bluuebunny/crossref_metadata_2025 huggingface dataset:
Exogenous serotonin regulates colorectal motility via the 5‐HT2 and 5‐HT3 receptors in the spinal cord of rats
Authors: Nakamori H. , Naitou K. , Sano Y. , Shimaoka H. , Shiina T. , Shimizu Y.
Published: August 2017

Background

We previously reported that intrathecal injection of noradrenaline or dopamine causes enhancement of colorectal motility. As these monoamines are neurotransmitters of descending pain inhibitory pathways in the spinal cord, we hypothesized that serotonin, which is one of the neurotransmitters involved in descending pain inhibition, also influences the lumbosacral defecation center. Therefore, we examined whether serotonin acting on the spinal defecation center enhances colorectal motility.

Methods

Colorectal intraluminal pressure and propelled liquid volume were recorded in vivo in anesthetized rats.

Key Results

Intrathecal injection of serotonin into the L6‐S1 spinal cord elicited periodic increases in colorectal intraluminal pressure, being associated with increases in liquid output. Pharmacological experiments revealed that the effect of serotonin is mediated by both 5‐HT2 and 5‐HT3 receptors. The serotonin‐induced enhancement of colorectal motility was unaffected even after disconnection of the defecation center from supraspinal regions by cutting the T8 spinal cord, while transection of the parasympathetic pelvic nerves prevented the colokinetic effect of serotonin. Finally, we investigated interactions among serotonin, noradrenaline and dopamine. Simultaneous administration of sub‐effective doses of these monoamine neurotransmitters into the spinal cord caused propulsive colorectal motility slightly but substantially.

Conclusions and Inferences

These results demonstrate that exogenous serotonin acts on 5‐HT2 and 5‐HT3 receptors in the lumbosacral defecation center and activates the parasympathetic nervous system to enhance colorectal motility in cooperation with noradrenaline and dopamine.
Nanobody‐mediated resistance to Grapevine fanleaf virus in plants
Authors: Hemmer Caroline , Djennane Samia , Ackerer Léa , Hleibieh Kamal , Marmonier Aurélie , Gersch Sophie , Garcia Shahinez , Vigne Emmanuelle , Komar Véronique , Perrin Mireille , Gertz Claude , Belval Lorène , Berthold François , Monsion Baptiste , Schmitt‐Keichinger Corinne , Lemaire Olivier , Lorber Bernard , Gutiérrez Carlos , Muyldermans Serge , Demangeat Gérard , Ritzenthaler Christophe
Published: August 2017

Since their discovery, single‐domain antigen‐binding fragments of camelid‐derived heavy‐chain‐only antibodies, also known as nanobodies (Nbs), have proven to be of outstanding interest as therapeutics against human diseases and pathogens including viruses, but their use against phytopathogens remains limited. Many plant viruses including Grapevine fanleaf virus (GFLV), a nematode‐transmitted icosahedral virus and causal agent of fanleaf degenerative disease, have worldwide distribution and huge burden on crop yields representing billions of US dollars of losses annually, yet solutions to combat these viruses are often limited or inefficient. Here, we identified a Nb specific to GFLV that confers strong resistance to GFLV upon stable expression in the model plant Nicotiana benthamiana and also in grapevine rootstock, the natural host of the virus. We showed that resistance was effective against a broad range of GFLV isolates independently of the inoculation method including upon nematode transmission but not against its close relative, Arabis mosaic virus. We also demonstrated that virus neutralization occurs at an early step of the virus life cycle, prior to cell‐to‐cell movement. Our findings will not only be instrumental to confer resistance to GFLV in grapevine, but more generally they pave the way for the generation of novel antiviral strategies in plants based on Nbs.
Neurological comorbidity in children with neurofibromatosis type 1
Authors: Hirabaru Keiko , Matsuo Muneaki
Published: August 2017

Background

The aim of this study was to determine the frequency of central nervous system comorbidities in children with neurofibromatosis type 1 (NF1).

Methods

We performed a nationwide survey to investigate neurological comorbidities in 3–15‐year‐old children with NF1 in Japan by sending questionnaires to pediatricians and pediatric neurologists. A secondary questionnaire was sent to the parents of identified NF1 patients to assess neurological comorbidities including headache, attention deficit–hyperactivity disorder (ADHD) Rating Scale (RS), and the Social Responsiveness Scale 2.

Results

The primary survey identified 760 NF1 patients, and the parents of 565 patients were sent the secondary questionnaire. The parental response rate was 25.7% (145; 63 girls, 81 boys, one unspecified). Among the patients, 42.9% (55/128; 35 girls, 20 boys) were reported to exhibit intellectual problems. On the ADHD‐RS, 40.2% (47/117) of NF1 patients aged 6–15 had ADHD (RS score >93rd percentile), with a rate of 47.7% in boys and 30.8% in girls. Furthermore, 20.2% of patients had suspected autism spectrum disorder (29/143; 10 girls, 19 boys), with Social Responsiveness Scale score ≥76. Headache was reported by 49.6% (61/123) of children over 5 years old, and 25.2% (31/123; 10 girls, 21 boys) reported migraine. Other neurological comorbidities included 20 cases of epilepsy (13.8%), 11 cases of optic nerve glioma (7.6%), five cases of brain tumor (3.4%), six cases of cerebrovascular disease (4.1%), and two cases of hydrocephalus (1.4%).

Conclusion

Intellectual problems, ADHD, autism spectrum disorder, and migraine are major neurological comorbidities in NF1.
Physiological condition and wing pigmentation expression in a damselfly with seasonal polyphenism
Authors: Castaños Clara E. , Córdoba‐Aguilar Alex , Munguía‐Steyer Roberto
Published: August 2017

Secondary sexual traits can be indicators of individual condition that may present seasonal polyphenism as a result of the differential costs of expression along the season. Wing spots in male damselflies of the Calopterygidae family are secondary sexual traits associated with intrasexual competition and mate choice. Hetaerina titia Drury is a calopterygid damselfly where males show red and black wing spots, contrasting with other species of the genus whose males only express a red wing spot. In the present study, we evaluate the seasonal variation of the expression of male's red and black wing spots and their allometric patterns. Additionally, we measure male condition in the form of proteins, lipids, soluble carbohydrates and glycogen in early and late seasons. Black wing spots present higher variation than red wing spots and males of the late season are more pigmented. Allometry is positive for wing red spot in the early season and for black spot in the late season. Males of the late season present a higher concentration of proteins, soluble carbohydrates and glycogen, although there is no variation in the lipid content. The results of the present study suggest that, in H. titia males, black pigmentation replaces the function of the red pigmentation to signal condition. Both traits, however, may be heavily affected by environmental situations (e.g. food availability).
A High‐dimensional Focused Information Criterion
Authors: Gueuning Thomas , Claeskens Gerda
Published: August 2017

The focused information criterion for model selection is constructed to select the model that best estimates a particular quantity of interest, the focus, in terms of mean squared error. We extend this focused selection process to the high‐dimensional regression setting with potentially a larger number of parameters than the size of the sample. We distinguish two cases: (i) the case where the considered submodel is of low dimension and (ii) the case where it is of high dimension. In the former case, we obtain an alternative expression of the low‐dimensional focused information criterion that can directly be applied. In the latter case, we use a desparsified estimator that allows us to derive the mean squared error of the focus estimator. We illustrate the performance of the high‐dimensional focused information criterion with a numerical study and a real dataset.
The asymptotic distribution of the determinant of a random correlation matrix
Authors: Hanea A. M. , Nane G. F.
Published: August 2017

Our main result gives the asymptotic distribution of the determinant of a random correlation matrix sampled in a particular way from the space of d×d correlation matrices. Several spin‐off results are proven along the way, and an interesting connection with the law of the determinant of general random matrices is investigated. As different methods for generating random correlation matrices are proposed in the literature, one application of our result is that in can be employed to differentiate between those methods.
Sheath fold development in monoclinic shear zones
Authors: Adamuszek Marta , Dabrowski Marcin
Published: August 2017

We use numerical simulations to investigate the evolution of sheath folds around slip surfaces in simple‐shear‐dominated monoclinic shear zones. A variety of sheath fold shapes develops under general shear, including tubular folds with low aspect ratio eye patterns and tongue‐like structures showing bivergent flanking structures in sections normal to the sheath elongation, which may potentially lead to confusing shear sense interpretations. Not all investigated monoclinic flow end‐members lead to the development of sheath folds sensu stricto (folds with apical angle <90°). The aspect ratio of the eye patterns, Ryz, correlates with the ratio between the principal strain in the Y‐direction and the smaller of the principal strains in the X–Z plane, and thus it could be used in strain analysis.
Impact of carbapenem‐resistant Klebsiella pneumoniae (CR‐KP) infections in kidney transplantation
Authors: Varotti Giovanni , Dodi Ferdinando , Terulla Alessia , Santori Gregorio , Mariottini Gabriele , Bertocchi Massimo , Marchese Anna , Fontana Iris
Published: August 2017

Background

Carbapenem‐resistant Klebsiella pneumoniae (CR‐KP) infections in solid organ transplant patients are progressively increasing and are associated with worse outcomes, although potential risk factors and therapeutic strategies are still not well defined.

Methods

We conducted a retrospective matched‐pair analysis in which we compared 26 recipients CR‐KP‐positive after kidney transplantation (KT) with 52 CR‐KP‐negative patients transplanted in the same period, during a CR‐KP outbreak that occurred in our hospital. Twenty‐one patients (80%) received a combined antibiotic treatment. At the end of the follow‐up, of the 26 CR‐KP infected patients, 11 (42.3%) experienced at least one episode of re‐infection, 9 (34.6%) remained colonized, and 6 (23.0%) had a symptomatic infection. Two of the 11 patients with re‐infection died, while 9 were colonized at the end of the study.

Results

A significantly better patient (P = .043) and graft (P < .001) survival was observed in CR‐KP‐negative patients. Univariate analysis identified the following variables as potential risk factors associated with CR‐KP infection after KT: lower body mass index (P = .020); higher creatinine levels at post‐transplant days 7 (P = .009), 15 (P = .026), and 30 (P = .019); longer hospital stay (P = .007); longer cold ischemia time (P = .004); delayed graft function (P = .020); and higher Clavien‐Dindo score (P = .006).

Conclusion

The study confirmed that a CR‐KP positivity may affect the outcome of a kidney transplant population. In severe CR‐KP infections with sepsis, a combined antibiotic treatment seems to be advisable.
Safe and effective administration of BCG for bladder carcinoma in situ after umbilical cord blood stem cell transplantation
Authors: Magaribuchi Toshihiro , Akamatsu Shusuke , Kobayashi Takashi , Kawabata Hiroshi , Yamasaki Toshinari , Inoue Takahiro , Ogawa Osamu
Published: August 2017

Although intravesical Bacillus Calmette‐Guérin (BCG) instillation is the standard treatment for carcinoma in situ of the bladder, it is generally contraindicated in immunocompromised patients. Here we report the first case, to our knowledge, of BCG treatment for a bladder cancer patient who had received umbilical cord blood stem cell transplantation (UCBSCT). BCG can be given safely and effectively in select cases where reconstitution of the immune system has been achieved at least 2 years after UCBSCT.
Tackling female genital mutilation in the UK
Authors: Hussain Sadiya , Rymer Janice
Published: August 2017

Key content

In the UK, female genital mutilation (FGM) has been outlawed since 1985, yet the practice continues. The multiplicity of reasons given for the practice include tradition, religion and preservation of virginity.

The procedure can lead to numerous and deleterious physical, psychological and sexual effects.

Legislating against FGM provides an official platform to back up the position of activists and community members that do not wish to continue with the practice.

However, the legislative developments, including mandatory recording and reporting of FGM cases, need to go hand in hand with the training of healthcare professionals, improving health and social service provisions, robust political commitment and education and empowerment of FGM‐practising communities.

Learning objectives

To define FGM, to understand the practice, the procedure and its consequences.

To examine the legislative development in the UK.

To look at how we can improve the services that care for women at risk or who have undergone FGM.

Ethical issues

Female genital cosmetic surgery.

Mandatory reporting of FGM.

Gender inequalities.

Cultural/racial sensitivity.
Evaluation of the use of shock index in identifying acute blood loss in healthy blood donor dogs
Authors: McGowan Erin E. , Marryott Kimberly , Drobatz Kenneth J. , Reineke Erica L.
Published: August 2017

Objective

To determine if shock index (SI) would increase following blood donation and if it would be a more sensitive assessment of acute blood loss as compared with heart rate (HR), blood pressure, and plasma lactate.

Design

Prospective study.

Setting

University teaching hospital.

Animals

Twenty client‐owned clinically normal dogs.

Interventions

Peripheral venous blood measurements and blood donation.

Measurements and Main Results

Data were collected at 3 time points: prior to donation (Tpre), immediately after donation (T0), and 10 minutes following completion of donation (T10). HR and systolic blood pressure (SBP) were recorded and used to calculate SI at time pointsTpre,T0, andT10. Packed cell volume (PCV), total plasma protein (TPP), and plasma lactate were evaluated from a peripheral venous blood sample atTpreandT10.The mean SI was significantly increased at both time points following blood donation as compared to baseline (SIpre= 0.88 ± 0.19 vs SI0= 1.17 ± 0.21 vs SI10= 1.12 ± 0.25 (P= 0.0002 and 0.0003, respectively). Following blood donation, the mean SBP was significantly lower (SBPpre= 149 ± 24 mm Hg, SBP0= 118 ± 20 mm Hg;P= 0.0001, SBP10= 133 ± 21 mm Hg;P= 0.011). The mean HR was not significantly different atT0but was significantly increased atT10(HRpre= 128 ± 21/min, HR0= 136 ± 25/min,P= 0.193; HR10= 146 ± 29/min,P= 0.003). There was no significant difference in mean PCV (PCVpre= 50 ± 4%, PCV10= 48 ± 4%,P= 0.08). The mean TPP and plasma lactate were significantly different following donation but still within the reference interval (TPPpre= 6.8 ± 0.4 g/dL, TPP10= 6.4 ± 0.4 g/dL,P= 0.0014; Lacpre= 1.7 ± 0.7mmol/L, Lac10= 1.9 ± 0.8 mmol/L,P= 0.04). A receiver operating characteristic (ROC) analysis comparing area under the curve (AUC) for SI, HR, and SBP atT0andT10compared toTprefound that SI (AUC atT0: 0.858, CI: 0.730, 0.984 AUC atT10: 0.769 CI: 0.617, 0.921) was a better indicator of blood loss than SBP at bothT0(AUC 0.165, CI: 0.0384, 0.292,P < 0.0001) andT10(AUC 0.288, CI: 0.124, 0.451,P < 0.001) and better than HR atT0(AUC 0.574, CI: 0.392, 0.756,P < 0.001). An SI cut‐off of 1.064 was 80% specific and 85% sensitive atT0for detecting blood loss.

Conclusions

An SI > 1.0 is a sensitive and specific tool for detecting acute small volume blood loss in healthy dogs.
Interventions to Reduce Perceived Stress Among Graduate Students: A Systematic Review With Implications for Evidence‐Based Practice
Authors: Stillwell Susan B. , Vermeesch Amber L. , Scott Jane G.
Published: August 2017

Background

Stress is a part of daily life for graduate students, including graduate nursing students. Contemporary graduate nursing students are facing unprecedented challenges to meet rigorous academic standards as they prepare for their advanced professional role to meet the demands of the nation's complex and ever‐changing healthcare system. Empowering graduate nursing students to ease their perceived stress and minimize undesirable health effects may benefit their capacity to adapt and successfully manage perceived stress in their future healthcare role.

Aims

To conduct a systematic review to evaluate the existing evidence with the aim of identifying evidence‐based self‐care interventions for coping with perceived stress.

Methods

We conducted a systematic review, searching CINAHL Plus with Full Text, PsycINFO, and MEDLINE. Inclusion criteria included self‐care, graduate students, perceived stress as measured by Perceived Stress Scale, quantitative analysis, conducted within the United States, English language, and peer reviewed. Two authors completed an asynchronous review of the articles, and one expert evidence‐based practice mentor and one wellness expert conducted rigorous appraisal of the eight identified studies. Evidence was evaluated and synthesized, and recommendations for practice were determined.

Results

Eight studies meeting the criteria for this systematic review were critically appraised. The interventions varied from a stress management course to mind‐body‐stress‐reduction (MBSR) techniques, such as yoga, breath work, meditation, and mindfulness. All studies measured the outcome of stress with the Perceived Stress Scale. Each study demonstrated a reduction in perceived stress postintervention.

Linking Evidence to Action

Most effective self‐care MBSR interventions include (a) a didactic component, (b) a guided MBSR practice session, and (c) homework. Consideration should be given to a trained or certified MBSR instructor to teach the intervention.
An In-Process Intervention to Mitigate the Effect of Built-Up Edges in Micromilling
Authors: Altman Robert G. , Nowak James F. , Samuel Johnson
Published: August 2017

This paper is focused on developing an in-process intervention technique that mitigates the effect of built-up edges (BUEs) during micromilling of aluminum. The technique relies on the intermittent removal of the BUEs formed during the machining process. This is achieved using a three-stage intervention that consists first of the mechanical removal of mesoscale BUEs, followed by an abrasive slurry treatment to remove the microscale BUEs. Finally, the tool is cleaned using a nonwoven fibrous mat to remove the slurry debris. An on-machine implementation of this intervention technique is demonstrated, followed by a study of its influence on key micromachining outcomes such as tool wear, cutting forces, part geometry, and burr formation. In general, all relevant machining measures are found to improve significantly with the intervention. The key attributes of this intervention that makes it viable for micromachining processes include the following: (i) an experimental setup that can be implemented within the working volume of the microscale machine tool; (ii) no removal of the tool from the spindle, which ensures that the intervention does not change critical process parameters such as tool runout and offset values; and (iii) implementation in the form of canned G-code subroutines dispersed within the regular micromachining operation.
Convective Eigenvalue Problems for Convergence Enhancement of Eigenfunction Expansions in Convection–Diffusion Problems
Authors: Cotta Renato M. , Naveira-Cotta Carolina P. , Knupp Diego C.
Published: August 2017

The present work considers the application of the generalized integral transform technique (GITT) in the solution of a class of linear or nonlinear convection–diffusion problems, by fully or partially incorporating the convective effects into the chosen eigenvalue problem that forms the basis of the proposed eigenfunction expansion. The aim is to improve convergence behavior of the eigenfunction expansions, especially in the case of formulations with significant convective effects, by simultaneously accounting for the relative importance of convective and diffusive effects within the eigenfunctions themselves, in comparison against the more traditional GITT solution path, which adopts a purely diffusive eigenvalue problem, and the convective effects are fully incorporated into the problem source term. After identifying a characteristic convective operator, and through a straightforward algebraic transformation of the original convection–diffusion problem, basically by redefining the coefficients associated with the transient and diffusive terms, the characteristic convective term is merged into a generalized diffusion operator with a space-variable diffusion coefficient. The generalized diffusion problem then naturally leads to the eigenvalue problem to be chosen in proposing the eigenfunction expansion for the linear situation, as well as for the appropriate linearized version in the case of a nonlinear application. The resulting eigenvalue problem with space variable coefficients is then solved through the GITT itself, yielding the corresponding algebraic eigenvalue problem, upon selection of a simple auxiliary eigenvalue problem of known analytical solution. The GITT is also employed in the solution of the generalized diffusion problem, and the resulting transformed ordinary differential equations (ODE) system is solved either analytically, for the linear case, or numerically, for the general nonlinear formulation. The developed methodology is illustrated for linear and nonlinear applications, both in one-dimensional (1D) and multidimensional formulations, as represented by test cases based on Burgers' equation.
Towards a joint reflection-distortion otoacoustic emission profile: Results in normal and impaired ears
Authors: Abdala Carolina , Kalluri Radha
Published: August 2017

Otoacoustic emissions (OAEs) provide salient information about cochlear function and dysfunction. Two broad classes of emissions, linear reflection and nonlinear distortion, arise via distinct cochlear processes and hence, appear to provide independent information about cochlear health and hearing. Considered in combination, these two OAE types may characterize sensory hearing loss most effectively. In this study, the level-dependent growth of stimulus-frequency OAEs (a reflection-type emission) and distortion-product OAEs (a distortion-type emission) were measured in ten normal-hearing ears and eight ears with slight-to-moderate sensorineural hearing loss. Metrics of OAE strength and compression were derived from OAE input/output functions and then considered in a combined fashion. Results indicate that SFOAEs and DPOAEs differ significantly in their strength and compression features. When SFOAE and DPOAE metrics are displayed together on a two-dimensional plot, relatively well-defined data clusters describe their normative relationship. In hearing-impaired ears, this relationship is disrupted but not in a uniform way across ears; ears with similar audiograms showed differently altered joint-OAE profiles. Hearing loss sometimes affected only one OAE or one more than the other. Results suggest a joint-OAE profile is promising and warrants study in a large group of subjects with sensory hearing loss of varied etiologies.
Circumstellar disks of the most vigorously accreting young stars
Authors: Liu Hauyu Baobab , Takami Michihiro , Kudo Tomoyuki , Hashimoto Jun , Dong Ruobing , Vorobyov Eduard I. , Pyo Tae-Soo , Fukagawa Misato , Tamura Motohide , Henning Thomas , Dunham Michael M. , Karr Jennifer L. , Kusakabe Nobuhiko , Tsuribe Toru
Published: August 2017

Subaru-HiCIAO observations on FU Orionis objects revealed asymmetric structures on 10
2
to 10
3
AU scales of circumstellar disks and envelopes.
Toughness of carbon nanotubes conforms to classic fracture mechanics
Authors: Yang Lin , Greenfeld Israel , Wagner H. Daniel
Published: August 2017

The classic theory of fracture mechanics is found to be valid at the scale of single-walled carbon nanotubes.
Draft Genome Sequence of
Magnetospirillum
sp. Strain 15-1, a Denitrifying Toluene Degrader Isolated from a Planted Fixed-Bed Reactor
Authors: Meyer-Cifuentes Ingrid , Fiedler Stefan , Müller Jochen A. , Kappelmeyer Uwe , Mäusezahl Ines , Heipieper Hermann J.
Published: August 2017

Here, we report the draft genome sequence of
Magnetospirillum
sp. 15-1. This strain was isolated from a planted fixed-bed reactor based on its ability to degrade toluene under anaerobic conditions. The genome assembly consists of 5.4 Mb in 28 contigs and 5,095 coding sequences containing the genes involved in anaerobic toluene degradation.
Discovery and Validation of a Six-Marker Serum Protein Signature for the Diagnosis of Active Pulmonary Tuberculosis
Authors: De Groote Mary A. , Sterling David G. , Hraha Thomas , Russell Theresa M. , Green Louis S. , Wall Kirsten , Kraemer Stephan , Ostroff Rachel , Janjic Nebojsa , Ochsner Urs A.
Published: August 2017

New non-sputum biomarker tests for active tuberculosis (TB) diagnostics are of the highest priority for global TB control. We performed in-depth proteomic analysis using the 4,000-plex SOMAscan assay on 1,470 serum samples from seven countries where TB is endemic. All samples were from patients with symptoms and signs suggestive of active pulmonary TB that were systematically confirmed or ruled out for TB by culture and clinical follow-up. HIV coinfection was present in 34% of samples, and 25% were sputum smear negative. Serum protein biomarkers were identified by stability selection using L1-regularized logistic regression and by Kolmogorov-Smirnov (KS) statistics. A naive Bayes classifier using six host response markers (HR6 model), including SYWC, kallistatin, complement C9, gelsolin, testican-2, and aldolase C, performed well in a training set (area under the sensitivity-specificity curve [AUC] of 0.94) and in a blinded verification set (AUC of 0.92) to distinguish TB and non-TB samples. Differential expression was also highly significant (
P
< 10
−20
) for previously described TB markers, such as IP-10, LBP, FCG3B, and TSP4, and for many novel proteins not previously associated with TB. Proteins with the largest median fold changes were SAA (serum amyloid protein A), NPS-PLA2 (secreted phospholipase A2), and CA6 (carbonic anhydrase 6). Target product profiles (TPPs) for a non-sputum biomarker test to diagnose active TB for treatment initiation (TPP#1) and for a community-based triage or referral test (TPP#2) have been published by the WHO. With 90% sensitivity and 80% specificity, the HR6 model fell short of TPP#1 but reached TPP#2 performance criteria. In conclusion, we identified and validated a six-marker signature for active TB that warrants diagnostic development on a patient-near platform.
Comparative Genomics Study of Staphylococcus epidermidis Isolates from Orthopedic-Device-Related Infections Correlated with Patient Outcome
Authors: Post Virginia , Harris Llinos G. , Morgenstern Mario , Mageiros Leonardos , Hitchings Matthew D. , Méric Guillaume , Pascoe Ben , Sheppard Samuel K. , Richards R. Geoff , Moriarty T. Fintan
Published: August 2017

Staphylococcus epidermidis
has emerged as an important opportunistic pathogen causing orthopedic-device-related infections (ODRI). This study investigated the association of genome variation and phenotypic features of the infecting
S. epidermidis
isolate with the clinical outcome for the infected patient.
S. epidermidis
isolates were collected from 104 patients with ODRI. Their clinical outcomes were evaluated, after an average of 26 months, as either “cured” or “not cured.” The isolates were tested for antibiotic susceptibility and biofilm formation. Whole-genome sequencing was performed on all isolates, and genomic variation was related to features associated with “cured” and “not cured.” Strong biofilm formation and aminoglycoside resistance were associated with a “not-cured” outcome (
P
= 0.031 and
P
< 0.001, respectively). Based on gene-by-gene analysis, some accessory genes were more prevalent in isolates from the “not-cured” group. These included the biofilm-associated
bhp
gene, the antiseptic resistance
qacA
gene, the cassette chromosome recombinase-encoding genes
ccrA
and
ccrB
, and the IS
256
-like transposase gene. This study identifies biofilm formation and antibiotic resistance as associated with poor outcome in
S. epidermidis
ODRI. Whole-genome sequencing identified specific genes associated with a “not-cured” outcome that should be validated in future studies. (The study has been registered at ClinicalTrials.gov with identifier NCT02640937.)
Sorafenib Impedes Rift Valley Fever Virus Egress by Inhibiting Valosin-Containing Protein Function in the Cellular Secretory Pathway
Authors: Brahms Ashwini , Mudhasani Rajini , Pinkham Chelsea , Kota Krishna , Nasar Farooq , Zamani Rouzbeh , Bavari Sina , Kehn-Hall Kylene
Published: August 2017

There is an urgent need for therapeutic development to combat infections caused by Rift Valley fever virus (RVFV), which causes devastating disease in both humans and animals. In an effort to repurpose drugs for RVFV treatment, our previous studies screened a library of FDA-approved drugs. The most promising candidate identified was the hepatocellular and renal cell carcinoma drug sorafenib. Mechanism-of-action studies indicated that sorafenib targeted a late stage in virus infection and caused a buildup of virions within cells. In addition, small interfering RNA (siRNA) knockdown studies suggested that nonclassical targets of sorafenib are important for the propagation of RVFV. Here we extend our previous findings to identify the mechanism by which sorafenib inhibits the release of RVFV virions from the cell. Confocal microscopy imaging revealed that glycoprotein Gn colocalizes and accumulates within the endoplasmic reticulum (ER) and the transport of Gn from the Golgi complex to the host cell membrane is reduced. Transmission electron microscopy demonstrated that sorafenib caused virions to be present inside large vacuoles inside the cells. p97/valosin-containing protein (VCP), which is involved in membrane remodeling in the secretory pathway and a known target of sorafenib, was found to be important for RVFV egress. Knockdown of VCP resulted in decreased RVFV replication, reduced Gn Golgi complex localization, and increased Gn ER accumulation. The intracellular accumulation of RVFV virions was also observed in cells transfected with siRNA targeting VCP. Collectively, these data indicate that sorafenib causes a disruption in viral egress by targeting VCP and the secretory pathway, resulting in a buildup of virions within dilated ER vesicles.

IMPORTANCE
In humans, symptoms of RVFV infection mainly include a self-limiting febrile illness. However, in some cases, infected individuals can also experience hemorrhagic fever, neurological disorders, liver failure, and blindness, which could collectively be lethal. The ability of RVFV to expand geographically outside sub-Saharan Africa is of concern, particularly to the Americas, where native mosquito species are capable of virus transmission. Currently, there are no FDA-approved therapeutics to treat RVFV infection, and thus, there is an urgent need to understand the mechanisms by which the virus hijacks the host cell machinery to replicate. The significance of our research is in identifying the cellular target of sorafenib that inhibits RVFV propagation, so that this information can be used as a tool for the further development of therapeutics used to treat RVFV infection.
Interferon-Inducible CD169/Siglec1 Attenuates Anti-HIV-1 Effects of Alpha Interferon
Authors: Akiyama Hisashi , Ramirez Nora-Guadalupe Pina , Gibson Gregory , Kline Christopher , Watkins Simon , Ambrose Zandrea , Gummuluru Suryaram
Published: August 2017

A hallmark of human immunodeficiency virus type 1 (HIV-1) infectionin vivois chronic immune activation concomitant with type I interferon (IFN) production. Although type I IFN induces an antiviral state in many cell types, HIV-1 can replicatein vivovia mechanisms that have remained unclear. We have recently identified a type I IFN-inducible protein, CD169, as the HIV-1 attachment factor on dendritic cells (DCs) that can mediate robust infection of CD4+T cells intrans. Since CD169 expression on macrophages is also induced by type I IFN, we hypothesized that type I IFN-inducible CD169 could facilitate productive HIV-1 infection in myeloid cells incisand CD4+T cells intransand thus offset antiviral effects of type I IFN. In support of this hypothesis, infection of HIV-1 or murine leukemia virus Env (MLV-Env)-pseudotyped HIV-1 particles was enhanced in IFN-α-treated THP-1 monocytoid cells, and this enhancement was primarily dependent on CD169-mediated enhancement at the virus entry step, a phenomenon phenocopied in HIV-1 infections of IFN-α-treated primary monocyte-derived macrophages (MDMs). Furthermore, expression of CD169, a marker of type I IFN-induced immune activationin vivo, was enhanced in lymph nodes from pigtailed macaques infected with simian immunodeficiency virus (SIV) carrying HIV-1 reverse transcriptase (RT-SHIV), compared to uninfected macaques, and interestingly, there was extensive colocalization of p27gagand CD169, suggesting productive infection of CD169+myeloid cellsin vivo. While cell-free HIV-1 infection of IFN-α-treated CD4+T cells was robustly decreased, initiation of infection intransvia coculture with CD169+IFN-α-treated DCs restored infection, suggesting that HIV-1 exploits CD169 incisand intransto attenuate a type I IFN-induced antiviral state.

IMPORTANCEHIV-1 infection in humans causes immune activation characterized by elevated levels of proinflammatory cytokines, including type I interferons (IFN). Although type I IFN induces an antiviral state in many cell typesin vitro, HIV-1 can replicatein vivovia mechanisms that have remained unclear. In this study, we tested the hypothesis that CD169, a type I IFN-inducible HIV-1 attachment factor, offsets antiviral effects of type I IFN. Infection of HIV-1 was rescued in IFN-α-treated myeloid cells via upregulation of CD169 and a subsequent increase in CD169-dependent virus entry. Furthermore, extensive colocalization of viral Gag and CD169 was observed in lymph nodes of infected pigtailed macaques, suggesting productive infection of CD169+cellsin vivo. Treatment of dendritic cell (DC)-T cell cocultures with IFN-α upregulated CD169 expression on DCs and rescued HIV-1 infection of CD4+T cells intrans, suggesting that HIV-1 exploits CD169 to attenuate type I IFN-induced restrictions.
Structure-Based Design of Hepatitis C Virus Vaccines That Elicit Neutralizing Antibody Responses to a Conserved Epitope
Authors: Pierce Brian G. , Boucher Elisabeth N. , Piepenbrink Kurt H. , Ejemel Monir , Rapp Chelsea A. , Thomas William D. , Sundberg Eric J. , Weng Zhiping , Wang Yang
Published: August 2017

Despite recent advances in therapeutic options, hepatitis C virus (HCV) remains a severe global disease burden, and a vaccine can substantially reduce its incidence. Due to its extremely high sequence variability, HCV can readily escape the immune response; thus, an effective vaccine must target conserved, functionally important epitopes. Using the structure of a broadly neutralizing antibody in complex with a conserved linear epitope from the HCV E2 envelope glycoprotein (residues 412 to 423; epitope I), we performed structure-based design of immunogens to induce antibody responses to this epitope. This resulted in epitope-based immunogens based on a cyclic defensin protein, as well as a bivalent immunogen with two copies of the epitope on the E2 surface. We solved the X-ray structure of a cyclic immunogen in complex with the HCV1 antibody and confirmed preservation of the epitope conformation and the HCV1 interface. Mice vaccinated with our designed immunogens produced robust antibody responses to epitope I, and their serum could neutralize HCV. Notably, the cyclic designs induced greater epitope-specific responses and neutralization than the native peptide epitope. Beyond successfully designing several novel HCV immunogens, this study demonstrates the principle that neutralizing anti-HCV antibodies can be induced by epitope-based, engineered vaccines and provides the basis for further efforts in structure-based design of HCV vaccines.

IMPORTANCE
Hepatitis C virus is a leading cause of liver disease and liver cancer, with approximately 3% of the world's population infected. To combat this virus, an effective vaccine would have distinct advantages over current therapeutic options, yet experimental vaccines have not been successful to date, due in part to the virus's high sequence variability leading to immune escape. In this study, we rationally designed several vaccine immunogens based on the structure of a conserved epitope that is the target of broadly neutralizing antibodies.
In vivo
results in mice indicated that these antigens elicited epitope-specific neutralizing antibodies, with various degrees of potency and breadth. These promising results suggest that a rational design approach can be used to generate an effective vaccine for this virus.
Adenovirus Core Protein VII Downregulates the DNA Damage Response on the Host Genome
Authors: Avgousti Daphne C. , Della Fera Ashley N. , Otter Clayton J. , Herrmann Christin , Pancholi Neha J. , Weitzman Matthew D.
Published: August 2017

Viral manipulation of cellular proteins allows viruses to suppress host defenses and generate infectious progeny. Due to the linear double-stranded DNA nature of the adenovirus genome, the cellular DNA damage response (DDR) is considered a barrier to successful infection. The adenovirus genome is packaged with protein VII, a virally encoded histone-like core protein that is suggested to protect incoming viral genomes from detection by the cellular DNA damage machinery. We showed that protein VII localizes to host chromatin during infection, leading us to hypothesize that protein VII may affect DNA damage responses on the cellular genome. Here we show that protein VII at cellular chromatin results in a significant decrease in accumulation of phosphorylated H2AX (γH2AX) following irradiation, indicating that protein VII inhibits DDR signaling. The oncoprotein SET was recently suggested to modulate the DDR by affecting access of repair proteins to chromatin. Since protein VII binds SET, we investigated a role for SET in DDR inhibition by protein VII. We show that knockdown of SET partially rescues the protein VII-induced decrease in γH2AX accumulation on the host genome, suggesting that SET is required for inhibition. Finally, we show that knockdown of SET also allows ATM to localize to incoming viral genomes bound by protein VII during infection with a mutant lacking early region E4. Together, our data suggest that the protein VII-SET interaction contributes to DDR evasion by adenovirus. Our results provide an additional example of a strategy used by adenovirus to abrogate the host DDR and show how viruses can modify cellular processes through manipulation of host chromatin.

IMPORTANCE
The DNA damage response (DDR) is a cellular network that is crucial for maintaining genome integrity. DNA viruses replicating in the nucleus challenge the resident genome and must overcome cellular responses, including the DDR. Adenoviruses are prevalent human pathogens that can cause a multitude of diseases, such as respiratory infections and conjunctivitis. Here we describe how a small adenovirus core protein that localizes to host chromatin during infection can globally downregulate the DDR. Our study focuses on key players in the damage signaling pathway and highlights how viral manipulation of chromatin may influence access of DDR proteins to the host genome.
Effects of Acupuncture on the Urinary Metabolome of Spontaneously Hypertensive Rats
Authors: Wang Ying , Li Yang , Zhou Liang , Guo Lin
Published: August 2017

Background

The mechanism of action underlying the putative effects of acupuncture in essential hypertension remains unknown but neuronal mechanisms have been explored most extensively to date. We aimed to explore the effects of manual acupuncture (MA) with manual stimulation on blood pressure (BP) and urine metabolites in the spontaneously hypertensive rat (SHR) model of hypertension.

Methods

After adaptive feeding (with a standard laboratory diet and distilled water) for 1 week, five normotensive Wistar Kyoto (WKY) rats with normal BP formed the control group. Ten SHRs were randomised into two groups (n=5 each), one of which received MA at ST9 for a total of 14 days (SHR+MA group). The other (SHR group) and the WKY control group underwent needle insertion without manual stimulation. BP was measured pre- and post-acupuncture in all groups and urinary metabolic profiles were investigated using metabonomics methods based on 1H nuclear magnetic resonance (NMR) spectroscopy coupled with principal component analysis, partial least squares discriminant analysis, and orthogonal to partial least squares discriminant analysis.

Results

A total of 46 metabolites were clearly separated in the urine by 1H NMR. Loading plots showed significant changes in urinary metabolite contents after acupuncture treatment as well as significant differences between SHR and WKY rats. Acupuncture at ST9 in SHRs increased urine metabolites including α-ketoglutaric acid, N-acetyl glutamic acid, and betaine. Furthermore, systolic and diastolic BP, mean arterial pressure and heart rate were significantly reduced after acupuncture.

Conclusions

Acupuncture may decrease BP in SHRs by improving the metabolic disorder associated with hypertension.
The majority of irregular menstrual cycles in adolescence are ovulatory: results of a prospective study
Authors: Peña Alexia S , Doherty Dorota A , Atkinson Helen C , Hickey Martha , Norman Robert J , Hart Roger
Published: August 2017

Purpose

While ovulation is most likely to occur in adolescent girls with regular menstrual cycles, there are limited data on the incidence of ovulation in girls with irregular menstrual cycles in early postmenarcheal years. The aim of the study was to evaluate the presence of ovulation in healthy postmenarcheal girls with irregular menstrual cycles.

Methods, design and subjects

Prospective cohort study over 12 weeks including 40 healthy postmenarcheal girls recruited from the population-based cohort of adolescents from Western Australian Pregnancy Cohort (Raine) Study with irregular menstrual cycles defined by either menstrual cycles <21 days or >35 days in duration or cycle length that varied from month to month by >4 days according to menstrual diaries.

Main outcome measure

Ovulation defined by urinary pregnanediol-3α–glucuronide/creatinine measurements higher than three times above minimum value obtained from 12 samples (1 per week).

Results

Forty girls (37 Caucasians) with irregular menstrual cycles aged 15.1 (median (IQR) 14.9–15.4) years who were 2.3 (1.9–3.3) years postmenarche were assessed. Urinary pregnanediol-3α–glucuronide/creatinine values identified that 33 girls (82.5%) ovulated during the 3 months of observation and 7 girls had anovulatory cycles. Menstrual diaries collected for a median (IQR) of 159 (137.5–188.2) days showed median minimal and maximum menstrual cycle duration of 24 (11.5–29) and 38.5 (35–48) days, respectively.

Conclusions

A large proportion of healthy adolescent girls with irregular menstrual cycles are still ovulating despite irregular and infrequent menses.
Diagnostic delay in Canadian children with inflammatory bowel disease is more common in Crohn’s disease and associated with decreased height
Authors: Ricciuto Amanda , Fish Jennifer R , Tomalty Diane E , Carman Nicholas , Crowley Eileen , Popalis Cynthia , Muise Aleixo , Walters Thomas D , Griffiths Anne M , Church Peter C
Published: August 2017

Objectives

To determine time to diagnosis in a paediatric inflammatory bowel disease (IBD) cohort and the relative contribution of the component intervals, and to identify factors associated with diagnostic delay.

Design

Prospective cohort study

Setting

Single-centre study including children with incident IBD at the Hospital for Sick Children diagnosed between December 2013 and December 2015.

Interventions

Time to diagnosis and its subintervals were determined and patient, disease and institutional factors were tested for associations.

Results

Among 111 children, the median overall time to diagnosis was 4.5 (IQR 2.1–8.8) months. Time to diagnosis was longer in Crohn’s disease (CD) than ulcerative colitis (UC) (median 6.8 (IQR 2.9–12.5) vs 2.4 (IQR 1.3–5.3) months) and patients with isolated small bowel disease. Twenty per cent of patients were diagnosed≥1 year after symptom onset (86% CD, 14% UC, p=0.003). Time from symptom onset to gastroenterology referral was the greatest contributor to overall time to diagnosis (median 2.9 (IQR 1.6–8.2) months). Height impairment was independently associated with diagnostic delay (OR 0.59, p=0.02, for height-for-age z-score (HAZ), signifying almost 70% increased odds of delay for every 1 SD decrease in HAZ). This height discrepancy persisted 1 year after diagnosis. Bloody diarrhoea was protective against delay (OR 0.28, p=0.02). The subinterval from referral to diagnosis was shorter in patients with laboratory abnormalities, particularly hypoalbuminaemia.

Conclusions

Diagnostic delay was more common in CD and associated with height impairment that persisted 1 year after presentation. The greatest contributor to time to diagnosis was time from symptom onset to referral.
A rare urological presentation of appendicitis
Authors: Simson Nick , Stonier Thomas , Coscione Alberto , Qteishat Ahmed
Published: August 2017

A 17-year-old boy with no medical comorbidities, but a significant family history of malignancy, presented to Accident and Emergency following 3 days of increasing rectal pain, symptoms of bladder outflow obstruction (poor flow, intermittent stream and hesitancy) and dysuria. Notably he had no abdominal pain. Digital rectal examination revealed a tender, enlarged prostate. Inflammatory markers were significantly raised (white cell count 17.7, C reactive protein 191). He was diagnosed clinically as prostatitis and commenced on intravenous antibiotics. Despite this his pain and inflammatory markers deteriorated, necessitating a CT of his abdomen and pelvis. This demonstrated multiloculated large thick-walled abscesses in the pelvis closely related to the rectum, prostate and seminal vesicles with some bowel wall thickening. Laparoscopy demonstrated a large colonic mass adherent to surrounding structures. The procedure was converted to laparotomy to enable resection of the mass via a limited right haemicolectomy. He recovered well and was discharged. Histopathological analysis of the specimen revealed appendicitis.