletes to preinjury levels of participation. The most recent systematic review in 2011 examined the spectrum of treatments for osteitis pubis and found only level 4 (case report or case series) evidence with varying approaches to treatment. Due to the amount of time since the last published review, there is a need to critically appraise the recent literature to see if more high-quality research has been published that measured nonoperative interventions for athletes with osteitis pubis.

Focused Clinical Question:

Is there evidence to suggest that nonoperative rehabilitation programs for osteitis pubis are effective at returning athletes to their preinjury levels of participation?

Summary of Key Findings:

Four studies met the inclusion criteria. Only level 4 evidence was found. All studies reported using a structured nonoperative rehabilitation program with a successful return to preinjury participation between 4 and 14 wk, except for 1 study reporting a successful return at 30 wk. Successful long-term follow-up was reported at 6–48 mo for all patients.

Clinical Bottom Line:

There is weak evidence to support the efficacy of nonoperative rehabilitation programs at returning athletes to their preinjury levels of participation.

Strength of Recommendation:

There is grade D evidence that a nonoperative program for osteitis pubis is effective at helping athletes return to their preinjury level of participation. The Centre of Evidence Based Medicine recommends a grade D for level 4 evidence with consistent findings.
Drugs may play a PPARt against preeclampsia
Authors: Nusinovich Yevgeniya
Published: June 2015

Reduction of vascular RGS5 causes hypertension and preeclampsia, which can be reversed by PPAR agonist treatment in mouse models.
MK2 inhibitory peptide delivered in nanopolyplexes prevents vascular graft intimal hyperplasia
Authors: Evans Brian C. , Hocking Kyle M. , Osgood Michael J. , Voskresensky Igor , Dmowska Julia , Kilchrist Kameron V. , Brophy Colleen M. , Duvall Craig L.
Published: June 2015

Nanopolyplexes formulated from a pH-responsive, endosomolytic polymer with a peptide inhibitor of MAPKAP kinase 2 block inflammatory and migratory signaling in vascular smooth muscle cells and prevent intimal hyperplasia in human saphenous vein grafts.
Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells
Authors: Huang Bonnie , Abraham Wuhbet D. , Zheng Yiran , Bustamante López Sandra C. , Luo Samantha S. , Irvine Darrell J.
Published: June 2015

Nanoparticle-functionalized T cells actively transport a cytotoxic drug to systemic sites of lymphoma dissemination, enhancing the efficacy of antitumor chemotherapy.
Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia
Authors: Lim Yiting , Gondek Lukasz , Li Li , Wang Qiuju , Ma Hayley , Chang Emily , Huso David L. , Foerster Sarah , Marchionni Luigi , McGovern Karen , Watkins David Neil , Peacock Craig D. , Levis Mark , Smith Bruce Douglas , Merchant Akil A. , Small Donald , Matsui William
Published: June 2015

Activation of the Hedgehog pathway drives FLT3-mutated leukemia, and dual pathway inhibition effectively inhibits tumor growth.
Drugging immune regulation
Authors: Marson Alexander
Published: June 2015

A chemical screen highlights a new pathway controlling regulatory T cell differentiation.
Relative Strengths of Promoters Provided by Common Mobile Genetic Elements Associated with Resistance Gene Expression in Gram-Negative Bacteria
Authors: Kamruzzaman Muhammad , Patterson Jason D. , Shoma Shereen , Ginn Andrew N. , Partridge Sally R. , Iredell Jonathan R.
Published: June 2015

Comparison of green fluorescent protein expression from outward-facing promoters (P
OUT
) of IS
Aba1
, IS
Ecp1
, and IS
Aba125
revealed approximate equivalence in strength, intermediate between P
C
S (strong) and P
C
W
TGN-10
(weak) class 1 integron promoter variants, >30-fold stronger than P
OUT
of IS
CR1
, and >5 times stronger than P
tac
. Consistent with its usual role, P
C
W
TGN-10
produces more mRNA from a “downstream”
gfp
gene transcriptionally linked to a “usual” P
C
W
TGN-10
-associated gene cassette than does P
OUT
of IS
Aba1
.
Antiviral Efficacy of a Respiratory Syncytial Virus (RSV) Fusion Inhibitor in a Bovine Model of RSV Infection
Authors: Jordan Robert , Shao Matt , Mackman Richard L. , Perron Michel , Cihlar Tomas , Lewis Sandy A. , Eisenberg Eugene J. , Carey Anne , Strickley Robert G. , Chien Jason W. , Anderson Mark L. , McEligot Heather A. , Behrens Nicole E. , Gershwin Laurel J.
Published: June 2015

Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants. Effective treatment for RSV infection is a significant unmet medical need. While new RSV therapeutics are now in development, there are very few animal models that mimic the pathogenesis of human RSV, making it difficult to evaluate new disease interventions. Experimental infection of Holstein calves with bovine RSV (bRSV) causes a severe respiratory infection that is similar to human RSV infection, providing a relevant model for testing novel therapeutic agents. In this model, viral load is readily detected in nasal secretions by quantitative real-time PCR (qRT-PCR), and cumulative symptom scoring together with histopathology evaluations of infected tissue allow for the assessment of disease severity. The bovine RSV model was used to evaluate the antiviral activity of an RSV fusion inhibitor, GS1, which blocks virus entry by inhibiting the fusion of the viral envelope with the host cell membrane. The efficacy of GS1, a close structural analog of GS-5806 that is being developed to treat RSV infection in humans was evaluated in two randomized, blind, placebo-controlled studies in bRSV-infected calves. Intravenous administration of GS1 at 4 mg/kg of body weight/day for 7 days starting 24 h or 72 h postinoculation provided clear therapeutic benefit by reducing the viral load, disease symptom score, respiration rate, and lung pathology associated with bRSV infection. These data support the use of the bovine RSV model for evaluation of experimental therapeutics for treatment of RSV.
In Vitro
Antifungal Activity of ME1111, a New Topical Agent for Onychomycosis, against Clinical Isolates of Dermatophytes
Authors: Ghannoum M. , Isham N. , Long L.
Published: June 2015

The treatment of onychomycosis has improved considerably over the past several decades following the introduction of the oral antifungals terbinafine and itraconazole. However, these oral agents suffer from certain disadvantages, including drug interactions and potential liver toxicity. Thus, there is a need for new topical agents that are effective against onychomycosis. ME1111 is a novel selective inhibitor of succinate dehydrogenase (complex II) of dermatophyte species, whose small molecular weight enhances its ability to penetrate the nail plate. In this study, we determined the antifungal activity of ME1111 against dermatophyte strains, most of which are known to cause nail infections, as measured by the MIC (
n
= 400) and the minimum fungicidal concentration (MFC) (
n
= 300). Additionally, we examined the potential for resistance development in dermatophytes (
n
= 4) following repeated exposure to ME1111. Our data show that the MIC
90
of ME1111 against dermatophyte strains was 0.25 μg/ml, which was equivalent to that of the comparators amorolfine and ciclopirox (0.25 and 0.5 μg/ml, respectively). ME1111 was fungicidal at clinically achievable concentrations against dermatophytes, and its MFC
90
s against
Trichophyton rubrum
and
Trichophyton mentagrophytes
were 8 μg/ml, comparable to those of ciclopirox. Furthermore, ME1111, as well as ciclopirox, did not induce resistance in 4 dermatophytes tested. Our studies show that ME1111 possesses potent antifungal activity and suggest that it has low potential for the development of resistance in dermatophytes.
Salinomycin and Other Ionophores as a New Class of Antimalarial Drugs with Transmission-Blocking Activity
Authors: D'Alessandro Sarah , Corbett Yolanda , Ilboudo Denise P. , Misiano Paola , Dahiya Nisha , Abay Solomon M. , Habluetzel Annette , Grande Romualdo , Gismondo Maria R. , Dechering Koen J. , Koolen Karin M. J. , Sauerwein Robert W. , Taramelli Donatella , Basilico Nicoletta , Parapini Silvia
Published: June 2015

The drug target profile proposed by the Medicines for Malaria Venture for a malaria elimination/eradication policy focuses on molecules active on both asexual and sexual stages of
Plasmodium
, thus with both curative and transmission-blocking activities. The aim of the present work was to investigate whether the class of monovalent ionophores, which includes drugs used in veterinary medicine and that were recently proposed as human anticancer agents, meets these requirements. The activity of salinomycin, monensin, and nigericin on
Plasmodium falciparum
asexual and sexual erythrocytic stages and on the development of the
Plasmodium berghei
and
P. falciparum
mosquito stages is reported here. Gametocytogenesis of the
P. falciparum
strain 3D7 was induced
in vitro
, and gametocytes at stage II and III or stage IV and V of development were treated for different lengths of time with the ionophores and their viability measured with the parasite lactate dehydrogenase (pLDH) assay. The monovalent ionophores efficiently killed both asexual parasites and gametocytes with a nanomolar 50% inhibitory concentration (IC
50
). Salinomycin showed a fast speed of kill compared to that of standard drugs, and the potency was higher on stage IV and V than on stage II and III gametocytes. The ionophores inhibited ookinete development and subsequent oocyst formation in the mosquito midgut, confirming their transmission-blocking activity. Potential toxicity due to hemolysis was excluded, since only infected and not normal erythrocytes were damaged by ionophores. Our data strongly support the downstream exploration of monovalent ionophores for repositioning as new antimalarial and transmission-blocking leads.
NDM-1-Producing Citrobacter freundii, Escherichia coli, and Acinetobacter baumannii Identified from a Single Patient in China
Authors: Huang Ying-Min , Zhong Lan-lan , Zhang Xue-Fei , Hu Hang-tong , Li Yu-qi , Yang Xiao-rong , Feng Lian-Qiang , Huang Xi , Tian Guo-Bao
Published: June 2015

We identified New Delhi metallo-β-lactamase (NDM-1)-producing
Citrobacter freundii
GB032,
Escherichia coli
GB102, and
Acinetobacter baumannii
GB661 in urine and stool samples from a single patient in China. Plasmid profiling and Southern blotting indicated that
bla
NDM-1
from GB032 and that from GB102 were likely located on the same plasmid, while
bla
NDM-1
from GB661 was located on a very large (>400-kb) plasmid. This case underscores the broad host range of
bla
NDM-1
and its potential to spread between members of the family
Enterobacteriaceae
and
A. baumannii
.
TREM-1 Signaling Promotes Host Defense during the Early Stage of Infection with Highly Pathogenic Streptococcus suis
Authors: Yang Chao , Chen Bo , Zhao Jianqing , Lin Lan , Han Li , Pan Shan , Fu Lei , Jin Meilin , Chen Huanchun , Zhang Anding
Published: June 2015

Infection with highly pathogenic
Streptococcus suis
can cause septic shock, which is characterized by high levels of inflammatory cytokines and a high mortality rate. Our previous study indicated that TREM-1 (triggering receptor expressed on myeloid cells 1) was upregulated in swine spleen cells in response to
S. suis
infection. The role of TREM-1 signaling in enhancement of the proinflammatory response promoted us to examine its effect on the outcome of
S. suis
infection. In the present study, the recombinant extracellular domain of TREM-1 (rTREM-1) and an agonistic TREM-1 antibody were used to inhibit and activate TREM-1 signaling to evaluate its role in neutrophil activation, pathogen clearance, proinflammatory cytokine response, and the outcome of highly pathogenic
S. suis
infection in a mouse model. Blockage of TREM-1 signaling caused a more severe proinflammatory response to
S. suis
infection and increased the mortality rate, while its activation had the opposite effect. Blockage or activation of TREM-1 signaling lowered or raised the number of neutrophils in the blood, which correlated well with host clearance of
S. suis
. In conclusion, the TREM-1-mediated innate immune response played an essential role in the activation of neutrophils and
S. suis
clearance, which further reduced severe inflammation and finally benefited the outcome of the infection.
Members of the PpaA/AerR Antirepressor Family Bind Cobalamin
Authors: Vermeulen Arjan J. , Bauer Carl E.
Published: June 2015

PpaA from
Rhodobacter sphaeroides
is a member of a family of proteins that are thought to function as antirepressors of PpsR, a widely disseminated repressor of photosystem genes in purple photosynthetic bacteria. PpaA family members exhibit sequence similarity to a previously defined SCHIC (
s
ensor
c
ontaining
h
eme
i
nstead of
c
obalamin) domain; however, the tetrapyrrole-binding specificity of PpaA family members has been unclear, as
R. sphaeroides
PpaA has been reported to bind heme while the
Rhodobacter capsulatus
homolog has been reported to bind cobalamin. In this study, we reinvestigated tetrapyrrole binding of PpaA from
R. sphaeroides
and show that it is not a heme-binding protein but is instead a cobalamin-binding protein. We also use bacterial two-hybrid analysis to show that PpaA is able to interact with PpsR and activate the expression of photosynthesis genes
in vivo
. Mutations in PpaA that cause loss of cobalamin binding also disrupt PpaA antirepressor activity
in vivo
. We also tested a number of PpaA homologs from other purple bacterial species and found that cobalamin binding is a conserved feature among members of this family of proteins.

IMPORTANCE
Cobalamin (vitamin B
12
) has only recently been recognized as a cofactor that affects gene expression by interacting in a light-dependent manner with transcription factors. A group of related antirepressors known as the AppA/PpaA/AerR family are known to control the expression of photosynthesis genes in part by interacting with either heme or cobalamin. The specificity of which tetrapyrroles that members of this family interact with has, however, remained cloudy. In this study, we address the tetrapyrrole-binding specificity of the PpaA/AerR subgroup and establish that it preferentially binds cobalamin over heme.
Cathepsin W Is Required for Escape of Influenza A Virus from Late Endosomes
Authors: Edinger Thomas O. , Pohl Marie O. , Yángüez Emilio , Stertz Silke
Published: June 2015

Human cathepsin W (CtsW) is a cysteine protease, which was identified in a genome-wide RNA interference (RNAi) screen to be required for influenza A virus (IAV) replication. In this study, we show that reducing the levels of expression of CtsW reduces viral titers for different subtypes of IAV, and we map the target step of CtsW requirement to viral entry. Using a set of small interfering RNAs (siRNAs) targeting CtsW, we demonstrate that knockdown of CtsW results in a decrease of IAV nucleoprotein accumulation in the nuclei of infected cells at 3 h postinfection. Assays specific for the individual stages of IAV entry further show that attachment, internalization, and early endosomal trafficking are not affected by CtsW knockdown. However, we detected impaired escape of viral particles from late endosomes in CtsW knockdown cells. Moreover, fusion analysis with a dual-labeled influenza virus revealed a significant reduction in fusion events, with no detectable impact on endosomal pH, suggesting that CtsW is required at the stage of viral fusion. The defect in IAV entry upon CtsW knockdown could be rescued by ectopic expression of wild-type CtsW but not by the expression of a catalytically inactive mutant of CtsW, suggesting that the proteolytic activity of CtsW is required for successful entry of IAV. Our results establish CtsW as an important host factor for entry of IAV into target cells and suggest that CtsW could be a promising target for the development of future antiviral drugs.

IMPORTANCE
Increasing levels of resistance of influenza viruses to available antiviral drugs have been observed. Development of novel treatment options is therefore of high priority. In parallel to the classical approach of targeting viral enzymes, a novel strategy is pursued: cell-dependent factors of the virus are identified with the aim of developing small-molecule inhibitors against a cellular target that the virus relies on. For influenza A virus, several genome-wide RNA interference (RNAi) screens revealed hundreds of potential cellular targets. However, we have only limited knowledge on how these factors support virus replication, which would be required for drug development. We have characterized cathepsin W, one of the candidate factors, and found that cathepsin W is required for escape of influenza virus from the late endosome. Importantly, this required the proteolytic activity of cathepsin W. We therefore suggest that cathepsin W could be a target for future host cell-directed antiviral therapies.
Acetic Acid Acts as a Volatile Signal To Stimulate Bacterial Biofilm Formation
Authors: Chen Yun , Gozzi Kevin , Yan Fang , Chai Yunrong
Published: June 2015

Volatiles are small air-transmittable chemicals with diverse biological activities. In this study, we showed that volatiles produced by the bacterium
Bacillus subtilis
had a profound effect on biofilm formation of neighboring
B. subtilis
cells that grew in proximity but were physically separated. We further demonstrated that one such volatile, acetic acid, is particularly potent in stimulating biofilm formation. Multiple lines of genetic evidence based on
B. subtilis
mutants that are defective in either acetic acid production or transportation suggest that
B. subtilis
uses acetic acid as a metabolic signal to coordinate the timing of biofilm formation. Lastly, we investigated how
B. subtilis
cells sense and respond to acetic acid in regulating biofilm formation. We showed the possible involvement of three sets of genes (
ywbHG
,
ysbAB
, and
yxaKC
), all encoding putative holin-antiholin-like proteins, in cells responding to acetic acid and stimulating biofilm formation. All three sets of genes were induced by acetate. A mutant with a triple mutation of those genes showed a severe delay in biofilm formation, whereas a strain overexpressing
ywbHG
showed early and robust biofilm formation. Results of our studies suggest that
B. subtilis
and possibly other bacteria use acetic acid as a metabolic signal to regulate biofilm formation as well as a quorum-sensing-like airborne signal to coordinate the timing of biofilm formation by physically separated cells in the community.

IMPORTANCE
Volatiles are small, air-transmittable molecules produced by all kingdoms of organisms including bacteria. Volatiles possess diverse biological activities and play important roles in bacteria-bacteria and bacteria-host interactions. Although volatiles can be used as a novel and important way of cell-cell communication due to their air-transmittable nature, little is known about how the volatile-mediated signaling mechanism works. In this study, we demonstrate that the bacterium
Bacillus subtilis
uses one such volatile, acetic acid, as a quorum-sensing-like signal to coordinate the timing of the formation of structurally complex cell communities, also known as biofilms. We further characterized the molecular mechanisms of how
B. subtilis
responds to acetic acid in stimulating biofilm formation. Our study also suggests that acetic acid may be used as a volatile signal for cross-species communication.