bluuebunny/crossref_metadata_2025 huggingface dataset:
The intervention mechanism of folic acid for benzo(a)pyrene toxic effects in vitro and in vivo
Authors: Wang Pengcheng , Chen Yuwei , Wang Lei , Wu Yang , Wang Lichun , Wu Yongning , Gong Zhiyong
Published: July 2018

Folic acid is a necessary micronutrient for normal human growth and development. Benzo(a)pyrene (BaP) is a ubiquitously distributed environmental pollutant and its metabolite, benzo(a)pyrene-diol-epoxide, is known to exert a strong teratogenic and carcinogenic effect on the body’s tissues and cells. The aim of this study was to investigate the mechanism by which folic acid can inhibit the toxic effects of BaP both in vivo and in vitro. We measured changes in 16HBE cell activity affected by the intervention of folic acid on BaP using the cell counting kit-8 assay and that of cell cycle distribution by flow cytometry. At the same time, we assessed the xeroderma pigmentosum group A, xeroderma pigmentosum group C, excision repair cross complementation group 1, cyclinD1, and CKD4 mRNAs, and their related protein expression both in mouse lung tissue and in 16HBE cells. In conclusion, the mechanisms by which this effect is mediated were not entirely elucidated by our study, possibly because folic acid antagonizes the toxic effects of BaP by upregulating the levels of excision repair cross complementation group 1, xeroderma pigmentosum group A, and xeroderma pigmentosum group C gene expression to improve the rate of DNA repair, in turn accelerating the speed of repair for DNA damage caused by BaP. Meanwhile, folic acid could restrain BaP-induced cyclinD1 protein expression, which could help cells return to their normal cell cycle.
Soft Tissue and Skin Reinforcement with Acellular Dermal Matrix to Protect Implanted Cardioverters/Defibrillators and Pacemakers
Authors: Rudolph Ross , Curtis Guy
Published: July 2018

Cardiac pacemakers and implantable cardioverters/defibrillators are often placed in older patients with thin skin and scanty subcutaneous tissue. These devices and cardiac leads are at risk for progressive skin erosion and exposure leading to infection. To prevent this severe complication, we developed a reinforcing insertion of acellular dermal matrix. Twenty-two of 24 patients had successful implantation with long-term avoidance of skin erosion
VITRECTOMY WITH INTERNAL LIMITING MEMBRANE PEELING AND AIR TAMPONADE FOR MYOPIC FOVEOSCHISIS
Authors: Rizzo Stanislao , Giansanti Fabrizio , Finocchio Lucia , Caporossi Tomaso , Barca Francesco , Bacherini Daniela , Cocci Giulia , Vannucchi Martino , Tartaro Ruggero , Virgili Gianni
Published: July 2018

Purpose:

To evaluate the functional and anatomical outcomes of 23-gauge or 25-gauge pars plana vitrectomy with internal limiting membrane peeling and air tamponade for the treatment of myopic foveoschisis.

Methods:

Retrospective, noncomparative, interventional case series. The records of 29 patients (32 eyes), with myopic foveoschisis who were treated by 23-gauge or 25-gauge 3-port pars plana vitrectomy with internal limiting membrane peeling and air tamponade, were reviewed. At each visit, a complete ophthalmic examination, intraocular pressure, best-corrected visual acuity, and central foveal thickness measured using optical coherence tomography were assessed.

Results:

Twenty-five eyes of 23 patients (M:F = 4:19) matched the inclusion criteria, whereas 7 eyes of 6 patients were excluded. The mean logarithm of the minimum angle of resolution best-corrected visual acuity (Snellen equivalent) was 0.62 (20/80) (SE: 0.061), and the mean preoperative central foveal thickness was 619.5 µm (SE: 16.38) at baseline. Visual acuity significantly improved of 5 Early Treatment Diabetic Retinopathy Study letters (45 letters) at the 1-month follow-up (P < 0.001), 2 lines (50 Early Treatment Diabetic Retinopathy Study letters) at the 6-month follow-up (P < 0.001), and it reached 55 Early Treatment Diabetic Retinopathy Study letters at the 1-year follow-up visit (P < 0.001). Central foveal thickness decreased to 292.4 µm (SE: 15.93), to 227.3 µm (SE: 14.05), and to 208.8 µm (SE: 12.86), respectively, at the 1-, 6-, and 12-month follow-ups (for each P < 0.001). There were no differences in best-corrected visual acuity or central foveal thickness changes between the foveal detachment group and the nonfoveal detachment group (P > 0.05).

Conclusion:

Small-gauge vitrectomy with internal limiting membrane peeling and air tamponade results in favorable anatomical and functional outcomes for patients affected by myopic macular foveoschisis.
CHORIORETINAL CHANGES IN A GENETICALLY CONFIRMED CASE OF BOUCHER–NEUHÄUSER SYNDROME
Authors: DeNaro Brittany B. , Dhrami-Gavazi Elona , Rubaltelli David M. , Freund K. Bailey , Lee Winston , Yannuzzi Lawrence A. , Tsang Stephen H. , Kang Joann J.
Published: July 2018

Purpose:

To describe the retinal findings in a 25-year-old white woman in whom a diagnosis of Boucher–Neuhäuser Syndrome (BNS) was supported by genetic testing, which identified a missense and novel nonsense mutation in the PNPLA6 gene.

Methods:

Observational case report of a 25-year-old woman who presented with primary amenorrhea, cerebellar ataxia, and mild retinal pigmentary abnormalities. Neurologic, endocrine, and genetic evaluations established a diagnosis of BNS.

Results:

Clinical examination and multimodal imaging documented focal outer retinal and retinal pigment epithelium changes including bilateral foveal stippling and a circular area of hypopigmentation in the superior macula of the left eye. Optical coherence tomography showed a linear area of outer retinal attenuation superonasal to the fovea and multiple foci of pinpoint outer retinal defects in the temporal macula of the left eye. Humphrey visual field 24-2 testing showed nonspecific defects in both eyes. Full-field electroretinography showed no evidence of a generalized retinal dysfunction.

Conclusion:

Recognition that the chorioretinal abnormalities occurring in BNS can be rather subtle is essential because the diagnosis of BNS may depend on their detection. To the best of our knowledge, this is the first report in the ophthalmic literature of mild chorioretinal changes in a patient with BNS testing positive for a mutation in the PNPLA6 gene.
CYSTOID MACULAR EDEMA IN THE SETTING OF PRIMARY VITREORETINAL LYMPHOMA
Authors: Deák Gábor G. , Sneed Scott R. , Jampol Lee M.
Published: July 2018

Purpose:

To present a rare case of primary vitreoretinal lymphoma presenting with cystoid macular edema without previous surgical intervention or radiotherapy.

Methods:

Retrospective chart review of one patient.

Results:

A 74-year-old patient was seen with a history of cataract surgery in 1 eye and presumed ocular inflammation with recurrent cystoid macular edema in both eyes. On examination, subretinal pigment epithelial and intraretinal infiltrates raised the suspicion of primary vitreoretinal lymphoma despite the unusual presentation with cystoid macular edema. A magnetic resonance imaging and brain biopsy confirmed the diagnosis of vitreoretinal lymphoma in the setting of central nervous system lymphoma.

Conclusion:

Primary vitreoretinal lymphoma can present with cystoid macular edema in rare cases.
Unilateral and Bilateral Audiological Benefit With an Adhesively Attached, Noninvasive Bone Conduction Hearing System
Authors: Gawliczek Tom , Munzinger Fabio , Anschuetz Lukas , Caversaccio Marco , Kompis Martin , Wimmer Wilhelm
Published: July 2018

Objective:

To assess the audiological benefit of a noninvasive, adhesively attached bone conduction device (BCD1) in subjects with induced bilateral conductive hearing loss. Secondary objectives were to evaluate the additional benefit of bilateral fitting compared with unilateral fitting and to compare the outcomes with bone conduction devices attached to a softband (BCD2).

Study Design:

Prospective nonrandomized crossover study.

Setting:

Tertiary referral center.

Patients:

Fifteen subjects with induced bilateral conductive hearing loss.

Main Outcome Measures:

Sound field thresholds, speech understanding in quiet and in multinoise were assessed in unaided, unilateral, and bilateral treatment conditions. In addition, sound localization was evaluated in uni- and bilateral treatment conditions.

Results:

The outcomes of BCD1 and BCD2 were comparable. Sound field thresholds improved by 24.6 dB (BCD1) and 24.8 dB (BCD2) in the unilateral and 26.8 dB (BCD1) and 25.1 dB (BCD2) in the bilateral treatment condition. Speech reception thresholds (SRTs) in quiet improved by 20.0 dB (BCD1) and 21.7 dB (BCD2) in the unilateral and by 22.7 dB (BCD1) and 21.5 dB (BCD2) in the bilateral condition. If speech was presented from the front, SRTs in noise were improved by 3.6 dB and 4.2 dB (unilateral) and by 4.5 dB and 4.4 dB (bilateral) for BCD1 and BCD2, respectively. With speech presented from the unilateral side, SRTs were improved by 4.0 dB and 4.7 dB (unilateral) and 3.8 dB and 4.8 dB (bilateral) compared with the unaided situation. If noise was presented from the contralateral side, small differences (−0.6 dB and −0.1 dB) were observed. Bilateral fitting brought additional benefits for speech understanding in noise and sound localization.

Conclusions:

Both bone conduction devices seem to be a valid treatment for patients with conductive hearing loss and minor sensorineural hearing loss component.
Fatal Refractory Ventricular Fibrillation Due to Ingestion of Hydrofluoric Acid
Authors: Ozsoy Gamze , Kendirli Tanil , Ates Ufuk , Perk Oktay , Azapagasi Ebru , Ozcan Serhan , Baran Cagdas , Goktug Aytac , Dindar Huseyin
Published: July 2018

Hydrofluoric acid (HF) is a colorless and odorless solution of the hydrogen fluoride in water. It is used in some household products. The rapid onset of severe toxicity and death after the ingestion of HF is not reported often. Also, there is no reported fatal pediatric case after HF ingestion. In this case report, we present a 3.5-year-old girls who unintentionally drunk a rust remover that contained 8% HF. She died in a short period as a result of refractory ventricular fibrillation, which was developed due to fluoride intoxication.
Factors Influencing Pediatric Emergency Department Visits for Low-Acuity Conditions
Authors: Long Christina M. , Mehrhoff Casey , Abdel-Latief Eman , Rech Megan , Laubham Matthew
Published: July 2018

Objectives

Emergency department (ED) overcrowding is a growing problem, and pediatric patients are contributing. In this study, we aimed to determine which factors influence parents or guardians to choose the ED over their primary care physician (PCP).

Methods

A cross-sectional, online survey was administered in an academic hospital pediatric ED from September to October 2017. The 21-question survey was offered to the parents or guardians of pediatric patients triaged as low acuity. The survey assessed establishment and availability of their PCP, perception of illness or injury severity, reasons for choosing the ED, and demographic information.

Results

A total of 101 surveys were collected, with a 95% completion rate. Most patients had an established PCP. More than two-thirds did not attempt to contact their PCP prior to their ED visit. Nearly half stated their PCP did not offer after-hours or weekend availability. Most did not feel their child's condition was serious. Almost half would have waited to see their PCP if they could be seen within 24 hours.

Conclusions

There appears to be a common misperception that PCPs do not offer extended hours. In addition, the parent or guardian's perception of severity was oftentimes more serious than perceived by medical staff. These results suggest that improving health literacy among our patient population by educating them on PCP availability and capability, ancillary services offered by PCP, and appropriate usage of the ED could potentially reduce nonurgent ED visits.
Long-Term Results in Isolated Metopic Synostosis: The Oxford Experience over 22 Years
Authors: Natghian Hamidreza , Song Marie , Jayamohan Jayaratnam , Johnson David , Magdum Shailendra , Richards Peter , Wall Steven
Published: July 2018

Background:

Metopic synostosis causing trigonocephaly is treated by fronto-orbital advancement and remodeling to correct the deformity and cerebral distortion and to treat intracranial hypertension in a small number of cases. The aim of this study was to evaluate complications, revisions, and long-term outcomes.

Methods:

A retrospective chart review was performed on consecutive metopic craniosynostosis patients treated between February of 1995 and February of 2017 at the Oxford Craniofacial Unit.

Results:

Two hundred forty-five patients with isolated metopic synostosis were seen. Two hundred two patients underwent fronto-orbital advancement and remodeling. Fifty patients were girls and 152 patients were boys. Mean age at surgery was 16.8 months. Mean weight preoperatively was 12 kg. All patients received blood transfusion. Mean postoperative stay was 6 days. Average follow-up time was 8 years (range, 0.5 to 22 years). There were eight major complications (4 percent). Six patients (2.9 percent) required secondary calvarial expansion for late raised intracranial pressure. Thirty-one (15 percent) had other subsequent procedures, including wire removal and forehead shape contouring with alloplastic onlay. Raised intracranial pressure before surgery was confirmed in two cases by intracranial pressure monitoring.

Conclusions:

Trigonocephaly is caused by metopic synostosis and is treated by fronto-orbital advancement and remodeling to restore both internal and external skull configuration. After surgery, the authors identified a 2.9 percent risk of late raised intracranial pressure requiring a secondary calvarial expansion, necessitating prolonged follow-up in all cases. Temporal hollowing and forehead contour defects were not uncommon. This is the largest reported series of metopic synostosis.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Prognostic Value of FDG-PET/CT Metabolic Parameters in Metastatic Radioiodine-Refractory Differentiated Thyroid Cancer
Authors: Manohar Poorni M. , Beesley Lauren J. , Bellile Emily L. , Worden Francis P. , Avram Anca M.
Published: July 2018

Purpose

There are no standardized prognostication algorithms for metastatic radioiodine-refractory (RAI-R) differentiated thyroid cancer (DTC). We hypothesize that [18F]-FDG PET/CT may predict progression versus stability of disease based on quantitative analysis of metabolic tumor volume (MTV) and total lesion glycolysis (TLG).

Methods

Retrospective study of 62 patients with metastatic RAI-R DTC to determine clinical outcomes with median follow-up from initial diagnosis of 11.1 years (8.38, 14.1) (range, 1.2–20 years). Baseline [18F]-FDG PET/CT scans were evaluated qualitatively for regional and distant metastases and quantitatively for tumor burden based on MTV and TLG obtained using gradient segmentation method.

Results

After diagnosis of metastatic RAI-R disease was established, the 5-year overall survival (OS) probability was 34%, and median OS was 3.56 years (2.87, infinity). The 5-year progression-free survival (PFS) probability was 19%, and median PFS was 1.31 years (1.03, 2.38). TSH-suppressed thyroglobulin (Tg) levels greater than 100 ng/mL and Tg doubling time (Tg-DT) less than 6 months were significantly associated with worse OS and PFS. Higher than median values of MTV and TLG were associated with worse OS (P = 0.06) and PFS (P = 0.007). Higher hazard of death was noted for higher values of log-MTV and log-TLG (HR, 1.17 [95% confidence interval, 0.99–1.39], P = 0.05, and HR, 1.14 [95% confidence interval, 1.00–1.31], P = 0.05, respectively).

Conclusions

[18F]-FDG PET/CT metabolic parameters can help define the volume and biologic variations of metastatic tumor burden. Metabolic tumor volume and TLG can be used for dynamic risk stratification of patients with metastatic RAI-R DTC regarding PFS and complement Tg-DT for prognosis of clinical disease course.
Maxillofacial Spindle Cell Sarcoma With Lung Metastases on FDG PET/CT Imaging
Authors: Wu Xiaodong , Zhang Chunye , Huang Yan , Wang Huoqiang , Jiang Lei
Published: July 2018

A 45-year-old man presented with episodes of cough and chest discomfort. CT examination showed multiple nodules of bilateral lungs. The pathology of CT-guided biopsy was consistent with spindle cell sarcoma. FDG PET/CT scan was performed to detect the primary lesion, which showed that in addition to multiple hypermetabolic pulmonary nodules, a mass in the right maxillofacial region with high FDG uptake was also found. A biopsy confirmed spindle cell sarcoma.
Upper Airway Obstruction in a Panfacial Fracture
Authors: Colombo Luara Teixeira , Mulinari-Santos Gabriel , Souza Francisley Ávila
Published: July 2018

Panfacial fractures are considered the most aggressive and complex facial fracture, and most of them are the results of a high energy trauma. Therefore, a clinical report of a male patient with a panfacial fracture and Richards type 3 fracture resulting in an airway obstruction is presented. This type of fracture can promote an upper airway obstruction, which needs a correct and fast diagnosis to the life support of the patient.
Two Methods of Cleft Palate Repair in Patients With Complete Unilateral Cleft Lip and Palate
Authors: Rossell-Perry Percy
Published: July 2018

Objective:

The objective of this study was to compare the surgical outcome between 2 patient groups with complete unilateral cleft lip and palate who underwent different types of palatoplasty.

Methods:

This is a cohort study between 2 groups of patients with complete unilateral cleft lip and palate who were operated using different surgical techniques from 2008 to 2011. About 28 patients were operated using a primary lip nose repair with vomer flap for hard palate single-layer closure and delayed soft palate repair (modified Oslo protocol) and 32 patients were operated using our protocol in Lima. Data collection was accomplished by evaluation of symptomatic oronasal fistulas, presence of velopharyngeal insufficiency and evaluation of dental arch relationships (scored using the 5-year-olds’ index).

Results:

Our comparative study observed statistically significant differences between the 2 groups regarding the presence of oronasal fistulas and velopharyngeal insufficiency in favor of our palatoplasty technique. A statistically significant difference was not found in functional vestibular oronasal fistula development between the studied techniques for unilateral cleft palate repair. This comparative study did not observe significant differences in dental arch relationships between the studied techniques.

Conclusion:

In this study, better surgical outcome than modified Oslo protocol regarding oronasal fistulas and velopharyngeal insufficiency on patients with complete unilateral cleft lip and palate was observed. The results arising from this study do not provide evidence that one technique is enough to obtain better functional closure of the alveolar cleft and dental arch relationship at 5 years.
Identical Twin Small-bowel Transplantation Without Maintenance Immunosuppression: A 5-year Follow-up and Literature Review
Authors: Wu Guosheng , Zhao Qingchuan , Wang Mian , Wei Jiangpeng , Sun Hao , Zheng Jianyong , Fan Daiming
Published: July 2018

Background

The availability of an identical twin donor that allows avoidance of complications related to graft rejection and immunosuppression represents an ideal treatment option for irreversible intestinal failure.

Methods and Results

We described a 45-year-old woman who lost most of her small bowel due to acute superior mesenteric thrombosis received a living-related small bowel transplant from her identical-twin sister. Monozygosity was established by buccal smear DNA amplification using short tandem repeat. A pretransplant panel-reactive antibody was 47.5% with several HLA antibodies in higher titers. The patient received a brief course of steroids without any additional immunosuppressive agents after transplantation. Her postoperative course was uneventful without an episode of rejection or infection. The preformed HLA antibodies steadily declined over time after transplantation. At a 5-year follow-up, the patient achieved full enteral autonomy from parenteral nutrition with a regular lifestyle.

Conclusions

Identical-twin intestinal transplantation appears to provide the best outcomes by avoiding complications related to rejection and immunosuppression. We provide evidence that it may confer greater long-term immunological advantages even in a high-immunologic risk recipient.
Behaviour of nonhuman primate mothers toward their dead infants: uncovering mechanisms
Authors: Watson Claire F. I. , Matsuzawa Tetsuro
Published: July 2018

In comparative thanatology, most reports for nonhuman mammals concern mothers' behavioural responses to their dead offspring: most prominently, dead-infant carrying (sometimes of extended duration); but also inspection, proximity, maternal care such as grooming, protective behaviours and filial cannibalism. Documented across many primate species, these behaviours remain poorly understood in all. The literature is dominated by relatively brief qualitative descriptions of isolated anecdotal cases in apes and monkeys. We argue for quantitative coding in case reports, alongside analyses of longitudinal records of such events to allow objective evaluation of competing theories, and systematic comparisons within and across species and populations. Obtaining necessary datasets depends on raised awareness in researchers of the importance of recording occurrences and knowledge of pertinent data to collect. We review proposed explanatory hypotheses and outline data needed to test each empirically. To determine factors influencing infant-corpse carriage, we suggest analyses of deaths resulting in ‘carry’ versus ‘no carry’. For individual cases, we highlight behavioural variables to code and the need for hormonal samples. We discuss mothers' stress and welfare in relation to infant death, continued transportation and premature removal of the corpse. Elucidating underlying proximate and ultimate causes is important for understanding phylogeny of maternal responses to infant death.

This article is part of the theme issue ‘Evolutionary thanatology: impacts of the dead on the living in humans and other animals’.
Evolutionary thanatology
Authors: Anderson James R. , Biro Dora , Pettitt Paul
Published: July 2018

Societies, including those of humans, have evolved multiple ways of dealing with death across changing circumstances and pressures. Despite many studies focusing on specialized topics, for example necrophoresis in eusocial insects, mortuary activities in early human societies, or grief and mourning in bereavement, there has been little attempt to consider these disparate research endeavours from a broader evolutionary perspective. Evolutionary thanatology does this by adopting an explicit evolutionary stance for studies of death and dying within the sociological, psychological and biological disciplines. The collection of papers in this themed issue demonstrates the value of this approach by describing what is known about how various nonhuman species detect and respond to death in conspecifics, how problems of disposing of the dead have evolved in human societies across evolutionary time and also within much shorter time frames, how human adults' understanding of death develops, and how it is ultimately reflected in death-related language. The psychological significance and impact of death is clearly seen in some species' grief-like reactions to the loss of attachment figures, and perhaps uniquely in humans, the existence of certain psychological processes that may lead to suicide. Several research questions are proposed as starting points for building a more comprehensive picture of the ontogeny and phylogeny of how organisms deal with death.

This article is part of the theme issue ‘Evolutionary thanatology: impacts of the dead on the living in humans and other animals’.
Social bonds with the dead: how funerals transformed in the twentieth and twenty-first centuries
Authors: Shimane Katsumi
Published: July 2018

Evolutionary thanatology includes the study of necrophoresis—the removal of dead individuals by the living among social insects. In human societies, ‘necrophoresis' is performed via the funeral ceremony. In pre-modern societies, relatives and local community members helped to conduct funerals. In this way, holding a funeral was a form of mutual help, a social exchange of duty and responsibility essential to individuals. These societies developed systems to ensure the survival of humans as social animals based on mutual trust built over long periods of time within the same community. Contemporary societies are undermining these systems. Compared to funerals in pre-modern societies, holding a funeral in a modern society is a complicated process that requires professionals with specialized knowledge and skills. If people feel they can face mortality without support from relatives or the local community, and that they cannot necessarily expect a future return on the effort invested in community-based social relationships, they may begin to disengage from such relationships. In the context of modernization, the clearest changes in collective funerary behaviours include decreased funeral attendance and the above-mentioned outsourcing of funerary services. As such, it can be said that bonds with the dead changed completely under modernization, especially in the twentieth and twenty-first centuries. To establish a sociology of death with a clearer focus on how funeral ceremonies have been affected by modernization, there is a need for research concerned with human behavioural changes regarding the treatment of corpses—that is, a ‘funeralogy'. Accordingly, this study aimed to investigate how modernization has complexified the handling of deceased bodies as death-related services have become commoditized and outsourced while, at the same time, local communities are becoming disengaged from their traditional roles in funeral ceremonies. To this end, fieldwork was conducted in several countries. Moreover, data from surveys conducted by the Social Well-Being Research Consortium in Asia in five East and Southeast Asian countries were quantitatively analysed. The findings highlight the modernization of funerals with the outsourcing of funeral services from the perspective of socio-economic development.

This article is part of the theme issue ‘Evolutionary thanatology: impacts of the dead on the living in humans and other animals'.
Serum metabolomics and incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Alonso Alvaro , Yu Bing , Sun Yan V. , Chen Lin Y. , Loehr Laura R. , O’Neal Wesley T. , Soliman Elsayed Z. , Boerwinkle Eric
Published: July 2018

We have previously identified associations of two circulating secondary bile acids (glycocholenate and glycolithocolate sulfate) with atrial fibrillation (AF) risk among blacks. We aimed to replicate these findings in an independent sample including both whites and blacks, and performed a new metabolomic analysis in the combined sample. We studied 3,922 participants from the ARIC cohort followed between 1987 and 2013. Of these, 1,919 had been included in the prior analysis and 2,003 were new samples. Metabolomic profiling was done in baseline serum samples using gas and liquid chromatography mass spectrometry. AF was ascertained from electrocardiograms, hospitalizations, and death certificates. We used multivariable Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) of AF by one standard deviation difference of metabolite levels. Over a mean follow-up of 20 years, 608 participants developed AF. Glycocholenate sulfate was associated with AF in the replication and combined samples (HR 1.10, 95%CI 1.00, 1.21 and HR 1.13, 95%CI 1.04, 1.22, respectively). Glycolithocolate sulfate was not related to AF risk in the replication sample (HR 1.02, 95%CI 0.92, 1.13). An analysis of 245 metabolites in the combined cohort identified three additional metabolites associated with AF after multiple-comparison correction: pseudouridine (HR 1.18, 95%CI 1.10, 1.28), uridine (HR 0.86, 95%CI 0.79, 0.93) and acisoga (HR 1.17, 95%CI 1.09, 1.26). To conclude, we replicated a prospective association between a previously identified secondary bile acid, glycocholenate sulfate, and AF incidence, and identified new metabolites involved in nucleoside and polyamine metabolism as markers of AF risk.
Endogenous controllability of closed-loop brain-machine interfaces for pain
Authors: Zhang Suyi , Yoshida Wako , Mano Hiroaki , Yanagisawa Takufumi , Shibata Kazuhisa , Kawato Mitsuo , Seymour Ben
Published: July 2018

The ultimate aim of closed-loop brain-machine systems for pain is to directly titrate the ongoing level of an intervention to pain-related neural activity. However pain is highly susceptible to endogenous modulation, raising the possibility that active or passive changes in neural activity provoked by the operation of the system could enhance or interfere with the signals upon which it is based. We studied healthy subjects receiving intermittent pain stimuli in a real-time fMRI-based closed-loop feedback-stimulation task. We showed that multi-voxel pattern decoding of pain intensity could be used to train a control algorithm to learn to deliver less painful stimuli (adaptive decoded neurofeedback). However, the system engaged two types of endogenous processes in the brain. First, despite the inherent incentive for subjects to enhance the neural decodability of pain, decodability was either reduced or unchanged in classic pain-processing regions, including insula, dorsolateral prefrontal, and somatosensory cortices. However, increased decodability was observed in a putative pain modulatory region - the pregenual anterior cingulate cortex (pgACC). Second, we found that pain perception itself was modulated by an endogenous computational uncertainty signal engaged as subjects learned the success rate of the system in reducing pain - an effect that also correlated with pgACC responses. The results illustrate how regionally and computationally specific co-adaptive brain-machine learning influences the efficacy of closed-loop systems for pain, and shows that pgACC acts as a key hub in the endogenous controllability of pain.
Mining functional annotations across species
Authors: Warris Sven , Dijkxhoorn Steven , Sloten Teije van , Vossenberg Bart van de
Published: July 2018

Motivation

Numerous tools and databases exist to annotate and interpret the functions encoded in genomes (InterProScan, KEGG, GO etc.). However, analyzing and comparing functionality across a number of genomes, for example of related species, is not trivial.

Results

We present a novel approach, for which KEGG and Gene Ontology data are imported into a Neo4j graph database and InterProScan results from several species are added. Using the Neo4j plugin for Cytoscape, users can query this database and visualize functional annotations (sub)graphs, to compare and group functional annotation across species.
Anticlastogenic Effect of Ulva Fasciata, Against Cyclophosphamide and Mitomycin C Induced Chromosomal Damage in Swiss Albino Mice
Authors: Dolpady Jayashree , Vijayalaxmi K.K.
Published: July 2018

Chemoprevention is a strategy to reduce the incidence of human cancer either by inhibiting initiation of carcinogenesis or by preventing exposure to carcinogens, by the use of plant or animal derived ingredients. In the present study we investigated the anticlastogenic effect of ethanol extract of Ulva fasciata, a green seaweed, against the chromosomal aberration and micronucleus induced by the anticancer drugs cyclophosphamide and mitomycin C. Three doses of extract (25, 50 and 75 mg/kg.b.w) was given by oral gavage for 5 days at 24 hr. intervals and on the 5th day, CP (25 and 50mg/kg.b.w) or MMC (1 and 2mg/kg.b.w) were intraperitoneally injected and 24hrs. later micronucleus and chromosomal aberrations assays were performed. Our results show that Ulva extract gave significant protection against the CP and MMC induced damages by reducing micronucleus and chromosomal aberrations. The protection imparted by Ulva could be due to the synergistic and/or additive effects of biologically active ingredients present in the seaweed.
Non-parametric polygenic risk prediction using partitioned GWAS summary statistics
Authors: Chun Sung , Imakaev Maxim , Hui Daniel , Patsopoulos Nikolaos A. , Neale Benjamin M. , Kathiresan Sekar , Stitziel Nathan O. , Sunyaev Shamil R.
Published: July 2018

In complex trait genetics, the ability to predict phenotype from genotype is the ultimate measure of our understanding of genetic architecture underlying the heritability of a trait. A complete understanding of the genetic basis of a trait should allow for predictive methods with accuracies approaching the trait’s heritability. The highly polygenic nature of quantitative traits and most common phenotypes has motivated the development of statistical strategies focused on combining myriad individually non-significant genetic effects. Now that predictive accuracies are improving, there is a growing interest in practical utility of such methods for predicting risk of common diseases responsive to early therapeutic intervention. However, existing methods require individual level genotypes or depend on accurately specifying the genetic architecture underlying each disease to be predicted. Here, we propose a polygenic risk prediction method that does not require explicitly modeling any underlying genetic architecture. We start with summary statistics in the form of SNP effect sizes from a large GWAS cohort. We then remove the correlation structure across summary statistics arising due to linkage disequilibrium and apply a piecewise linear interpolation on conditional mean effects. In both simulated and real datasets, this new non-parametric shrinkage (NPS) method can reliably allow for linkage disequilibrium in summary statistics of 5 million dense genome-wide markers and consistently improves prediction accuracy. We show that NPS improves the identification of groups at high risk for Breast Cancer, Type 2 Diabetes, Inflammatory Bowel Disease and Coronary Heart Disease, all of which have available early intervention or prevention treatments.
Thermal Denaturation of DNA G-Quadruplexes and their Complexes with Ligands: Thermodynamic Analysis of the Multiple States Revealed by Mass Spectrometry
Authors: Marchand Adrien , Rosu Frédéric , Zenobi Renato , Gabelica Valérie
Published: July 2018

As the idea that G-quadruplex nucleic acid structures are involved in cellular processes is gaining support, it becomes important to develop ligands that specifically target G-quadruplexes. However, ligand design is complicated because there are multiple G-quadruplex target sequences, some sequences are polymorphic, and very few ligand-quadruplex structures in solution were solved to date. Further, structure alone does not reveal the driving forces for ligand binding. To knowwhya ligand binds, the thermodynamics of binding must be characterized. Electrospray mass spectrometry makes it possible to detect and quantify each specific stoichiometry in terms of number of strands, number of specific cations, and number of ligands, and thus allows one to simultaneously determine the equilibrium constants for the formation of each complex. We designed and built a temperature-controlled nano-electrospray source to monitor thermal denaturation by mass spectrometry (“MS-melting”). We studied the thermal denaturation of G-quadruplexes, including the c-myc promoter and several telomeric sequence variants, and their complexes with popular ligands (Phen-DC3, TrisQ, TMPyP4, Cu-ttpy). From the temperature dependence of the equilibrium constants, we determined the enthalpic and entropic contributions to the formation of each stoichiometric state. In absence of ligand, we untangled the potassium-induced G-quadruplex folding thermodynamics, one potassium ion at a time. The formation of each quartet-K+-quartet units is strongly enthalpy driven, with entropy penalty. In contrast, the formation of quartet-K+-triplet units is entropically driven. For this reason, such misfolded structures can become more abundant as the temperature increases. In the presence of ligands, mass spectrometry also revealed new states at intermediate temperatures. For example, even in cases where only a 1:1 (ligand:quadruplex) is observed at room temperature, a 2:1 complex predominates at intermediate temperatures. Mass spectrometry also makes it easy to distinguish ligand bound to the 2-quartet structures (containing 1 K+), the 3-quartet structures (containing 2 K+) and to the unfolded strand (no specific K+). We confirm that TrisQ binds preferably, but not exclusively, to 3-quartet structures, Phen-DC3 binds to a 2-quartet structure, while the porphyrin ligand TMPyP4 is characterized as non-selective, because it binds to all forms including the unfolded one. The thermodynamics of ligand binding to each form, one ligand at a time, provides unprecedented detail on the interplay between ligand binding and changes in G-quadruplex topology.

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For common community phylogenetic analyses, go ahead and use synthesis phylogenies
Authors: Li Daijiang , Trotta Lauren , Marx Hannah E. , Allen Julie M. , Sun Miao , Soltis Douglas E. , Soltis Pamela S. , Guralnick Robert P. , Baiser Benjamin
Published: July 2018

Should we build our own phylogenetic trees based on gene sequence data, or can we simply use available synthesis phylogenies? This is a fundamental question that any study involving a phylogenetic framework must face at the beginning of the project. Building a phylogeny from gene sequence data (purpose-built phylogeny) requires more effort, expertise, and cost than subsetting an already available phylogeny (synthesis-based phylogeny). However, we still lack a comparison of how these two approaches to building phylogenetic trees influence common community phylogenetic analyses such as comparing community phylogenetic diversity and estimating trait phylogenetic signal. Here, we generated three purpose-built phylogenies and their corresponding synthesis-based trees (two from Phylomatic and one from the Open Tree of Life [OTL]). We simulated 1,000 communities and 12,000 continuous traits along each purpose-built phylogeny. We then compared the effects of different trees on estimates of phylogenetic diversity (alpha and beta) and phylogenetic signal (Pagel’s λ and Blomberg’s K). Synthesis-based phylogenies generally yielded higher estimates of phylogenetic diversity when compared to purpose-built phylogenies. However, resulting measures of phylogenetic diversity from both types of phylogenies were highly correlated (Spearman’s ρ > 0.8 in most cases). Mean pairwise distance (both alpha and beta) is the index that is most robust to the differences in tree construction that we tested. Measures of phylogenetic diversity based on the OTL showed the highest correlation with measures based on the purpose-built phylogenies. Trait phylogenetic signal estimated with synthesis-based phylogenies, especially from the OTL, were also highly correlated with estimates of Blomberg’s K or close to Pagel’s λ from purpose-built phylogenies when traits were simulated under Brownian Motion. For commonly employed community phylogenetic analyses, our results justify taking advantage of recently developed and continuously improving synthesis trees, especially the Open Tree of Life.
A robust phylogenomic timetree for biotechnologically and medically important fungi in the genera Aspergillus and Penicillium
Authors: Steenwyk Jacob L. , Shen Xing-Xing , Lind Abigail L. , Goldman Gustavo H. , Rokas Antonis
Published: July 2018

Abbreviations:

NT, nucleotide; AA, amino acid; CI, credible interval; RCV, relative composition variability; IC, internode certainty; GSF, gene support frequencies; GLS, gene-wise log-likelihood scores; DVMC, degree of violation of a molecular clock

The filamentous fungal family Aspergillaceae contains > 1,000 known species, mostly in the genera Aspergillus and Penicillium. Several species are used in the food, biotechnology, and drug industries (e.g., Aspergillus oryzae, Penicillium camemberti), while others are dangerous human and plant pathogens (e.g., Aspergillus fumigatus, Penicillium digitatum). To infer a robust phylogeny and pinpoint poorly resolved branches and their likely underlying contributors, we used 81 genomes spanning the diversity of Aspergillus and Penicillium to construct a 1,668-gene data matrix. Phylogenies of the nucleotide and amino acid versions of this full data matrix as well as of five additional 834-gene data matrices constructed by subsampling the top 50% of genes according to different criteria associated with strong phylogenetic signal were generated using three different maximum likelihood schemes (i.e., gene-partitioned, unpartitioned, and coalescence). Examination of the topological agreement among these 36 phylogenies and measures of internode certainty identified 12 / 78 (15.4%) bipartitions that were incongruent and pinpoint the likely underlying contributing factors (incomplete lineage sorting, hybridization or introgression, and reconstruction artifacts associated with poor taxon sampling). Relaxed molecular clock analyses suggest that Aspergillaceae likely originated in the lower Cretaceous and the Aspergillus and Penicillium genera in the upper Cretaceous. Our results shed light on the ongoing debate on Aspergillus systematics and taxonomy and provide a robust evolutionary and temporal framework for comparative genomic analyses in Aspergillaceae. More broadly, our approach provides a general template for phylogenomic identification of resolved and contentious branches in densely genome-sequenced lineages across the tree of life.
A comprehensive characterization of cis-acting splicing-associated variants in human cancer
Authors: Shiraishi Yuichi , Kataoka Keisuke , Chiba Kenichi , Okada Ai , Kogure Yasunori , Tanaka Hiroko , Ogawa Seishi , Miyano Satoru
Published: July 2018

Although many driver mutations are thought to promote carcinogenesis via abnormal splicing, the landscape of splicing-associated variants (SAVs) remains unknown due to the complexity of splicing abnormalities. Here, we developed a statistical framework to systematically identify SAVs disrupting or newly creating splice site motifs and applied it to matched whole-exome and transcriptome sequencing data from 8976 samples across 31 cancer types, generating a catalog of 14,438 SAVs. Such a large collection of SAVs enabled us to characterize their genomic features, underlying mutational processes, and influence on cancer driver genes. In fact, ∼50% of SAVs identified were those disrupting noncanonical splice sites (non-GT-AG dinucleotides), including the third and fifth intronic bases of donor sites, or newly creating splice sites. Mutation signature analysis revealed that tobacco smoking is more strongly associated with SAVs, whereas ultraviolet exposure has less impact. SAVs showed remarkable enrichment of cancer-related genes, and as many as 14.7% of samples harbored at least one SAVs affecting them, particularly in tumor suppressors. In addition to intron retention, whose association with tumor suppressor inactivation has been previously reported, exon skipping and alternative splice site usage caused by SAVs frequently affected tumor suppressors. Finally, we described high-resolution distributions of SAVs along the gene and their splicing outcomes in commonly disrupted genes, including TP53, PIK3R1, GATA3, and CDKN2A, which offers genetic clues for understanding their functional properties. Collectively, our findings delineate a comprehensive portrait of SAVs, novel insights into transcriptional de-regulation in cancer.
Surprise and destabilize: prediction error influences episodic memory reconsolidation
Authors: Sinclair Alyssa H. , Barense Morgan D.
Published: July 2018

Through the process of “reconsolidation,” reminders can temporarily destabilize memories and render them vulnerable to change. Recent rodent research has proposed that prediction error, or the element of surprise, is a key component of this process; yet, this hypothesis has never before been extended to complex episodic memories in humans. In our novel paradigm, we used naturalistic stimuli to demonstrate that prediction error enables adaptive updating of episodic memories. In Study 1, participants (N = 48) viewed 18 videos, each depicting an action–outcome event. The next day, we reactivated these memories by presenting the videos again. We found that incomplete reminders, which interrupted videos before the outcome, made memories vulnerable to subsequent interference from a new set of videos, producing false memories. In Study 2 (N = 408), an independent sample rated qualities of the stimuli. We found that videos that were more surprising when interrupted produced more false memories. Last, in Study 3 (N = 24), we tested competing predictions of reconsolidation theory and the Temporal Context Model, an alternative account of source confusion. Consistent with the mechanistic time-course of reconsolidation, our effects were crucially time-dependent. Overall, we synthesize prior animal and human research to present compelling evidence that prediction error destabilizes episodic memories and drives dynamic updating in the face of new information.
Predictability matters: role of the hippocampus and prefrontal cortex in disambiguation of overlapping sequences
Authors: Cohen Justine E. , Ross Robert S. , Stern Chantal E.
Published: July 2018

Previous research has demonstrated that areas in the medial temporal lobe and prefrontal cortex (PFC) show increased activation during retrieval of overlapping sequences. In this study, we designed a task in which degree of overlap varied between conditions in order to parse out the contributions of hippocampal and prefrontal subregions as overlap between associations increased. In the task, participants learned sequential associations consisting of a picture frame, a face within the picture frame, and an outdoor scene. The control condition consisted of a single frame-face-scene sequence. In the low overlap condition, each frame was paired with two faces and two scenes. In the high overlap condition, each frame was paired with four faces and four scenes. In all conditions the correct scene was chosen among four possible scenes and was dependent on the frame and face that preceded the choice point. One day after training, participants were tested on the retrieval of learned sequences during fMRI scanning. Results showed that the middle and posterior hippocampus (HC) was active at times when participants acquired information that increased predictability of the correct response in the overlapping sequences. Activation of dorsolateral PFC occurred at time points when the participant was able to ascertain which set of sequences the correct response belonged to. The ventrolateral PFC was active when inhibition was required, either of irrelevant stimuli or incorrect responses. These results indicate that areas of lateral PFC work in concert with the HC to disambiguate between overlapping sequences and that sequence predictability is key to when specific brain regions become active.