bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment for Lentigo Maligna of the Head and Neck: Survey of Practices in Ontario, Canada
Authors: Liu Annie , Botkin Alexis , Murray Christian , Goldstein David , Hofer Stefan O.P. , Solish Nowell , Kitchen Jessica , Chan An-Wen
Published: March 2018

BACKGROUND

Lentigo maligna is an in situ form of cutaneous melanoma that commonly arises on the head and neck. Various surgical and nonsurgical treatment options are available but no randomized trials exist to guide practice.

OBJECTIVE

To determine the current treatment practices for lentigo maligna of the head and neck in Ontario, Canada.

MATERIALS AND METHODS

Cross-sectional survey of dermatologists, plastic surgeons, and head and neck surgeons.

RESULTS

The response rate was 35% (190/542). Wide excision with immediate reconstruction was the most commonly recommended treatment for tumors on the cheek (69%), whereas staged excision with margin control was recommended most often for tumors on the nasal ala (60%). Overall, 5 mm was the most frequently recommended initial surgical margin (69%); 26.5% of respondents recommended margins wider than 5 mm. For tumors on the nasal ala, eyelid, and ear helix, more than 30% of respondents recommended an initial margin narrower than 5 mm.

CONCLUSION

Although surgical excision is the predominant treatment modality for lentigo maligna on the head and neck, practices vary considerably in terms of the type of excision and the initial margin used. Potential response bias and the geographic restriction of our sample may limit the generalizability of our results.
Accelerometer-Measured Daily Activity Levels and Related Factors in Patients With Heart Failure
Authors: Pozehl Bunny J. , Mcguire Rita , Duncan Kathleen , Hertzog Melody , Deka Pallav , Norman Joseph , Artinian Nancy T. , Saval Matthew A. , Keteyian Steven J.
Published: March 2018

Background:

Few studies report objective accelerometer-measured daily physical activity levels in patients with heart failure (HF).

Objective:

We examined baseline accelerometer-measured physical activity from the Heart Failure Exercise and Resistance Training Camp trial, a federally funded (R01-HL112979) 18-month intervention study to promote adherence to exercise in patients with HF. Factors associated with physical activity levels were also explored.

Methods:

Patients with diagnosed HF (stage C chronic HF confirmed by echocardiography and clinical evaluation) were recruited from 2 urban medical centers. Physical activity energy expenditure and the number of minutes of moderate or vigorous physical activity (MVPA) were obtained from 7 full days of measurement with the accelerometer (Actigraph Model GT3X, Pensacola, Florida) for 182 subjects who met minimum valid wear time parameters. Additional measures of health-related factors were included to explore the association with physical activity levels.

Results:

Subjects had 10.2 ± 10.5 minutes of MVPA per day. Total physical activity energy expenditure was 304 ± 173 kcal on average per day. There were 23 individuals (12.6%) who met the recommended goal of 150 minutes of MVPA per week. Men, whites, New York Heart Association class II, and subjects with better physical function had significantly higher levels of activity.

Conclusions:

Consistent with previous research, patients with HF are not meeting recommended guidelines for 150 minutes of MVPA per week.
Mechanisms for intestinal regeneration
Authors: Dubrovsky Genia , Dunn James C.Y.
Published: March 2018

Purpose of review

The purpose of this review is to briefly summarize the notable structures and pathways in intestinal epithelial growth before presenting the current main areas of active research in intestinal regeneration. As a rapidly advancing field, a number of breakthroughs have recently been made related to the culture of intestinal stem cells (ISCs) and to the engineering of intestinal tissue.

Recent findings

ISCs can be derived from fibroblasts and can be cultured in hydrogels under xenogeneic-free conditions. Intestinal organoids can be cultured with neural crest cells to form small intestinal tissues with neuromuscular networks. Endoluminal devices can be placed inside the native intestine to exert mechanical force to induce novel tissue growth.

A number of recent advances in the field of intestinal regeneration are encouraging and suggest that novel therapies for a wide range of intestinal disorders may be developed in the near future. There are still a number of obstacles before such stem cell therapies can be safely used in humans.
“I Wasn't Gonna Let It Stop Me”: Exploring Women's Experiences of Getting Through Chemotherapy for Ovarian Cancer
Authors: Staneva Aleksandra A. , Beesley Vanessa L. , Niranjan Navin , Gibson Alexandra F. , Rowlands Ingrid , Webb Penelope M.
Published: March 2018

Background

Many women with ovarian cancer experience significant chemotherapy-related adverse effects during treatment and thus cannot complete it without dose reductions and/or delays. There is some indication that chemotherapy completion is associated with improved survival, although currently little is known about what helps women get through chemotherapy.

Objective

The aim of this study was to explore women's accounts of the factors they believed were helpful during their ovarian cancer treatment.

Methods

Using a qualitative approach within a critical realist framework, we conducted interviews with 18 women who had received chemotherapy for ovarian cancer and analyzed the data thematically.

Results

We identified 3 main themes related to women's experiences of dealing with chemotherapy: “optimistic tenacity,” which illustrates a specific stoic identity that women assumed during treatment; “self-care,” which reflects the health behaviors and activities women engaged in and lifestyle adjustments they made; and “support systems,” which emphasizes the importance of social, emotional, and medical support and the specific needs shared by women undergoing treatment for ovarian cancer.

Conclusions

Our findings contribute to a deeper understanding of women's unique experiences of treatment that may influence whether they complete chemotherapy for ovarian cancer.

Implications for Practice

This study highlights the central role of women's optimistic determination within a wider self-caring and well-supported context of treatment; we aim to provide feedback and guidance to health professionals caring for women with ovarian cancer.
Emergency Medicine Providers' Knowledge and Management of Pediatric Tropical Diseases
Authors: Thomas Vanessa A. , Crouse Heather L. , Murray Kristy O. , Hsu Deborah C. , Camp Elizabeth A. , Cruz Andrea T.
Published: March 2018

Objective

The aim of this study was to perform a needs assessment of pediatric (PEM) and general emergency medicine (EM) provider knowledge, comfort, and current practice patterns in the evaluation of pediatric tropical infectious diseases.

Methods

An online survey was developed based on educational priorities identified by an expert panel via modified Delphi methodology. The survey included assessment of providers' typical evaluation, diagnosis, and treatment of tropical diseases and was distributed to PEM and EM providers in 2 large professional organizations.

Results

A total of 333 physicians (285 PEM, 32 EM, 8 combined PEM/EM, and 8 general pediatricians in emergency department) participated. Fifty-five percent of vignettes were answered correctly. Those who trained outside the United States or Canada (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.1–3.0) and PEM-trained providers (OR, 2.6; 95% CI, 1.2–5.9) were more likely to answer questions correctly. Providers answered more questions correctly about dengue (76%) and tuberculosis (77%) than typhoid (53%) and malaria (39%) (OR, 3.8; 95% CI, 3.0–4.9). Diagnostic evaluation for tropical diseases was variable with greater than 75% agreement for only 2 tests: blood smears in febrile patients from Africa (86%) and bacterial stool cultures in patients with bloody stools from Africa, Asia, or Latin America (94%). Providers had low (62%) or medium (35%) comfort level with pediatric tropical diseases, and 93% were interested in accessing emergency department–specific resources.

Conclusions

Pediatric EM and EM providers' knowledge and evaluation for pediatric tropical diseases are variable. Providers recognized their knowledge gaps and expressed interest in gaining access to resources and guidelines to standardize and improve evaluation and treatment of these diseases.
Scaphoid Fractures in Children
Authors: Porter Jonathan , Porter Robert , Chan Kevin Joseph
Published: March 2018

Objectives

The purpose of this study is to determine the predictive value of clinical suspicion for scaphoid fracture in children aged 4 to 11 years, to look at the efficiency and practicality of current management of children presenting to the emergency department, and to help quantify the burden of the treatment strategy of immobilization for 10 to 14 days on clinical grounds despite negative or equivocal x-rays on presentation.

Methods

We performed a retrospective chart review study of a consecutive sample of all children aged 4 to 11 years old who presented to a tertiary pediatric emergency department from January 1, 2009, to December 31, 2013, within 24 hours of a wrist injury, with a clinical suspicion sufficient to order a scaphoid x-ray. Our primary outcome of interest was the positive predictive value of clinical suspicion of a scaphoid fracture.

Results

There were 142 patients (144 wrists) included in the study. Of these, 110 had a normal initial x-ray. Initial x-rays showed evidence of nonscaphoid fractures in 30 wrists and equivocal scaphoid fractures in 4 wrists. Of the 110 wrists with normal initial x-rays, 69 were immobilized and 52 of those had a follow-up x-ray (47 normal, 1 scaphoid fracture, 1 nonscaphoid fracture, and 3 equivocal evidence of a scaphoid fracture). The positive predictive value was found to be 2.1% to 12.5%.

Conclusions

This study suggests that children aged 4 to 11 years with clinical suspicion for scaphoid fractures do not necessarily need to be x-rayed or immobilized. A larger multicentered prospective clinical trial would confirm this.
Barriers and Facilitators to Central Venous Catheter Insertion: A Qualitative Study
Authors: Cameron Kenzie A. , Cohen Elaine R. , Hertz Joelle R. , Wayne Diane B. , Mitra Debi , Barsuk Jeffrey H.
Published: March 2018

Objectives

The aims of the study were to identify perceived barriers and facilitators to central venous catheter (CVC) insertion among healthcare providers and to understand the extent to which an existing Simulation-Based Mastery Learning (SBML) program may address barriers and leverage facilitators.

Methods

Providers participating in a CVC insertion SBML train-the-trainer program, in addition to intensive care unit nurse managers, were purposively sampled from Veterans Administration Medical Centers located in geographically diverse areas. We conducted semistructured interviews to assess perceptions of barriers and facilitators to CVC insertion. Deidentified transcripts were analyzed using a grounded theory approach and the constant comparative method. We subsequently mapped identified barriers and facilitators to our SBML curriculum to determine whether or not the curriculum addresses these factors.

Results

We interviewed 28 providers at six Veterans Administration Medical Centers, identifying the following five overarching factors of perceived barriers to CVC insertion: (1) equipment, (2) personnel/staff, (3) setting or organizational context, (4) patient or provider, and (5) time-related barriers. Three overarching factors of facilitators emerged: (1) equipment, (2) personnel, and (3) setting or organizational context facilitators. The SBML curriculum seems to address most identified barriers, while leveraging many facilitators; building on the commonly identified facilitator of nursing staff contribution by expanding the curriculum to explicitly include nurse involvement could improve team efficiency and organizational culture of safety.

Conclusions

Many identified facilitators (e.g., ability to use ultrasound, personnel confidence/competence) were also identified as barriers. Evidence-based SBML programs have the potential to amplify these facilitators while addressing the barriers by providing an opportunity to practice and master CVC insertion skills.
The Scintigraphic Drooping Lily Sign
Authors: Sahakyan Karine , Spevak Melissa R. , Ziessman Harvey A. , Gorin Michael A. , Rowe Steven P.
Published: March 2018

The “drooping lily” sign is identified on intravenous urography or voiding cystourethrography in patients with a duplicated renal collecting system and refers to inferolateral displacement of a functioning lower pole moiety by an obstructed upper pole collecting system. In this case, a 2-month-old girl with a prenatal diagnosis of hydronephrosis was found to have a “scintigraphic drooping lily” sign on 99mTc-dimercaptosuccinic acid renal scan. Evaluation with ultrasound and voiding cystourethrography confirmed a duplicated collecting system and obstructed upper pole moiety. Correlation with anatomic imaging can help avoid mistaking the scintigraphic “drooped” lower pole for an inferiorly positioned normal kidney.
Synchronous Detection of Male Breast Cancer and Prostatic Cancer in a Patient With Suspected Prostatic Carcinoma on 68Ga-PSMA PET/CT Imaging
Authors: Kumar Rajender , Mittal Bhagwant Rai , Bhattacharya Anish , Singh Harmandeep , Singh Shrawan Kumar
Published: March 2018

The male breast cancer is very less common as compared with the female breast cancer. We report a case of 64-year-old man who presented with the history of lower urinary tract symptoms. The digital rectal examination revealed hard and nodular prostate, and serum prostate-specific antigen level was 23.4 ng/mL. 68Ga-labeled prostate-specific membrane antigen PET/CT revealed prostate-specific membrane antigen–expressing lesions in the prostate, axillary tail of the right breast, and axillary lymph nodes. Histology from prostate revealed prostate carcinoma, whereas fine-needle aspiration from the breast revealed invasive ductal carcinoma of the breast.
Transplantation of Autogenous Bone Block With an Osseointegrated Implant: Seedling Technique With Twelve-Month Follow-Up
Authors: Kutlu Huseyin Burak , Goyushov Samir , Calisan Bünyamin , Tözüm Tolga F.
Published: March 2018

Objective:

Loss of teeth frequently results in compound horizontal and vertical alveolar bone defects. An appropriate bone structure is the key for implant placement and bony support of soft tissues. Advanced bone augmentation techniques are required for the reconstruction of these defects. This report will present a new bone block grafting technique with 12-month follow-up.

Method:

The seedling technique was used to augment the alveolar bone 3-dimensionally with autologous bone block and an osseointegrated implant in a 2-stage procedure. Horizontal and vertical bone loss is revealed after cone beam radiographic examination in the right maxillary lateral incisor area. Initially, the implant was placed at the right maxillary tuber area, where the bone was abundant. After 2-months healing phase, the osseointegrated implant was harvested with the surrounding bone and transplanted to the anterior region of maxilla to augment the horizontal and the vertical components of the recipient site. Transplanted implant inserted into autogenous bone block was fixed with mini plate to the adjacent native bone. Prosthetic restoration was applied 4 months after the transplantation.

Results:

Seven months after the first surgery, treatment of anterior bone deficiency was accomplished. The patient was fully satisfied with the function and the esthetics of the restoration. The radiological and clinical examinations at 1-year follow-up evaluation showed successful outcome of transplanted autogenous bone block without any resorption.

Conclusion:

This clinical report demonstrated that anterior maxillary single-tooth replacement, according to seedling concept of autogenous bone block with osseointegrated implant, is a successful and predictable treatment modality.
Proximal penetrating extremity injuries—An opportunity to decrease overtriage?
Authors: Martin Grace E. , He Heng , Makley Amy T. , Pritts Timothy A. , Elterman Joel B. , Johannigman Jay A. , Goodman Michael D.
Published: March 2018

BACKGROUND

Penetrating injuries to the extremity proximal to the elbow or knee are anatomic criteria for full trauma team activation (FFTA) by the American College of Surgeon’s Committee on Trauma standards. This criterion lacks objective evidence-based support. Overtriage of trauma team activation may result in excessive costs and resource burden at trauma centers. We hypothesized that FFTA for penetrating injuries to the proximal extremities by anatomic criteria alone may lead to significant overtriage.

METHODS

A 3-year retrospective review (2013–2015) was completed of all patients evaluated at an urban Level I trauma center with isolated penetrating extremity injuries. Data included the number of full and limited trauma team activations as well as criterion met, Injury Severity Score (ISS), injury, limb characteristics, and disposition. Overtriage was defined as FFTA for an ISS of 15 or less, with a goal rate less than 50%.

RESULTS

We identified 6,335 total trauma team activations with 795 isolated penetrating extremity injuries. Of these injuries, 413 (51.9%) were injuries proximal to the joint. Within this subgroup, 71.2% of patients were discharged from the emergency department with a median ISS of 1 and no additional intervention. Only 5.3% of patients that did not meet additional FFTA criteria underwent immediate operative intervention. By comparison, 21% of FFTAs and 5.8% of limited trauma team activations underwent immediate operative intervention during the 3-year period. Of the 413 isolated penetrating proximal-extremity injuries, only one had an ISS of 15 or greater, resulting in a 99.7% overtriage rate.

CONCLUSION

Penetrating injuries to the extremities are common in urban trauma centers. Full trauma team activation based on anatomic, rather than physiologic, criteria may lead to a significant overtriage rate. Further distinction in the level of trauma team activation may be made based on hard signs of neurovascular injury.

LEVEL OF EVIDENCE

Epidemiological study, level III; Care Management, level IV.
Predicting the effects of parasite co-infection across species boundaries
Authors: Lello Joanne , McClure Susan J. , Tyrrell Kerri , Viney Mark E.
Published: March 2018

It is normal for hosts to be co-infected by parasites. Interactions among co-infecting species can have profound consequences, including changing parasite transmission dynamics, altering disease severity and confounding attempts at parasite control. Despite the importance of co-infection, there is currently no way to predict how different parasite species may interact with one another, nor the consequences of those interactions. Here, we demonstrate a method that enables such prediction by identifying two nematode parasite groups based on taxonomy and characteristics of the parasitological niche. From an understanding of the interactions between the two defined groups in one host system (wild rabbits), we predict how two different nematode species, from the same defined groups, will interact in co-infections in a different host system (sheep), and then we test this experimentally. We show that, as predicted, in co-infections, the blood-feeding nematode
Haemonchus contortus
suppresses aspects of the sheep immune response, thereby facilitating the establishment and/or survival of the nematode
Trichostrongylus colubriformis
; and that the
T. colubriformis
-induced immune response negatively affects
H. contortus
. This work is, to our knowledge, the first to use empirical data from one host system to successfully predict the specific outcome of a different co-infection in a second host species. The study therefore takes the first step in defining a practical framework for predicting interspecific parasite interactions in other animal systems.
Early hatching enhances survival despite beneficial phenotypic effects of late-season developmental environments
Authors: Pearson P. R. , Warner D. A.
Published: March 2018

Seasonal shifts in environmental conditions provide predictable cues to which organisms can respond in adaptive ways. For example, seasonal changes in temperature can induce phenotypes at different times of the year that have season-specific fitness benefits. Here, we tested the hypothesis that embryo responses to seasonal changes in thermal environments are adaptively matched to the timing of reproduction (environmental-matching hypothesis). We collected eggs of the brown anole lizard (Anolis sagrei) from early and late seasons, and exposed them to early and late thermal regimes that mimic nest temperatures. After measuring offspring morphology and performance, we quantified their survival in the field. Females had higher fecundity, but produced smaller eggs, early in the season compared with late in the season. Late-season eggs exposed to late thermal regimes had relatively high survival, but early-season eggs exposed to early thermal regimes had similar survival rates to those exposed to mismatched conditions. Late-season nest temperatures and late-season eggs produced offspring that were relatively large and fast runners. However, despite phenotypic benefits of late-season conditions, early-season hatchlings had greater survival in the field. Our results do not fully support the environmental-matching hypothesis but suggest that selection favours seasonal shifts in reproductive investment of mothers (high early-season fecundity) over plastic responses of embryos to seasonal environmental changes.
Reviewing the effects of food provisioning on wildlife immunity
Authors: Strandin Tomas , Babayan Simon A. , Forbes Kristian M.
Published: March 2018

While urban expansion increasingly encroaches on natural habitats, many wildlife species capitalize on anthropogenic food resources, which have the potential to both positively and negatively influence their responses to infection. Here we examine how food availability and key nutrients have been reported to shape innate and adaptive immunity in wildlife by drawing from field-based studies, as well as captive and food restriction studies with wildlife species. Examples of food provisioning and key nutrients enhancing immune function were seen across the three study type distinctions, as were cases of trace metals and pharmaceuticals impairing the immunity of wildlife species. More generally, food provisioning in field studies tended to increase innate and adaptive responses to certain immune challenges, whereas patterns were less clear in captive studies. Mild food restriction often enhanced, whereas severe food restriction frequently impaired immunity. However, to enable stronger conclusions we stress a need for further research, especially field studies, and highlight the importance of integrating nutritional manipulation, immune challenge, and functional outcomes. Despite current gaps in research on this topic, modern high throughput molecular approaches are increasingly feasible for wildlife studies and offer great opportunities to better understand human influences on wildlife health.

This article is part of the theme issue ‘Anthropogenic resource subsidies and host–parasite dynamics in wildlife’.
Fungemia caused by Aureobasidium pullulans in a patient with advanced AIDS: a case report and review of the medical literature
Authors: Mittal Jaimie , Szymczak Wendy A. , Pirofski Liise-anne , Galen Benjamin T.
Published: March 2018

Introduction.
Aureobasidium pullulans is a dematiaceous, yeast-like fungus that is ubiquitous in nature and can colonize human hair and skin. It has been implicated clinically as causing skin and soft tissue infections, meningitis, splenic abscesses and peritonitis. We present, to our knowledge, the second case of isolation of this organism in a patient with AIDS along with a review of the literature on human infection with A. pullulans.

Case presentation. A 49-year-old man with advanced AIDS and a history of recurrent oesophageal candidiasis was admitted with nausea with vomiting, and odynophagia. He was treated as having a recurrence of oesophageal candidiasis. Given prior Candida albicans isolate susceptibilities and chronic suppression with fluconazole, he was started on micafungin with eventual improvement in his symptoms. A positive blood culture from admission was initially reported to be growing yeast, but four days later the isolate was recognized as a dematiaceous fungus. The final identification of A. pullulans was not available until 1 month after admission. He had completed a 3-week course of micafungin prior to the identification of the isolate, and repeat cultures were negative.

Conclusion.
A. pullulans fungemia is rare but can occur in patients with immune suppression or indwelling catheters. The significance of isolating A. pullulans from a blood culture in terms of whether it is the causative agent of a state of disease often cannot be determined because skin colonization is possible. Further work is needed to clarify the clinical implications of A. pullulans fungemia.
Coupling between cerebral blood flow and cerebral blood volume: Contributions of different vascular compartments
Authors: Wesolowski Roman , Blockley Nicholas P. , Driver Ian D. , Francis Susan T. , Gowland Penny A.
Published: March 2018

A better understanding of the coupling between changes in cerebral blood flow (CBF) and cerebral blood volume (CBV) is vital for furthering our understanding of the BOLD response. The aim of this study was to measure CBF-CBV coupling in different vascular compartments during neural activation. Three haemodynamic parameters were measured during a visual stimulus. Look-Locker Flow-sensitive Alternating Inversion Recovery (LL-FAIR) was used to measure changes in CBF and arterial CBV (CBVa) using sequence parameters optimised for each contrast. Changes in total CBV (CBVtot) were measured using a Gadolinium based contrast agent technique. Haemodynamic changes were extracted from a region of interest based on voxels that were activated in the CBF experiments. The CBF-CBVtot coupling constant αtot was measured as 0.16±0.14 and the CBF-CBVa coupling constant αa was measured as 0.65±0.24. Using a two compartment model of the vasculature (arterial and venous), the change in venous CBV (CBVv) was predicted for an assumed value of baseline arterial and venous blood volume. These results will enhance the accuracy and reliability of applications that rely on models of the BOLD response, such as calibrated BOLD.
Efficient CRISPR/Cas9-based genome editing and its application to conditional genetic analysis in Marchantia polymorpha
Authors: Sugano Shigeo S. , Nishihama Ryuichi , Shirakawa Makoto , Takagi Junpei , Matsuda Yoriko , Ishida Sakiko , Shimada Tomoo , Hara-Nishimura Ikuko , Osakabe Keishi , Kohchi Takayuki
Published: March 2018

Marchantia polymorpha is one of the model species of basal land plants. Although CRISPR/Cas9-based genome editing has already been demonstrated for this plant, the efficiency was too low to apply to functional analysis. In this study, we show the establishment of CRISPR/Cas9 genome editing vectors with high efficiency for both construction and genome editing. Codon optimization of Cas9 to Arabidopsis achieved over 70% genome editing efficiency at two loci tested. Systematic assessment revealed that guide sequences of 17 nt or shorter dramatically decreased this efficiency. We also demonstrated that a combinatorial use of this system and a floxed complementation construct enabled conditional analysis of a nearly essential gene. This study reports that simple, rapid, and efficient genome editing is feasible with the series of developed vectors.
Arsenite exposure inhibits histone acetyltransferase p300 for attenuating H3K27ac at enhancers in low-dose exposed mouse embryonic fibroblast cells
Authors: Zhu Yan , Li Yanqiang , Lou Dan , Gao Yang , Yu Jing , Kong Dehui , Zhang Qiang , Jia Yankai , Zhang Haimou , Wang Zhibin
Published: March 2018

Epidemiological investigations have validated the positive relationships between arsenic in drinking water and several cancers, including skin, liver and lung cancers. Besides genotoxicity, arsenic exposure-related pathogenesis of disease is widely considered through epigenetic mechanisms; however, the underlying mechanistic insight remains elusive. Herein we explore the initial epigenetic changes via acute low-dose arsenite exposures of mouse embryonic fibroblast (MEF) cells and Dot1L knockout MEF (Dot1L-/- for abbreviation) cells. Our RNA-seq and Western blot data demonstrated that, in both cell lines, acute low-dose arsenite exposure abolished histone acetyltransferase p300 at the RNA level and subsequent protein level. Consequently, p300-specific main target histone H3K27ac, a marker separating active from poised enhancers, decreased dramatically as validated by both Western blot and ChIP-seq analyses. Concomitantly, H3K4me1 as another well-known marker for enhancers also showed significant decreases, suggesting an underappreciated crosstalk between H3K4me1 and H3K27ac involved in arsenite exposure. Significantly, arsenite exposure-reduced H3K27ac and H3K4me1 inhibit the expression of genes includingEP300itself andKruppel Like Factor 4(Klf4), a tumor suppressor gene. Collectively, our investigations identify p300 as an internal bridging factor within cells to sense external environmental arsenite exposure to alter chromatin, thereby changing gene transcription for disease pathogenesis.
Mercury-methylating bacteria are associated with zooplankton: a proof-of-principle survey in the Baltic Sea
Authors: Gorokhova Elena , Soerensen Anne L. , Motwani Nisha H.
Published: March 2018

Methylmercury (MeHg) is a potent neurotoxin that biomagnifies in marine food-webs. Inorganic mercury (Hg) methylation is generally considered to be conducted by bacteria associated with sediment or detritus, but endogenous methylation by the gut microbiome of animals in the lower food webs is another possible source. We examined the occurrence of the bacterial gene (hgcA), required for Hg methylation, in the guts of dominant Baltic zooplankters. A qPCR assay targeting thehgcAsequence in three main clades (Deltaproteobacteria, FirmicutesandArchaea) was used in the field-collected specimens of copepods (Acartia bifilosa, Eurytemora affinis, Pseudocalanus acuspesandLimnocalanus macrurus) and cladocerans (Bosmina coregoni maritimaandCercopagis pengoi). All copepods were found to carryhgcAgenes in their gut microbiome, whereas no positive amplification was recorded in the cladocerans. In the copepods,hgcAgenes belonging to onlyDeltaproteobacteriaandFirmicuteswere detected. These findings suggest that endogenous Hg methylation can occur in zooplankton and may contribute to seasonal, spatial and vertical MeHg variability in water column and food webs. Additional molecular and metagenomics studies are needed to identify bacteria carryinghgcAgenes and improve their quantification in microbiota.
Breast cancer susceptibility: an integrative analysis of genomic data
Authors: Mocellin Simone , Valpione Sara , Rossi Carlo Riccardo , Pooley Karen
Published: March 2018

Background

Genome wide association studies (GWAS) are greatly accelerating the pace of discovery of germline variants underlying the genetic architecture of sporadic breast cancer predisposition. We have built the first knowledge-base dedicated to this field and used it to generate hypotheses on the molecular pathways involved in disease susceptibility.

Methods

We gathered data on the common single nucleotide polymorphisms (SNPs) discovered by breast cancer risk GWAS. Information on SNP functional effect (including data on linkage disequilibrium, expression quantitative trait locus, and SNP relationship with regulatory motifs or promoter/enhancer histone marks) was utilized to select putative breast cancer predisposition genes (BCPGs). Ultimately, BCPGs were subject to pathway (gene set enrichment) analysis and network (protein-protein interaction) analysis.

Results

Data from 38 studies (28 original case-control GWAS enrolling 383,260 patients with breast cancer; and 10 GWAS meta-analyses) were retrieved. Overall, 281 SNPs were associated with the risk of breast cancer with a P-value <10E-06 and a minor allele frequency >1%. Based on functional information, we identified 296 putative BCPGs. Primary analysis showed that germline perturbation of classical cancer-related pathways (e.g., apoptosis, cell cycle, signal transduction including estrogen receptor signaling) play a significant role in breast carcinogenesis. Other less established pathways (such as ribosome and peroxisome machineries) were also highlighted. In the main subgroup analysis, we considered the BCPGs encoding transcription factors (n=36), which in turn target 252 genes. Interestingly, pathway and network analysis of these genes yielded results resembling those of primary analyses, suggesting that most of the effect of genetic variation on disease risk hinges upon transcriptional regulons.

Conclusions

This knowledge-base, which is freely available and will be annually updated, can inform future studies dedicated to breast cancer molecular epidemiology as well as genetic susceptibility and development.

Abbreviations

GWAS

genome-wide association study

SNP

single nucleotide polymorphism

BCPG

breast cancer predisposition gene

LD

linkage disequilibrium
De novoassembly, characterization, functional annotation and expression patterns of the black tiger shrimp (Penaeus monodon) transcriptome
Authors: Huerlimann Roger , Wade Nicholas M , Gordon Lavinia , Montenegro Juan D , Goodall Jake , McWilliam Sean , Tinning Matthew , Siemering Kirby , Giardina Erika , Donovan Dallas , Sellars Melony J , Cowley Jeff A , Condon Kelly , Coman Greg J , Khatkar Mehar S , Raadsma Herman W , Maes Gregory , Zenger Kyall R , Jerry Dean R
Published: March 2018

The black tiger shrimp (Penaeus monodon) remains the second most widely cultured shrimp species globally. However, issues with disease and domestication have seen production levels stagnate over the past two decades. To help identify innovative solutions needed to resolve bottlenecks hampering the culture of this species, it is important to generate genetic and genomic resources. Towards this aim, we have produced the most complete publicly availableP. monodontranscriptome database to date. The assembly was carried out in multiple assemblers using 2×125 bp HiSeq data from PolyA selected, ribo-depleted RNA extracted from nine adult tissues and eight early life-history stages. In total, approximately 700 million high-quality sequence reads were obtained and assembled into 236,388 clusters. These were then further segregated into 99,203 adult tissue specific clusters, and 58,678 early life-history stage specific clusters. The final transcriptome had a high TransRate score of 0.37, with 88% of all reads successfully mapping back to the transcriptome. BUSCO statistics showed the assembly to be highly complete with low fragmentation, few genes missing, but higher redundancy or transcript duplication (Complete: 98.2% (Duplicated: 51.3%), Fragmented: 0.8%, Missing: 1.0%), and to greatly exceed the completeness of existingP. monodontranscriptomes. While annotation rates were low (approximately 30%), as is typical for a non-model organisms, annotated transcript clusters were successfully mapped to several hundred functional KEGG pathways. To help address the lack of annotation, transcripts were clustered into groups within tissues and early life-history stages, providing initial evidence for their roles in specific tissue functions, or developmental transitions. Additionally, transcripts of shrimp viruses previously not known to occur in Australia were also discovered. We expect the transcriptome to provide an essential resource to investigate the molecular basis of commercially relevant-significant traits inP. monodonand other shrimp species.
The Dynamics and Energy Landscape of DNA Plectoneme Nucleation
Authors: Walker Philipp U. , Vanderlinden Willem , Lipfert Jan
Published: March 2018

DNA buckling is the fundamental step for plectoneme nucleation and supercoil dynamics that are critical in the processing of genetic information. Here we systematically quantify DNA buckling dynamics using high-speed magnetic tweezers. Buckling times are ∼10-100 ms and depend exponentially on both applied force and twist. By deconvolving measured time traces with the instrument response, we reconstruct full 2D extension-twist energy landscapes of the buckling transition that reveal an asymmetry between the pre- and post-buckling states and suggest a highly bend transition state conformation.
Utp14 interaction with the Small Subunit Processome
Authors: Black Joshua J. , Wang Zhaohui , Goering Lisa M. , Johnson Arlen W.
Published: March 2018

The SSU Processome (sometimes referred to as 90S) is an early stabile intermediate in the small ribosomal subunit biogenesis pathway of eukaryotes. Progression of the SSU Processome to a pre-40S particle requires a large-scale compaction of the RNA and release of many biogenesis factors. The U3 snoRNA is a primary component of the SSU Processome and hybridizes to the rRNA at multiple locations to organize the structure of the SSU Processome. Thus, release of U3 is prerequisite for the transition to pre-40S. Our lab proposed that the RNA helicase Dhr1 plays a crucial role in the transition by unwinding U3 and that this activity is controlled by the SSU Processome protein Utp14. How Utp14 times the activation of Dhr1 is an open question. Despite being highly conserved, Utp14 contains no recognizable domains, and how Utp14 interacts with the SSU Processome is not well characterized. Here, we used UV crosslinking and analysis of cDNA and yeast two-hybrid interaction to characterize how Utp14 interacts with the pre-ribosome. Moreover, proteomic analysis of SSU particles lacking Utp14 revealed that Utp14 is needed for efficient recruitment of the RNA exosome. Our analysis positions Utp14 to be uniquely poised to communicate the status of assembly of the SSU Processome to Dhr1 and possibly the exosome as well.
Wheat shovelomics II: Revealing relationships between root crown traits and crop growth
Authors: Slack Shaunagh , York Larry M. , Roghazai Yadgar , Lynch Jonathan , Bennett Malcolm , Foulkes John
Published: March 2018

Optimization of root system architecture represents an important goal in wheat breeding. Adopting new field methods for root phenotyping is key to delivering this goal. A novel ‘shovelomics’ method was applied for phenotyping root crown traits to characterize the Savannah x Rialto doubled-haploid (DH) population in two field experiments under irrigated and rain-fed conditions. Trait validation was carried out through soil coring on a subset of 14 DH lines and the two parents. We observed that drought reduced grain yield per plant by 21.0%. Under rain-fed conditions, nodal root angle and roots shoot-1 were positively associated with root length density (RLD) at 40-60 cm depth; RLD was also positively correlated with grain yield. Nodal root angle and roots shoot-1 were also positively associated with canopy stay green and grain yield under rain-fed conditions. We conclude that shovelomics is a valuable technique for quantifying genetic variation in nodal root traits in wheat, revealing nodal root angle and root number per shoot provide useful selection criteria in breeding programs aimed at improving drought tolerance in wheat.

Highlight

Nodal root angle and number shoot-1 measured using ‘shovelomics’ were positively associated with root density at depth and yield under drought in a Savanah x Rialto wheat DH population.
Coordinated cerebellar climbing fiber activity signals learned sensorimotor predictions
Authors: Heffley William , Song Eun Young , Xu Ziye , Taylor Benjamin N. , Hughes Mary Anne , McKinney Andrew , Joshua Mati , Hull Court
Published: March 2018

The prevailing model of cerebellar learning states that climbing fibers (CFs) are both driven by, and serve to correct, erroneous motor output. However, this model is grounded largely in studies of behaviors that utilize hardwired neural pathways to link sensory input to motor output. To test whether this model applies to more flexible learning regimes that require arbitrary sensorimotor associations, we have developed a cerebellar-dependent motor learning paradigm compatible with both mesoscale and single dendrite resolution calcium imaging in mice. Here, we find that CFs are preferentially driven by and more time-locked to correctly executed movements and other task parameters that predict reward outcome, exhibiting widespread correlated activity within parasagittal processing zones that is governed by these predictions. Together, such CF activity patterns are well-suited to drive learning by providing predictive instructional input consistent with an unsigned reinforcement learning signal that does not rely exclusively on motor errors.
MoonFit, a minimal interface for fitting ODE dynamical models, bridging simulation by experimentalists and customization by C++ programmers
Authors: Robert Philippe A. , Jönsson Henrik , Meyer-Hermann Michael
Published: March 2018

The modelling of biological systems often consists into differential equation models that need to be fitted to experimental data. During this complex process, the practical experience of the biologist and the theoretical abstraction of the modeller require back-and-forth refinements of the model, design of new experiments and inclusion of more data-points into the fitting procedure. Available optimization interfaces rarely simultaneously allow customizations by the programmer and the capacity for the biologist to perform simulations or optimizations with a simple interface.

Here, we provide the C++ code of a graphical user interface based on a user defined minimal C++ ODE model class. The graphical interface allows to perform simulations and optimizations without any knowledge in programming. The code was designed minimal and modular to be easily modified, with maximal freedom to link customized optimization libraries, solver or hand-made scripts. Moonfit is powerful enough to fit and compare models with high dimensionality, multiple datasets, to automatize optimizations, and to perform iterative fittings using data interpolation. We believe this will ease the interaction between modellers and experimental partners.

Availability:Moonfit is freely available via c++ source code and accompanying scripts from gitlab.com/Moonfit/MoonLight.
A novel role for the HLH protein Inhibitor of Differentiation 4 (ID4) in the DNA damage response in basal-like breast cancer
Authors: Baker Laura A. , Krisp Christoph , Roden Daniel , Holliday Holly , Wu Sunny Z. , Junankar Simon , Serandour Aurelien A. , Mohammed Hisham , Nair Radhika , Chan Chia-Ling , Yang Jessica , Foreman Nicola , Fitzpatrick Breanna , Sankaranarayanan Geetha , Law Andrew M.K. , Ormandy Chris , Naylor Matthew J. , McFarland Andrea , Simpson Peter T. , Lakhani Sunil , O’Toole Sandra , Selinger Christina , Anderson Lyndal , Samimi Goli , Hacker Neville F. , Kaplan Warren , Carroll Jason S. , Molloy Mark , Swarbrick Alexander
Published: March 2018

Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies. Inhibitor of Differentiation 4 (ID4) is a helix-loop-helix transcriptional regulator required for mammary gland development. ID4 is overexpressed in a subset of BLBC patients, associating with a stem-like poor prognosis phenotype, and is necessary for the growth of cell line models of BLBC, through unknown mechanisms. Here, we have defined a molecular mechanism of action for ID4 in BLBC and the related disease highgrade serous ovarian cancer (HGSOV), by combining RIME proteomic analysis and ChIP-Seq mapping of genomic binding sites. Remarkably, these studies have revealed novel interactions with DNA damage response proteins, in particular, mediator of DNA damage checkpoint protein 1 (MDC1). Through MDC1, ID4 interacts with other DNA repair proteins (γH2AX and BRCA1) at fragile chromatin sites. ID4 does not affect transcription at these sites, instead binding to chromatin following DNA damage and regulating DNA damage signalling. Clinical analysis demonstrates that ID4 is amplified and overexpressed at a higher frequency inBRCA1-mutant BLBC compared with sporadic BLBC, providing genetic evidence for an interaction between ID4 and DNA damage repair pathways. These data link the interactions of ID4 with MDC1 to DNA damage repair in the aetiology of BLBC and HGSOV.
Internal gain modulations, but not changes in stimulus contrast, preserve the neural code
Authors: Lee Sangkyun , Park Jiyoung , Smirnakis Stelios M.
Published: March 2018

Neurons in primary visual cortex (V1) are strongly modulated both by stimulus contrast and by fluctuations of internal inputs. An important question is whether population codes are preserved under these conditions. Changes in stimulus contrast are thought to leave population codes invariant, whereas the effect of internal gain modulations remains unknown. To address these questions we studied how the direction-of-motion of oriented gratings is encoded in layer 2/3 of mouse V1. Surprisingly, we found that, because contrast gain responses across cells are heterogeneous, a change in contrast alters the information distribution profile across cells leading to the failure of contrast invariance. Remarkably, internal input fluctuations that cause commensurate firing rate modulations at the single-cell level, do respect population code invariance. These observations have important implications for visual information encoding, and argue that the brain strives to maintain the stability of the neural code in the face of fluctuating internal inputs.
Generation of iPSC-Derived Human Peripheral Sensory Neurons Releasing Substance P Elicited by TRPV1 Agonists
Authors: P. Guimarães Marília Zaluar , Vecchi Rodrigo De , Vitória Gabriela , Sochacki Jaroslaw K. , Paulsen Bruna S. , Lima Igor , da Silva Felipe Rodrigues , da Costa Rodrigo F. Madeiro , Breton Lionel , Rehen Stevens K.
Published: March 2018

Neural crest stem cells (NCPCs) have been shown to differentiate into various cell types and tissues during embryonic development, including sensory neurons. The few studies addressing the generation of NCPCs and peripheral sensory neurons (PSNs) from human induced Pluripotent Stem Cells (hiPSCs), generated sensory cells without displaying robust activity. Here, we describe an efficient strategy for hiPSCs differentiation into NCPCs and functional PSNs using chemically defined media and factors to achieve efficient differentiation, confirmed by the expression of specific markers. After 10 days hiPSCs differentiated into NCPCs, cells were then maintained in neural induction medium containing defined growth factors for PSNs differentiation, followed by 10 days in neonatal human epidermal keratinocytes-(HEKn-) conditioned medium. We observed a further increase in PSN markers expression and neurites length after conditioned medium treatment. The resulting neurons released substance P (SP) in response to nociceptive agents such as anandamide and resiniferatoxin. Anandamide induced substance P release via activation of TRPV1 and not CB1. Transcriptomic analysis of the PSNs revealed the main dorsal root ganglia (DRG) neuronal markers and a transcriptional profile compatible with C-LTMR. TRPV1 was detected by immunofluorescence and RNA-Seq in multiple experiments. In conclusion, the developed strategy generated PSNs useful for drug screening that could be applied to patient-derived hiPSCs, consisting in a powerful tool to model human diseases in vitro.