bluuebunny/crossref_metadata_2025 huggingface dataset:
Carbon Monoxide Improves Efficacy of Mesenchymal Stromal Cells During Sepsis by Production of Specialized Proresolving Lipid Mediators*
Authors: Tsoyi Konstantin , Hall Sean R. R. , Dalli Jesmond , Colas Romain A. , Ghanta Sailaja , Ith Bonna , Coronata Anna , Fredenburgh Laura E. , Baron Rebecca M. , Choi Augustine M. K. , Serhan Charles N. , Liu Xiaoli , Perrella Mark A.
Published: August 2016

Objectives:

Mesenchymal stromal cells are being investigated as a cell-based therapy for a number of disease processes, with promising results in animal models of systemic inflammation and sepsis. Studies are ongoing to determine ways to further improve the therapeutic potential of mesenchymal stromal cells. A gas molecule that improves outcome in experimental sepsis is carbon monoxide. We hypothesized that preconditioning of mesenchymal stromal cells with carbon monoxide ex vivo would promote further therapeutic benefit when cells are administered in vivo after the onset of polymicrobial sepsis in mice.

Design:

Animal study and primary cell culture.

Setting:

Laboratory investigation.

Subjects:

BALB/c mice.

Interventions:

Polymicrobial sepsis was induced by cecal ligation and puncture. Mesenchymal stromal cells, mesenchymal stromal cells-conditioned with carbon monoxide, fibroblasts, or fibroblasts-conditioned with carbon monoxide were delivered by tail vein injections to septic mice. The mice were assessed for survival, bacterial clearance, and the inflammatory response during sepsis in each of the groups. Mesenchymal stromal cells were also assessed for their ability to promote bacterial phagocytosis by neutrophils, the production of specialized proresolving lipid mediators, and their importance for mesenchymal stromal cells function using gene silencing.

Measurements and Main Results:

Ex vivo preconditioning with carbon monoxide allowed mesenchymal stromal cells to be administered later after the onset of sepsis (6 hr), and yet maintain their therapeutic effect with increased survival. Carbon monoxide preconditioned mesenchymal stromal cells were also able to alleviate organ injury, improve bacterial clearance, and promote the resolution of inflammation. Mesenchymal stromal cells exposed to carbon monoxide, with docosahexaenoic acid substrate, produced specialized proresolving lipid mediators, particularly D-series resolvins, which promoted survival. Silencing of lipoxygenase pathways (5-lipoxygenase and 12/15-lipoxygenase), which are important enzymes for specialized proresolving lipid mediator biosynthesis, resulted in a loss of therapeutic benefit bestowed on mesenchymal stromal cells by carbon monoxide.

Conclusions:

Taken together, these data suggest that production of specialized proresolving lipid mediators contribute to improved mesenchymal stromal cell efficacy when exposed to carbon monoxide, resulting in an improved therapeutic response during sepsis.
XAV939 Inhibits Intima Formation by Decreasing Vascular Smooth Muscle Cell Proliferation and Migration Through Blocking Wnt Signaling
Authors: Chen Luoman , Zhuang Jianhui , Singh Shekhar , Wang Kai , Xiong Mengting , Xu Dachun , Chen Wei , Pang Jinjiang , Xu Yawei , Li Xiankai
Published: August 2016

Background:

Excessive proliferation, migration, and oxidative stress of vascular smooth muscle cells (VSMCs) are key mechanisms involved in intima formation, which is the basic pathological process of in stent restenosis. This study aims at exploring the role of XAV939 in proliferation, migration, and reactive oxygen species (ROS) generation of VSMCs, and hence evaluating its effects on intima formation.

Methods:

Carotid artery ligation models for C57BL/6 mice were established and gave them different intervention: saline, XAV939, Axin2 overexpression adenovirus, and negative control adenovirus. The intima formation was assayed by intima area and intima/media ratio. To investigate the underlying mechanisms, primary rat VSMCs were cultured and treated with XAV939 and platelet-derived growth factor-BB. EdU, direct cell counting, cell wound–healing assay, and flow cytometry were used to measure proliferation, migration, cell cycle, apoptosis, and ROS generation of VSMCs, respectively. By Western blot, we examined proliferating cell nuclear antigen, Cyclin D1, Cyclin E, p21, β-actin, JNK, phosphorylated JNK, Axin2 and β-catenin expression. Immunofluorescence staining and confocal microscopy were conducted to detect translocation of β-catenin.

Results:

XAV939 inhibited intima formation, which was exhibited by the loss of intima area and I/M ratio and attenuated proliferation, migration, and ROS generation, as well as promoted cell cycle arrest of VSMCs. Specifically, XAV939 inhibited Wnt pathway.

Conclusions:

XAV939 attenuates intima formation because of its inhibition of proliferation, migration, and apoptosis of VSMCs through suppression of Wnt signaling pathway.
Exploring the basic science of prolapse meshes
Authors: Liang Rui , Knight Katrina , Abramowitch Steve , Moalli Pamela A.
Published: August 2016

Purpose of review

Polypropylene mesh has been widely used in the surgical repair of pelvic organ prolapse. However, low but persistent rates of complications related to mesh, most commonly mesh exposure and pain, have hampered its use. Complications are higher following transvaginal implantation prompting the Food and Drug Administration to release two public health notifications warning of complications associated with transvaginal mesh use (PHN 2008 and 2011) and to upclassify transvaginal prolapse meshes from Class II to Class III devices. Although there have been numerous studies to determine the incidence and management of mesh complications as well as impact on quality of life, few studies have focused on mechanisms.

Recent findings

In this review, we summarize the current understanding of how mesh textile properties and mechanical behavior impact vaginal structure and function, as well as the local immune response. We also discuss how mesh properties change in response to loading.

We highlight a few areas of current and future research to emphasize collaborative strategies that incorporate basic science research to improve patient outcomes.
Systematic review with meta-analysis of childhood and adolescent risk and prognostic factors for musculoskeletal pain
Authors: Huguet Anna , Tougas Michelle E. , Hayden Jill , McGrath Patrick J. , Stinson Jennifer N. , Chambers Christine T.
Published: August 2016

A variety of factors may be involved in the development and course of musculoskeletal (MSK) pain. We undertook a systematic review with meta-analysis to synthesize and evaluate the quality of evidence about childhood and adolescent factors associated with onset and persistence of MSK pain, and its related disability. Studies were identified from searches of electronic databases (PubMed, EMBASE, PsycINFO, CINAHL, and Web of Science), references of included studies, and the Pediatric Pain mail list. Two independent reviewers assessed study inclusion, completed data extraction, and evaluated the quality of evidence using a modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Thirty-six studies reporting on 21 cohorts were included. These studies examined 65 potential risk factors for onset of MSK pain and 43 potential prognosis factors for persistence of MSK pain. No study was identified that examined prognostic factors for MSK pain–related disability. High-quality evidence suggests that low socioeconomic status is a risk factor for onset of MSK pain in studies exploring long-term follow-up. Moderate-quality evidence suggests that negative emotional symptoms and regularly smoking in childhood or adolescence may be associated with later MSK pain. However, moderate-quality evidence also suggests that high body mass index, taller height, and having joint hypermobility are not risk factors for onset of MSK pain. We found other risk and prognostic factors explored were associated with low or very low quality of evidence. Additional well-conducted primary studies are needed to increase confidence in the available evidence, and to explore new childhood risk and prognostic factors for MSK pain.
The Impact of Standardized Acuity Assessment and a Fast-Track on Length of Stay in Obstetric Triage
Authors: Smithson David S. , Twohey Rachel , Watts Nancy , Gratton Robert J.
Published: August 2016

To prospectively assess the impact of a standardized 5-category Obstetrical Triage Acuity Scale (OTAS) and a fast-track for lower-acuity patients on patient flow. Length of stay (LOS) data of women presenting to obstetric triage were abstracted from the electronic medical record prior to (July 1, 2011, to March 30, 2012) and following OTAS implementation (April 1 to December 31, 2012). Following computerized simulation modeling, a fast-track for lower acuity women was implemented (January 1, 2013, to February 28, 2014). Prior to OTAS implementation (8085 visits), the median LOS was 105 (interquartile range [IQR] = 52-178) minutes. Following OTAS implementation (8131 visits), the median LOS decreased to 101 (IQR = 49-175) minutes (P = .04). The LOS did not correlate well with acuity. Simulation modeling predicted that a fast-track for OTAS 4 and 5 patients would reduce the LOS. The LOS for lower-acuity patients in the fast-track decreased to 73 (IQR = 40-140) minutes (P = .005). In addition, the overall LOS (12 576 visits) decreased to 98 (IQR = 47-172) minutes (6.9% reduction; P < .001). Standardized assessment of acuity and a fast-track for lower acuity pregnant women decreased the overall LOS and the LOS of lower-acuity patients.
Use of the SF-36v2 Health Survey as a Screen for Risk of Major Depressive Disorder in a US Population-based Sample and Subgroup With Chronic Pain
Authors: Bell Jill A. , daCosta DiBonaventura Marco , Witt Edward A. , Ben-Joseph Rami , Reeve Bryce B.
Published: August 2016

Study Objectives:

To assess the feasibility of using the SF-36v2 mental health (MH) and mental component summary (MCS) scores for classification of risk for major depressive disorder (MDD), and to determine cut-off scores based on the sensitivity and specificity in a general US representative sample, and a chronic pain subpopulation.

Methods:

Data were analyzed from the 2013 US National Health and Wellness Survey (adults 18 y old and above; N=75,000), and among a chronic pain subpopulation (n=6679). Risk of MDD was a score ≥10 on the Patient Health Questionnaire (PHQ-9). Logistic regression modeling was used to predict at risk for MDD and receiver operating characteristic curves were produced.

Results:

The total sample had MH scores of 48.8 and MCS scores of 48.9, similar to the normative US population mean. Percent of respondents with a PHQ-9≥10 were 15.0% and 29.1% for the total sample and chronic pain subpopulation, respectively. Cut-off scores (PHQ-9≥10) in the total sample for the MH and MCS were 43.0 and 46.0, respectively. Specificities for the MH and MCS were 77.8% and 76.1%; sensitivities were 84.9% and 88.1%, respectively. Among the subpopulation with chronic pain, cut-off scores for the MH and MCS were 40.4 and 43.1, respectively. Corresponding specificities for the MH and MCS were 77.9% and 73.9%; sensitivities were 78.3% and 83.4%, respectively.

Conclusions:

The SF-36v2 was found to have sufficient specificity and sensitivity to categorize participants at risk for MDD. If no depression questionnaire is available, it is feasible to use the SF-36v2 to characterize the MH of populations.
Fresh versus old red cell transfusions: what have the recent clinical trials found?
Authors: Shah Akshay , McKechnie Stuart , Brunskill Susan J. , Stanworth Simon J.
Published: August 2016

Purpose of review

Red blood cell transfusion is a common treatment for anaemia worldwide, but concerns continue to be raised about adverse effects of cellular blood components, which are biological products. One hypothesis for the adverse effects associated with blood transfusion is the harmful effects of storage on red cells that have been demonstrated in laboratory and animal studies. Over the past few years, a number of more significant randomized controlled trials comparing ‘fresh’ versus ‘older’ blood have been published in an attempt to address the clinical consequences of storage age, with two further large trials ongoing.

Recent findings

These recent trials enrolled approximately 4000 participants across a variety of populations – cardiac surgical, critically ill, paediatric and acute hospitalized in-patients. All trials achieved statistically significant separation of red cell storage duration between both groups. The results of all these trials have found no clinical benefit to using fresher red cells when compared with older or standard-issue red cells. However, certain subgroups of patients either receiving red cells stored at more extreme ages of storage or those with additional risks for impaired microcirculations (critically ill elderly, severe sepsis and major haemorrhage) were either underrepresented or not included in these trials.

At present, on the basis of recent trials, there is no indication for blood transfusion services to implement preferential utilization of fresher red cell units.
Histologic Spectrum of Giant Cell Tumor (GCT) of Bone in Patients 18 Years of Age and Below
Authors: Al-Ibraheemi Alyaa , Inwards Carrie Y. , Zreik Riyam T. , Wenger Doris E. , Jenkins Sarah M. , Carter Jodi M. , Boland Jennifer M. , Rose Peter S. , Jin Long , Oliveira Andre M. , Fritchie Karen J.
Published: August 2016

Although the majority of giant cell tumors (GCTs) of the bone occur in adult patients, occasionally they arise in the pediatric population. In this setting they may be mistaken for tumors more commonly seen in this age group, including osteosarcoma, aneurysmal bone cyst, and chondroblastoma. All cases of primary GCT of the bone arising in patients 18 years and below were retrieved from our institutional archives and examined with emphasis on the evaluation of various morphologic patterns. Clinical/radiologic records were reviewed when available. Analysis for H3F3A/H3F3B mutations was performed in a subset of cases. Sixty-three (of 710) patients treated at our institution for GCT were 18 years of age and below. The following morphologic patterns were identified: fibrosis (31 cases, 49%), reactive-appearing bone (26, 41%), cystic change (7, 11%), foamy histiocytes (6, 10%), secondary aneurysmal bone cyst (3, 5%), and cartilage (2, 3%). Infarct-like necrosis was present in 17 tumors (27%), and the mitotic rate ranged from 0 to 35 mitoses/10 high-power fields (median 5 mitoses/10 high-power field). Follow-up information (n=55; 6 mo to 69.6 y; median, 11.6 y) showed 21 patients with local recurrence (38%) and 2 patients with lung metastasis (4%). Polymerase chain reaction with sequencing showed that 5 of 5 tested cases harbored H3F3A mutations. In summary, GCT arising in the pediatric population is rare, representing 9% of GCTs seen at our institution. The morphologic spectrum of these tumors is broad and similar to that seen in patients above 18 years of age. It is important to recognize that matrix formation may be observed in GCT, including reactive-appearing bone and cartilage, as well as areas of fibrosis mimicking osteoid production, to avoid misclassification as osteosarcoma or other giant cell–rich lesions common in children.
Polyclonality in Sclerosing Angiomatoid Nodular Transformation of the Spleen
Authors: Chang Kung-Chao , Lee Jen-Chieh , Wang Yu-Chu , Hung Liang-Yi , Huang Yenlin , Huang Wan-Ting , Wang Ren-Ching , Chen Tse-Ching , Tsai Yi-Shan , Medeiros L. Jeffrey
Published: August 2016

Sclerosing angiomatoid nodular transformation (SANT) of the spleen is a morphologically distinctive lesion. Although the clinical course of SANT is benign, its reactive or neoplastic nature remains to be clarified. Furthermore, some investigators have suggested that SANT is related to IgG4 sclerosing lesion or inflammatory pseudotumor with stromal cells positive for Epstein-Barr virus (EBV). In this study, we assessed 22 cases of SANT derived from adult women. Clinical data and follow-up information were obtained by chart review. Immunohistochemical studies for IgG4, IgG, and CD21 stains and in situ hybridization to detect EBV-encoded small RNAs were performed. We also assessed genomic DNA extracted from paraffin-embedded tissue for human androgen-receptor α gene analysis using conventional and methylation-specific polymerase chain reaction methods. The median patient age was 41.5 years (range, 25 to 82 y). Most (77%) patients presented with a single mass that was detected incidentally (59%). The mean size of the lesions was 3.8 cm (range, 1.0 to 9.0 cm). Clinical symptoms correlated with multiple lesions (P=0.043) but not lesional size (P=0.637) or location in the spleen (hilum vs. periphery, P=0.696). None of the cases had evidence of IgG4-related disease or recurred after splenectomy. The mean number of IgG4+ cells was 27.7 (range, 4 to 125), and the mean IgG4/IgG ratio was 16.4% (range, 1.6% to 55.7%) with only 2 cases being >40%. Cases with higher IgG4+ cells did not correlate with inflammatory pseudotumor–like morphology. No lesions were positive for EBV-encoded small RNAs, and almost all cases with informative results (n=19) showed a polyclonal pattern. We conclude that SANT is a polyclonal, reactive lesion rather than a neoplasm.
Utilizing a Collaborative Learning Model to Promote Early Extubation Following Infant Heart Surgery*
Authors: Mahle William T. , Nicolson Susan C. , Hollenbeck-Pringle Danielle , Gaies Michael G. , Witte Madolin K. , Lee Eva K , Goldsworthy Michelle , Stark Paul C. , Burns Kristin M. , Scheurer Mark A. , Cooper David S. , Thiagarajan Ravi , Sivarajan V. Ben , Colan Steven D. , Schamberger Marcus S. , Shekerdemian Lara S.
Published: August 2016

Objective:

To determine whether a collaborative learning strategy-derived clinical practice guideline can reduce the duration of endotracheal intubation following infant heart surgery.

Design:

Prospective and retrospective data collected from the Pediatric Heart Network in the 12 months pre- and post-clinical practice guideline implementation at the four sites participating in the collaborative (active sites) compared with data from five Pediatric Heart Network centers not participating in collaborative learning (control sites).

Setting:

Ten children’s hospitals.

Patients:

Data were collected for infants following two-index operations: 1) repair of isolated coarctation of the aorta (birth to 365 d) and 2) repair of tetralogy of Fallot (29–365 d). There were 240 subjects eligible for the clinical practice guideline at active sites and 259 subjects at control sites.

Interventions:

Development and application of early extubation clinical practice guideline.

Measurements and Main Results:

After clinical practice guideline implementation, the rate of early extubation at active sites increased significantly from 11.7% to 66.9% (p < 0.001) with no increase in reintubation rate. The median duration of postoperative intubation among active sites decreased from 21.2 to 4.5 hours (p < 0.001). No statistically significant change in early extubation rates was found in the control sites 11.7% to 13.7% (p = 0.63). At active sites, clinical practice guideline implementation had no statistically significant impact on median ICU length of stay (71.9 hr pre- vs 69.2 hr postimplementation; p = 0.29) for the entire cohort. There was a trend toward shorter ICU length of stay in the tetralogy of Fallot subgroup (71.6 hr pre- vs 54.2 hr postimplementation, p = 0.068).

Conclusions:

A collaborative learning strategy designed clinical practice guideline significantly increased the rate of early extubation with no change in the rate of reintubation. The early extubation clinical practice guideline did not significantly change postoperative ICU length of stay.
Early Kidney Allograft Dysfunction (Threatened Allograft): Comparative Effectiveness of Continuing Versus Discontinuation of Tacrolimus and Use of Sirolimus to Prevent Graft Failure: A Retrospective Patient-Centered Outcome Study
Authors: Wali Ravinder K. , Prentice Heather A. , Reddivari Venkata , Baffoe-Bonnie Geroge , Drachenberg Cinthia I. , Pappadimitriou John C. , Ramos Emilio , Cooper Matthew , Jonsson Johann , Bartlett Stephen , Weir Matthew R.
Published: August 2016

Background

Due to lack of treatment options for early acute allograft dysfunction in the presence of tubular-interstitial injury without histological features of rejection, kidney transplant recipients are often treated with sirolimus-based therapy to prevent cumulative calcineurin inhibitor exposure and to prevent premature graft failure.

Methods

We analyzed transplant recipients treated with sirolimus-based (n = 220) compared with continued tacrolimus-based (n = 276) immunosuppression in recipients of early-onset graft dysfunction (threatened allograft) with the use of propensity score-based inverse probability treatment weighted models to balance for potential confounding by indication between 2 nonrandomized groups.

Results

Weighted odds for death-censored graft failure (odds ratio [OR], 1.20; 95% confidence interval [95% CI], 0.66-2.19, P = 0.555) was similar in the 2 groups, but a trend for increased risk of greater than 50% loss in estimated glomerular filtration rate from baseline in sirolimus group (OR, 1.90; 95% CI, 0.96-3.76; P = 0.067) compared with tacrolimus group. Sirloimus group compared with tacrolimus group had increased risk for death with functioning graft (OR, 2.01; 95% CI, 1.29-3.14; P = 0.002) as well as increased risk of late death (death after graft failure while on dialysis) (OR, 2.39; 95% CI, 1.59-3.59; P < 0.001). Analysis of subgroups based on the absence or presence of T cell–mediated rejection or tubulointerstitial inflammation in the index biopsy, or the use of different types of induction agents, and all subgroups had increased risk of death with functioning graft and late death if exposed to sirolimus-based therapy.

Conclusions

Use of sirolimus compared with tacrolimus in recipients with early allograft dysfunction during the first year of transplant may not prevent worsening of allograft function and could potentially lead to poor survival along with increased risk of late death.
20/40 or Better Visual Acuity After Optic Neuritis: Not as Good as We Once Thought?
Authors: Sabadia Sakinah B. , Nolan Rachel C. , Galetta Kristin M. , Narayana Kannan M. , Wilson James A. , Calabresi Peter A. , Frohman Elliot M. , Galetta Steven L. , Balcer Laura J.
Published: August 2016

Background:

Although patients with acute optic neuritis (ON) recover high-contrast visual acuity (HCVA) to 20/40 or better in 95% of affected eyes, patients with a history of ON continue to note subjective abnormalities of vision. Furthermore, substantial and permanent thinning of the retinal nerve fiber layer (RNFL) and the ganglion cell layer (GCL) is now known to occur early in the course of ON. We measured vision-specific quality of life (QOL) in patients with a history of acute ON and recovery of VA to 20/40 or better in their affected eyes to determine how these QOL scores relate to RNFL and GCL thickness and low-contrast letter acuity (LCLA) across the spectrum of visual recovery.

Methods:

Data from an ongoing collaborative study of visual outcomes in multiple sclerosis and ON were analyzed for this cross-sectional observational cohort. Patients and disease-free control participants completed the 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and 10-Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25, as well as VA and LCLA testing for each eye separately and binocularly. Optical coherence tomography measures for each eye included peripapillary RNFL thickness and macular GCL + inner plexiform layer (GCL + IPL) thickness.

Results:

Patients with a history of acute ON and recovery to 20/40 or better VA (n = 113) had significantly reduced scores for the NEI-VFQ-25 (83.7 ± 15.4) and 10-Item Neuro-Ophthalmic Supplement (74.6 ± 17.4) compared with disease-free controls (98.2 ± 2.1 and 96.4 ± 5.2,P< 0.001, linear regression models, accounting for age and within-patient, intereye correlations). Most patients with 20/40 or better visual recovery (98/112, 88%) had monocular HCVA in their affected eye of 20/20 or better. Although patients with 20/50 or worse HCVA recovery demonstrated the worst performance on low-contrast acuity, affected eye RNFL and GCL + IPL thickness, and QOL scales, these measures were also significantly reduced among those with 20/40 or better HCVA recovery compared with controls.

Conclusions:

Patients with a history of ON and “good” visual recovery, defined in the literature as 20/40 or better HCVA, are left with clinically meaningful reductions in vision-specific QOL. Such patient-observed deficits reflect the underlying significant degrees of retinal axonal and neuronal loss and visual dysfunction that are now known to characterize ON even in the setting of maximal HCVA recovery. There remains an unmet therapeutic need for patients with ON.
Using approximate Bayesian computation to quantify cell-cell adhesion parameters in a cell migratory process
Authors: Ross Robert J. H. , Baker R. E. , Parker Andrew , Ford M. J. , Mort R. L. , Yates C. A.
Published: August 2016

In this work we implement approximate Bayesian computational methods to improve the design of a wound-healing assay used to quantify cell-cell interactions. This is important as cell-cell interactions, such as adhesion and repulsion, have been shown to play an important role in cell migration. Initially, we demonstrate with a model of anidealexperiment that we are able to identify model parameters for agent motility and adhesion, given we choose appropriate summary statistics. Following this, we replace our model of an ideal experiment with a model representative of a practically realisable experiment. We demonstrate that, given the current (and commonly used) experimental set-up, model parameters cannot be accurately identified using approximate Bayesian computation methods. We compare new experimental designs through simulation, and show more accurate identification of model parameters is possible by expanding the size of the domain upon which the experiment is performed, as opposed to increasing the number of experimental repeats. The results presented in this work therefore describe timeandcost-saving alterations for a commonly performed experiment for identifying cell motility parameters. Moreover, the results presented in this work will be of interest to those concerned with performing experiments that allow for the accurate identification of parameters governing cell migratory processes, especially cell migratory processes in which cell-cell adhesion or repulsion are known to play a significant role.
Contextual Fear Conditioning in Zebrafish
Authors: Kenney Justin W. , Scott Ian C. , Josselyn Sheena A. , Frankland Paul W.
Published: August 2016

Zebrafish are a genetically tractable vertebrate that hold considerable promise for elucidating the molecular basis of behavior. Although numerous recent advances have been made in the ability to precisely manipulate the zebrafish genome, much less is known about many aspects learning and memory in adult fish. Here, we develop a contextual fear conditioning paradigm using an electric shock as the aversive stimulus. We find that contextual fear conditioning is modulated by shock intensity, prevented by inhibition of (N-methyl-D-aspartate) NMDA receptors, lasts at least 14 days, and exhibits extinction. Furthermore, fish of various background strains (AB, Tu, and TL) are able to acquire fear conditioning, but differ in fear extinction rates. Taken together, we find that contextual fear conditioning in zebrafish shares many similarities with the widely used contextual fear conditioning paradigm in rodents. Combined with the amenability of genetic manipulation in zebrafish, we anticipate that our paradigm will prove to be a useful complementary system in which to examine the molecular basis of vertebrate learning and memory.
Survival of Captive Chimpanzees: Impact of Location and Transfers
Authors: Lauer Michael S.
Published: August 2016

To inform the retirement of NIH-owned chimpanzees, we analyzed the outcomes of 764 NIH-owned chimpanzees that were located at various points in time in at least one of 4 specific locations. All chimpanzees considered were alive and at least 10 years of age on January 1, 2005; transfers to a federal sanctuary began a few months later. During a median follow-up of just over 7 years, there were 314 deaths. In a Cox proportional hazards model that accounted for age, sex, and location (which was treated as a time-dependent covariate), age and sex were strong predictors of mortality, but location was only marginally predictive. Among 273 chimpanzees who were transferred to the federal sanctuary, we found no material increased risk in mortality in the first 30 days after arrival. During a median follow-up at the sanctuary of 3.5 years, age was strongly predictive of mortality, but other variables – sex, season of arrival, and ambient temperature on the day of arrival – were not predictive. We confirmed our regression findings using random survival forests. In summary, in a large cohort of captive chimpanzees, we find no evidence of materially important associations of location of residence or recent transfer with premature mortality.
DeepWAS: Multivariate genotype-phenotype associations by directly integrating regulatory information using deep learning
Authors: Arloth Janine , Eraslan Gökcen , Andlauer Till F.M. , Martins Jade , Iurato Stella , Kühnel Brigitte , Waldenberger Melanie , Frank Josef , Gold Ralf , Hemmer Bernhard , Luessi Felix , Nischwitz Sandra , Paul Friedemann , Wiendl Heinz , Gieger Christian , Heilmann-Heimbach Stefanie , Kacprowski Tim , Laudes Matthias , Meitinger Thomas , Peters Annette , Rawal Rajesh , Strauch Konstantin , Lucae Susanne , Müller-Myhsok Bertram , Rietschel Marcella , Theis Fabian J. , Binder Elisabeth B. , Mueller Nikola S.
Published: August 2016

Genome-wide association studies (GWAS) identify genetic variants associated with quantitative traits or disease. Thus, GWAS never directly link variants to regulatory mechanisms, which, in turn, are typically inferred during post-hoc analyses. In parallel, a recent deep learning-based method allows for prediction of regulatory effects per variant on currently up to 1,000 cell type-specific chromatin features. We here describe “DeepWAS”, a new approach that directly integrates predictions of these regulatory effects of single variants into a multivariate GWAS setting. As a result, single variants associated with a trait or disease are, by design, coupled to their impact on a chromatin feature in a cell type. Up to 40,000 regulatory single-nucleotide polymorphisms (SNPs) were associated with multiple sclerosis (MS, 4,888 cases and 10,395 controls), major depressive disorder (MDD, 1,475 cases and 2,144 controls), and height (5,974 individuals) to each identify 43-61 regulatory SNPs, called deepSNPs, which are shown to reach at least nominal significance in large GWAS. MS- and height-specific deepSNPs resided in active chromatin and introns, whereas MDD-specific deepSNPs located mostly to intragenic regions and repressive chromatin states. We found deepSNPs to be enriched in public or cohort-matched expression and methylation quantitative trait loci and demonstrate the potential of the DeepWAS method to directly generate testable functional hypotheses based on genotype data alone. DeepWAS is an innovative GWAS approach with the power to identify individual SNPs in non-coding regions with gene regulatory capacity with a joint contribution to disease risk. DeepWAS is available at https://github.com/cellmapslab/DeepWAS.
Exaggerated CpH Methylation in the Autism-Affected Brain
Authors: Ellis Shannon E. , Gupta Simone , Moes Anna , West Andrew B. , Arking Dan E.
Published: August 2016

The etiology of autism, a complex neurodevelopmental disorder, remains largely unexplained. Here, we explore the role of CpG and CpH (H=A, C, or T) methylation within autism-affected cortical brain tissue. While no individual site of methylation was significantly associated with autism after multi-test correction, methylated CpH di-nucleotides were markedly enriched in autism-affected brains (~2-fold enrichment at p <0.05 cut-off, p=0.002). These results further implicate epigenetic alterations in pathobiological mechanisms that underlie autism.
Critical roles of long noncoding RNAs in Drosophila spermatogenesis
Authors: Wen Kejia , Yang Lijuan , Xiong Tuanlin , Di Chao , Ma Danhui , Wu Menghua , Xue Zhaoyu , Zhang Xuedi , Long Li , Zhang Weimin , Zhang Jiaying , Bi Xiaolin , Dai Junbiao , Zhang Qiangfeng , Lu Zhi John , Gao Guanjun
Published: August 2016

Long noncoding RNAs (lncRNAs), a recently discovered class of cellular RNAs, play important roles in the regulation of many cellular developmental processes. Although lncRNAs have been systematically identified in various systems, most of them have not been functionally characterized in vivo in animal models. In this study, we identified 128 testis-specific Drosophila lncRNAs and knocked out 105 of them using an optimized three-component CRISPR/Cas9 system. Among the lncRNA knockouts, 33 (31%) exhibited a partial or complete loss of male fertility, accompanied by visual developmental defects in late spermatogenesis. In addition, six knockouts were fully or partially rescued by transgenes in a trans configuration, indicating that those lncRNAs primarily work in trans. Furthermore, gene expression profiles for five lncRNA mutants revealed that testis-specific lncRNAs regulate global gene expression, orchestrating late male germ cell differentiation. Compared with coding genes, the testis-specific lncRNAs evolved much faster. Moreover, lncRNAs of greater functional importance exhibited higher sequence conservation, suggesting that they are under constant evolutionary selection. Collectively, our results reveal critical functions of rapidly evolving testis-specific lncRNAs in late Drosophila spermatogenesis.
A robust method for high-precision quantification of the complex three-dimensional vasculatures acquired by X-ray microtomography
Authors: Tan Hai , Wang Dadong , Li Rongxin , Sun Changming , Lagerstrom Ryan , He You , Xue Yanling , Xiao Tiqiao
Published: August 2016

The quantification of micro-vasculatures is important for the analysis of angiogenesis on which the detection of tumor growth or hepatic fibrosis depends. Synchrotron-based X-ray computed micro-tomography (SR-µCT) allows rapid acquisition of micro-vasculature images at micrometer-scale spatial resolution. Through skeletonization, the statistical features of the micro-vasculature can be extracted from the skeleton of the micro-vasculatures. Thinning is a widely used algorithm to produce the vascular skeleton in medical research. Existing three-dimensional thinning methods normally emphasize the preservation of topological structure rather than geometrical features in generating the skeleton of a volumetric object. This results in three problems and limits the accuracy of the quantitative results related to the geometrical structure of the vasculature. The problems include the excessively shortened length of elongated objects, eliminated branches of blood vessel tree structure, and numerous noisy spurious branches. The inaccuracy of the skeleton directly introduces errors in the quantitative analysis, especially on the parameters concerning the vascular length and the counts of vessel segments and branching points. In this paper, a robust method using a consolidated end-point constraint for thinning, which generates geometry-preserving skeletons in addition to maintaining the topology of the vasculature, is presented. The improved skeleton can be used to produce more accurate quantitative results. Experimental results from high-resolution SR-µCT images show that the end-point constraint produced by the proposed method can significantly improve the accuracy of the skeleton obtained using the existingITKthree-dimensional thinning filter. The produced skeleton has laid the groundwork for accurate quantification of the angiogenesis. This is critical for the early detection of tumors and assessing anti-angiogenesis treatments.
Simultaneous X-ray fluorescence and scanning X-ray diffraction microscopy at the Australian Synchrotron XFM beamline
Authors: Jones Michael W. M. , Phillips Nicholas W. , van Riessen Grant A. , Abbey Brian , Vine David J. , Nashed Youssef S. G. , Mudie Stephen T. , Afshar Nader , Kirkham Robin , Chen Bo , Balaur Eugeniu , de Jonge Martin D.
Published: August 2016

Owing to its extreme sensitivity, quantitative mapping of elemental distributionsviaX-ray fluorescence microscopy (XFM) has become a key microanalytical technique. The recent realisation of scanning X-ray diffraction microscopy (SXDM) meanwhile provides an avenue for quantitative super-resolved ultra-structural visualization. The similarity of their experimental geometries indicates excellent prospects for simultaneous acquisition. Here, in both step- and fly-scanning modes, robust, simultaneous XFM-SXDM is demonstrated.
Crystal structure of bis[trans-dichloridobis(propane-1,3-diamine-κ2
N,N′)chromium(III)] dichromate from synchrotron data
Authors: Moon Dohyun , Ryoo Keon Sang , Choi Jong-Ha
Published: August 2016

The structure of the title compound, [CrCl2(tn)2]2[Cr2O7] (tn = propane-1,3-diamine; C3H10N2), has been determined from synchrotron data. The asymmetric unit contains one CrIII complex cation and half a [Cr2O7]2− anion. In the complex cation, the CrIII ion is coordinated by the four N atoms of two propane-1,3-diamine (tn) ligands in the equatorial plane and by two Cl atoms in a trans configuration, displaying a distorted octahedral coordination sphere. The two six-membered rings in the complex cation have an anti chair–chair conformation with respect to each other. The mean Cr—N(tn) and Cr—Cl bond lengths are 2.09 (1) and 2.320 (2) Å, respectively. The slightly bent dichromate anion is disordered over two sets of sites (occupancy ratio = 0.7:0.3) and has a staggered conformation. The crystal structure is stabilized by intermolecular hydrogen bonds involving the NH2 groups of the tn ligands as donors and the O atoms of the [Cr2O7]2− anion and chlorido ligands as acceptors.
5-(2-Hydroxy-5-methoxybenzoyl)-1-methyl-3-nitropyridin-2(1H)-one
Authors: Bargavi Srinivasan , Nataraj Poomathi , Perumal Paramasivam T. , Lakshmi Srinivasakannan
Published: August 2016

In the title compound, C14H12N2O6, the dihedral angle between the benzene and pyridine rings is 65.90 (7)°. The nitro group is disordered and tilted with respect to the mean plane of the pyridine ring by 21.5 (4) and 22.8 (5)°, for the major and minor components, respectively. In the crystal, molecules are linked by O—H...N hydrogen bonds, forming chains propagating along [10-1]. The chains are linked by C—H...O hydrogen bonds, forming a three-dimensional framework. The crystal packing is further stabilized by offset π–π stacking interactions [intercentroid distance = 3.6291 (9) Å]
N-{(Z)-3-Oxo-3-[(E)-(pyridin-2-ylmethyl)diazenyl]-1-(thiophen-2-yl)prop-1-en-2-yl}benzamide
Authors: Sharma Devinder K. , Subbulakshmi K. N. , Narayana B. , Sarojini B. K. , Anthal Sumati , Kant Rajni
Published: August 2016

In the title compound, C20H16N4O2S, the thiophene ring subtends dihedral angles of 58.6 (3) and 9.8 (3)° with the benzamide and pyridine rings, respectively, whereas these two rings are inclined to one another by 59.3 (3)°. There is an intramolecular C—H...π interaction present involving the pyridine and benzamide rings. In the crystal, molecules are linked by N—H...O hydrogen bonds, forming chains along the [010] direction. The chains are linked by C—H...S hydrogen bonds and C—H...π interactions, forming sheets parallel to theabplane.
Relevance and evolution of adaptive markets hypothesis: a review
Authors: Dhankar Raj S. , Shankar Devesh
Published: August 2016

Purpose

The purpose of this paper is to discuss the relevance and evolution of adaptive markets hypothesis (AMH) that has gained traction in the recent years, as it provides a dynamic perspective to the concept of informational efficiency.

Design/methodology/approach

This paper discusses several issues related to the concept of informationally efficient markets that have indicated efficient market hypothesis to be an incomplete portrayal of stock market behavior.

Findings

The authors find that a strict and perpetual adherence to informational efficiency is highly unlikely, and AMH provides a much more plausible description of the behavior of stock markets.

Originality/value

The authors provide a description of studies that examine the testable implications of AMH.
Linking microbial diversity and functionality of arctic glacial surface habitats
Authors: Lutz Stefanie , Anesio Alexandre M. , Edwards Arwyn , Benning Liane G.
Published: August 2016

Distinct microbial habitats on glacial surfaces are dominated by snow and ice algae, which are the critical players and the dominant primary colonisers and net producers during the melt season. Here for the first time we have evaluated the role of these algae in association with the full microbial community composition (i.e., algae, bacteria, archaea) in distinct surface habitats and on 12 glaciers and permanent snow fields in Svalbard and Arctic Sweden. We cross‐correlated these data with the analyses of specific metabolites such as fatty acids and pigments, and a full suite of potential critical physico‐chemical parameters including major and minor nutrients, and trace metals. It has been shown that correlations between single algal species, metabolites, and specific geochemical parameters can be used to unravel mixed metabolic signals in complex communities, further assign them to single species and infer their functionality. The data also clearly show that the production of metabolites in snow and ice algae is driven mainly by nitrogen and less so by phosphorus limitation. This is especially important for the synthesis of secondary carotenoids, which cause a darkening of glacial surfaces leading to a decrease in surface albedo and eventually higher melting rates.
Enhanced ferrihydrite dissolution by a unicellular, planktonic cyanobacterium: a biological contribution to particulate iron bioavailability
Authors: Kranzler Chana , Kessler Nivi , Keren Nir , Shaked Yeala
Published: August 2016

Iron (Fe) bioavailability, as determined by its sources, sinks, solubility and speciation, places severe environmental constraints on microorganisms in aquatic environments. Cyanobacteria are a widespread group of aquatic, photosynthetic microorganisms with especially high iron requirements. While iron exists predominantly in particulate form, little is known about its bioavailability to cyanobacteria. Some cyanobacteria secrete iron solubilizing ligands called siderophores, yet many environmentally relevant strains do not have this ability. This work explores the bioavailability of amorphous synthetic Fe‐oxides (ferrihydrite) to the non‐siderophore producing, unicellular cyanobacterium, Synechocystis sp PCC 6803. Iron uptake assays with 55ferrihydrite established dissolution as a critical prerequisite for iron transport. Dissolution assays with the iron binding ligand, desferrioxamine B, demonstrated that Synechocystis 6803 enhances ferrihydrite dissolution, exerting siderophore‐independent biological influence on ferrihydrite bioavailability. Dissolution mechanisms were studied using a range of experimental conditions; both cell‐particle physical proximity and cellular electron flow were shown to be important determinants of bio‐dissolution by Synechocystis 6803. Finally, the effects of ferrihydrite stability on bio‐dissolution rates and cell physiology were measured, integrating biological and chemical aspects of ferrihydrite bioavailability. Collectively, these findings demonstrate that Synechocystis 6803 actively dissolves ferrihydrite, highlighting a significant biological component to mineral phase iron bioavailability in aquatic environments.
China's Growing Government Debt in a Computable Overlapping Generations Model
Authors: Li Shiyu , Lin Shuanglin , Wang Yan , Zhai Fan
Published: August 2016

This paper simulates the effects of China's growing government debt in a computable equilibrium model of overlapping generations. Our model assumes that the government increases debt to finance its spending in the short run, and then increases taxes or cuts spending to keep the debt–GDP ratio constant. The spending‐driven government debt increases public capital and output in the short run, but decreases private investment, total capital stock, output, and net exports in the long run, and makes the future generations worse off. Among various means of debt control, a decrease in government spending seems to be the least harmful to private investment, capital stock, and output while an increase in capital taxation is most detrimental.
Gestational diabetes in the United States: temporal changes in prevalence rates between 1979 and 2010
Authors: Lavery JA , Friedman AM , Keyes KM , Wright JD , Ananth CV
Published: August 2016

Objective

To examine age–period–cohort effects on trends in gestational diabetes mellitus (GDM) prevalence in the US, and to evaluate how these trends have affected the rates of stillbirth and large for gestational age (LGA)/macrosomia.

Design

Retrospective cohort study.

Setting

USA, 1979–2010.

Population

Over 125 million pregnancies (3 337 284 GDM cases) associated with hospitalisations.

Methods

Trends in GDM prevalence were examined via weighted Poisson models to parse out the extent to which GDM trends can be attributed to maternal age, period of delivery, and maternal birth cohort. Multilevel models were used to assess the contribution of population effects to the rate of GDM. Log‐linear Poisson regression models were used to estimate the contributions of the increasing GDM rates to changes in the rates of LGA and stillbirth between 1979–81 and 2008–10.

Main outcome measures

Rates and rate ratios (RRs).

Results

Compared with 1979–1980 (0.3%), the rate of GDM has increased to 5.8% in 2008–10, indicating a strong period effect. Substantial age and modest cohort effects were evident. The period effect is partly explained by period trends in body mass index (BMI), race, and maternal smoking. The increasing prevalence of GDM is associated with a 184% (95% CI 180–188%) decline in the rate of LGA/macrosomia and a 0.75% (95% CI 0.74–0.76) increase in the rate of stillbirths for 2008–10, compared with 1979–81.

Conclusions

The temporal increase in GDM can be attributed to period of pregnancy and age. Increasing BMI appears to partially contribute to the GDM increase in the US.

Tweetable abstract

The increasing prevalence of GDM can be attributed to period of delivery and increasing maternal age.
Anal reconstruction after a rare complication of routine haemorrhoid treatment
Authors: Yeung Carol Kwan‐Lok , Choi Chi‐Yee , Chow Tam‐Lin
Published: August 2016

Anal stenosis is a well‐documented complication that can occur from anorectal surgery. This condition can be disabling and causes significant patient discomfort. Various surgical techniques for the treatment of anal stenosis have been described in the literature, however, its successful management still remains as a technical challenge. Here, we present a case of a patient who suffered from anal stenosis after a complication of sclerotherapy treatment of haemorrhoid, which was successfully managed by anal reconstruction with V‐Y advancement flaps.