bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and Efficacy of Low‐dose Domperidone for Treating Nausea and Vomiting Due to Acute Gastroenteritis in Children
Authors: Leitz Gerhard , Hu Peter , Appiani Carlos , Li Qing , Mitha Essack , Garces‐Sanchez Maria , Gupta Rajeev
Published: June 2019

Background:

This study was conducted based on a request from the European Medicines Agency to generate robust data on domperidone efficacy in children in the relief of symptoms of nausea and vomiting by assessing the effect of a low‐dose and short treatment duration.

Methods:

In this randomized, double‐blind, phase 3 study, children ages 6 months to 12 years with acute gastroenteritis randomly (1:1) received oral domperidone 0.25 mg/kg with oral rehydration therapy (ORT) or matching placebo thrice daily for 2 to 7 days. The proportion of patients with no vomiting episodes (primary endpoint) and patients ages ≥4 years with no nausea episodes (key secondary endpoint) within 48 hours of first treatment administration were evaluated.

Results:

The study was terminated early following futility analysis. At early termination, 292 patients randomly received domperidone (n = 147) or placebo (n = 145). The proportion of patients with no vomiting episodes within 48‐hours of first treatment administration was similar between domperidone (32.0%) and placebo groups (33.8%). Similarly, there was no significant difference in proportion of patients ages ≥4 years with no nausea episodes within 48 hours of first treatment administration between domperidone (35.7%) and placebo (38.6%). Total 13 patients (domperidone, 3.4% [5/147] vs placebo, 5.5% [8/145]) reported ≥1 treatment‐emergent adverse events. No deaths or adverse events of special interest (extrapyramidal symptoms and QT prolongation) were reported.

Conclusions:

Low‐dose of domperidone with ORT did not significantly differ from placebo in reducing vomiting and nausea episodes in pediatric patients with acute gastroenteritis (AG), and the safety profile was similar between both groups.
New Algorithm for the Integration of Ultrasound Into Cystic Fibrosis Liver Disease Screening
Authors: Sellers Zachary M. , Lee Lori W. , Barth Richard A. , Milla Carlos
Published: June 2019

Objectives:

Liver nodularity occurs across the spectrum of cystic fibrosis liver disease (CFLD), from regenerative nodules to cirrhosis, and can occur without liver enzyme abnormalities. Our aims were to determine if incorporating abdominal ultrasound (US) with annual laboratory testing improves the detection of CFLD and establish CF‐specific thresholds for liver screening labs.

Methods:

CF patients at least 6 years old who were exocrine pancreatic‐insufficient had an US with Doppler and shear wave elastography. Patients were divided into Normal, Echogenic, or Nodular groups, based on US findings. Results were compared with aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelets, AST to platelet ratio index (APRI), Fibrosis 4 (FIB‐4), and gamma‐glutamyl transferase (GGT) to platelet ratio (GPR). Receiver operator curve, sensitivity, specificity, positive predictive value, negative predictive value, and optimal cut‐off with Youden Index were calculated.

Results:

From 82 patients, incorporation of US identified more nodular livers than using labs alone. The Nodular group had significantly greater median AST (44), ALT (48), GGT (46), APRI (0.619), FIB‐4 (0.286), GPR (1.431). Optimal cut‐offs to detect liver nodularity in CF were AST >33, ALT >45, GGT >21, Platelets <230, APRI >0.367, FIB‐4 >0.222, GPR >0.682. Using GGT, APRI, and GPR, we generated an algorithm to direct the use of US in CFLD screening.

Conclusions:

Using modified serum lab thresholds, addition of liver fibrosis indices, and/or abdominal US can increase detection of liver nodularity in CF. A combination of GGT, GPR, and APRI can help direct which CF children should undergo US evaluation. These tools may improve earlier identification of fibrosis and/or cirrhosis in CF patients.
Abundant Expression of Lysyl Oxidase‐like 2 Protein in Intrahepatic Bile Ducts of Infants With Biliary Atresia
Authors: Honigbaum Stefany , Zhu Qingfeng , Layman Andrew , Anders Robert A. , Schwarz Kathleen B.
Published: June 2019

Introduction: :

Biliary atresia (BA) is characterized by rapidly progressive inflammation and fibrosis of the biliary tract, which usually progresses despite surgical intervention (Kasai hepatoportoenterostomy). Lysyl oxidase‐like (LOXL2) is an extracellular matrix enzyme that catalyzes the cross‐linking of fibrillar collagen and elastin and is thought to play a crucial role in tissue fibrosis; anti‐LOXL2 drugs have been shown to be antifibrotic in animals.

Objective:

The aim of the study was to investigate the presence of LOXL2 in BA livers and hepatic and extrahepatic control tissues.

Methods:

Liver wedge biopsies from infants with BA (n = 20) were obtained at Kasai, and were compared with non‐BA livers (n = 20). Liver fibrosis was scored using the Ishak scale, and immunohistochemistry was performed using a commercially available polyclonal anti‐LOXL2 antibody. The expression of LOXL2 was scored for intensity and for distribution of bile duct staining by a pathologist blinded to the diagnosis. Staining of LOXL2 in pediatric control tissue, muscle (n = 5), heart (n = 5), and bone (n = 10) was performed.

Results:

Tissue from patients with BA abundantly expressed LOXL2 (intensity score 2.0 vs 1.4 [P ⩽ 0.001]) for non‐BA and distribution of bile duct‐staining score of 3.0 versus 2.8 (P = 0.001) for non‐BA. Fibrosis score of all BA samples was 4.2 versus 3.1 for non‐BA. Nonhepatic pediatric tissue displayed minimal to no LOXL2 staining.

Conclusions:

There is significant overexpression of LOXL2 in BA hepatic tissue with minimal expression in extrahepatic tissue. The over expression noted in human hepatic tissue at Kasai suggests the rationale for further investigation of anti‐LOXL2 therapeutics in BA.
Using Patient-Reported Outcomes to Measure Symptoms in Children With Advanced Cancer
Authors: Montgomery Kathleen E. , Raybin Jennifer L. , Ward Jessica , Balian Chelsea , Gilger Elizabeth , Murray Paula , Li Zhanhai
Published: June 2019

Background

Children with advanced cancer experience symptoms despite access to quality care. Symptom research has previously relied upon retrospective designs and parent proxy rather than prospective measurement with self-report.

Objective

This study evaluated the feasibility of electronic data collection in children with advanced cancer using self-report of symptom frequency, severity, and distress.

Methods

A multisite prospective cohort design was used for this study. Children who were 7 to 18 years of age and English-speaking and had a diagnosis of advanced cancer were included. Symptom frequency, severity, and level of distress were measured every 2 weeks.

Results

Forty-six children completed 563 of 622 (91%) administered electronic symptom assessments. Pain, fatigue, nausea, and sleeping difficulties were the most reported symptoms across all assessments and during the last 12 weeks of life. Symptoms with the highest composite scores included pain, fatigue, nausea, and sleeping difficulties. During the last 12 weeks of life, pain, fatigue, diarrhea, and sleeping difficulties had the highest composite scores. When the domains of frequency, severity, and distress were compared between groups, children reported significantly higher frequency of pain and eating difficulty during the last 12 weeks of life.

Conclusions

Electronic data collection is a feasible way to evaluate the constellation of symptoms. Children with advanced cancer continue to experience physical and psychological symptoms, especially during the last 12 weeks of life despite quality care.

Implications for Practice

Assessment of symptom domains, including frequency, severity, and distress when symptoms are present may allow clinicians to better understand and manage symptoms of most concern to the patient.
Development and Validation of the Just Culture Assessment Tool for Nursing Education
Authors: Walker Danielle , Altmiller Gerry , Barkell Nina , Hromadik Lora , Toothaker Rebecca
Published: June 2019

Background

Patient safety efforts in practice have focused on creating a just culture where errors can be identified and reported, and system remedies created to prevent reoccurrence. The same is not true of nursing education where student experiences with error and the sequelae that follow focus on individual performance.

Purpose

The purpose of this study was to adapt the Just Culture Assessment Tool (JCAT) used in practice settings into a valid and reliable instrument to evaluate just culture in academic settings.

Methods

A 27-item instrument was adapted for academia. Content validity was established. Reliability was determined in a pilot study with 133 prelicensure nursing students.

Results

The scale content validity index (CVI) was calculated at 1. The reliability of the instrument is strong (α = .75).

Conclusions

The CVI and pilot study findings support the use of the JCAT for Nursing Education as a valid and reliable instrument to evaluate student perception of just culture in academia.
Experience of Perinatal Death From the Father’s Perspective
Authors: Lizcano Pabón Lucero del Mar , Moreno Fergusson María Elisa , Palacios Ana Maria
Published: June 2019

Background

Although perinatal deaths are still a common pregnancy outcome in developing countries, little is known about the effect perinatal death has on fathers.

Objective

The aim of the study was to understand and describe the meaning of perinatal death in a sample of fathers from northeastern Colombia.

Methods

Using purposive and snowball sampling approaches, we identified 15 participants from northeastern Colombia who agreed to participate. We used a descriptive phenomenological design. Data were collected through in-depth, semistructured interviews.

Results

Men suffer in solitude and hide their emotions as they feel the need to be the main supporters of their partners. Three major themes emerged: experience of loss, coming to terms with an irreparable loss, and overcoming the loss.

Discussion

While women are receiving care, health staff may neglect or forget men. Men suffer alone while seeking ways of attunement with their partners’ emotions to support them during the grieving process. Fathers can overcome and adjust to the loss when they transcend it and find new meaning. Men felt neglected and marginalized at hospitals while their partners were receiving treatment. Health professionals should recognize and acknowledge the pain of fathers who face perinatal death and include them as much as possible in the standard of care. The results identify opportunities for healthcare providers in clinical and outpatient settings to acknowledge the importance of men within the context of pregnancy and to learn about their pain and suffering when they face a perinatal death.
Immunophenotype of Atypical Polypoid Adenomyoma of the Uterus: Diagnostic Value and Insight on Pathogenesis
Authors: Travaglino Antonio , Raffone Antonio , Saccone Gabriele , Fuggi Mariano , De Placido Giuseppe , Mascolo Massimo , Mollo Antonio , Insabato Luigi , Zullo Fulvio
Published: June 2019

Atypical polypoid adenomyoma (APA) is a rare uterine lesion constituted by atypical endometrioid glands, squamous morules, and myofibromatous stroma. We aimed to assess the immunophenotype of the 3 components of APA, with regard to its pathogenesis and its differential diagnosis. A systematic review was performed by searching electronic databases from their inception to January 2019 for immunohistochemical studies of APA. Thirteen studies with 145 APA cases were included. APA glands appeared analogous to atypical endometrial hyperplasia (endometrioid cytokeratins pattern, Ki67≤50%, common PTEN loss, and occasional mismatch repair deficiency); the prominent expression of hormone receptors and nuclear β-catenin suggest that APA may be a precursor of “copy number-low,” CTNNB1-mutant endometrial cancers. Morules appeared as a peculiar type of hyperdifferentiation (low KI67, nuclear β-catenin+, CD10+, CDX2+, SATB2+, p63−, and p40−), analogous to morular metaplasia in other lesions and distinguishable immunohistochemically from both conventional squamous metaplasia and solid cancer growth. Stroma immunphenotype (low Ki67, α-smooth-muscle-actin+, h-caldesmon−, CD10−, or weak and patchy) suggested a derivation from a metaplasia of normal endometrial stroma. It was similar to that of nonatypical adenomyoma, and different from adenosarcoma (Ki67 increase and CD10+ in periglandular stroma) and myoinvasive endometrioid carcinoma (h-caldesmon+ in myometrium and periglandular fringe-like CD10 pattern).
BRAF Wild-type, PTEN Mutant Malignant Uveal Melanoma Arising Within a Mature Ovarian Teratoma: A Case Report and Review of the Literature
Authors: Lengyel Krisztina , Young Fergus , Kucukmetin Ali , Cresti Nicola , Plummer Ruth , Ralte Angela , O’Donnell Rachel Louise
Published: June 2019

Mature cystic teratomas are common in women of all ages; however, malignant transformation within them is rare and difficult to diagnosis preoperatively. Primary melanoma of the ovary is exceptionally rare and only occurs in relation to a teratoma where it can originate from sporadic somatic mutagenesis within epidermal junctional melanocytes, through malignant transformation of a benign nevus formed within the mature cystic teratoma or from other well differentiated pigment-containing structures such as the uvea. We present a case of primary malignant melanoma arising within a mature cystic teratoma in a young patient, who ultimately developed widespread metastasis necessitating systemic therapy. Our case highlights the role of molecular medicine not only in forming an understanding the origin of the melanoma, but also guiding targeted systemic therapies. Alongside the case we present a review of the literature describing the incidence of molecular aberrations within melanoma as well as the established and emerging techniques and cytotoxic agents for malignant melanoma.
Correlation Between p16/Ki-67 Expression and the Grade of Cervical Intraepithelial Neoplasias
Authors: Mandal Rananjit , Ghosh Ishita , Banerjee Dipanwita , Mittal Srabani , Muwonge Richard , Roy Chinmayi , Panda Chinmay , Vernekar Manisha , Frappart Lucien , Basu Partha
Published: June 2019

Interpretation of histopathology of cervical premalignant lesions suffers from marked interobserver variability due to its subjective nature. We aimed to evaluate the usefulness of the biomarkers p16 and Ki-67 in improving the diagnostic accuracy of cervical histopathology and assess the correlation between p16 expression and human papillomavirus test in different grades of cervical intraepithelial neoplasia (CIN). Cervical tissue specimens with a diagnosis of CIN 1 or worse (CIN 1+) on hematoxylin and eosin staining were selected for immunohistochemistry (IHC) staining for p16 and Ki-67. The IHC slides were examined by a gynecologic pathologist along with a review of hematoxylin and eosin slides. The review histopathology diagnosis was used to correlate with the IHC results. We observed that the proportion of women with overexpression of p16 increased with increasing histologic severity: 0% in women with normal histology; 33.3% in women with CIN 1; 58.1% in women with CIN 2; and 73.8% in women with CIN 3. Among the human papillomavirus–positive women, 76.3% (58/76) women with CIN 2/CIN 3 expressed p16, and only 8.9% (4/45) women with normal histopathology or CIN 1 expressed the same. A combination of p16 positivity and abnormal expression of Ki-67 beyond the lower third of the epithelium was observed in 0% of normal/CIN 1 and 60.5% (40/66) of CIN 3 detected on routine histopathology. We concluded that dual staining could be used as an adjunctive test to improve the diagnostic accuracy of histopathology. In addition, p16/Ki-67 IHC has a role in guiding management decisions in cases with discordant colposcopy and histopathology diagnoses.
Living Donor Nephrectomy: Is It as Safe as It Can Be? Analysis of Living Donor Deaths in the United States
Authors: Keith Douglas Scott , Brown Joe , Andreoni Kenneth
Published: June 2019

Introduction

The reported 90-day rate of death from living donor nephrectomy is 3 in 10,000 donations. Although this risk is low, the important question is how many deaths are preventable?

Methods

To study this question, all living donor nephrectomy cases, 139,186 procedures, recorded in the Scientific Registry of Transplant Recipients database since its inception in 1987 were analyzed to determine the death rate and the number of deaths that were potentially preventable. Preventable deaths were defined as any death in the first 7 days except due to clearly unrelated events or death from hemorrhage, pulmonary embolism, infection, cardiovascular cause, or suicide in the first 90 days.

Results

The numbers of deaths at 7, 30, 90, and 365 days after donation were 16, 26, 38, and 86, which translated into 1.15, 1.87, 2.73, and 6.18 deaths per 10,000 donations, respectively. From 2000 onward, when coding was available for cause of death, 19 of the 30 deaths were deemed potentially preventable. The nonrisk-adjusted rate of death with laparoscopic donation was higher than open nephrectomy, but this difference did not reach statistical significance. Conversion from laparoscopic to open nephrectomy occurs in approximately 1 in 100 surgeries, and this rate has remained fairly steady since 2005.

Conclusions

This analysis suggests that up to two thirds of deaths are potentially preventable. The transplant community should consider additional safety strategies such as simulation training of rare complications to lower donor risk.
The Impact of the Built Environment on Patient Falls in Hospital Rooms: An Integrative Review
Authors: Pati Debajyoti , Valipoor Shabboo , Lorusso Lesa , Mihandoust Sahar , Jamshidi Saman , Rane Apoorva , Kazem-Zadeh Mahshad
Published: June 2019

Objectives

The aims of this study were to identify and evaluate scientific evidence examining the impact of the built environment on patient falls in hospital rooms.

Methods

An integrative review (IR) with a systematic literature search was performed using the patient, intervention, comparison, outcome framework. We searched CINAHL, PsychINFO, PubMED, and Web of Science databases. The search included peer-reviewed studies from 1990 to 2017 written in English. An additional hand search was also conducted. Selected articles were reviewed and rated based on a hierarchical categorization, comprising six evidence levels, developed by the American Association of Critical-Care Nurses and adapted for evidence-based design systematic literature reviews.

Results

After a multitiered process, 30 articles met the selection criteria. Thematic areas were created based on the examined elements of the physical environment including patient room configuration and available space, bathroom configuration, bathtub and shower, door, bed height and bed rail, flooring, floor mats, patient chair, lighting, toilet, handrail, grab bars, intravenous pole, sink, ceiling lift, and wheelchair and walking aids. Findings of studies on each element are discussed in detail.

Conclusions

Some environmental elements have not been examined in past relational or causal studies, and the level of evidence for the examined attributes is not high enough to gain robust confidence in healthcare design decision-making. Because of the low level of evidence for several environmental elements, conclusions must be taken with caution. More studies using quantitative, relational, or causal designs are recommended to develop actionable interventions on patient falls in hospital rooms.
Role of Postoperative Anticoagulation in Predicting Digit Replantation and Revascularization Failure
Authors: Retrouvey Helene , Solaja Ogi , Baltzer Heather L.
Published: June 2019

Purpose

The use of intravenous heparin after digit replantation or revascularization (DRR) varies greatly. The insufficient evidence presents a lack of clinical equipoise needed for a randomized trial; as such, a matched propensity score analysis was performed to evaluate the role of postoperative anticoagulation after DRR. The purpose of this study was to determine if the use of postoperative therapeutic anticoagulation reduced the risk of digit failure.

Methods

A retrospective cohort of patients who underwent DRR from 2005 to 2016 was identified. A propensity score was calculated based on age, smoking, injury mechanism, procedure type, vein graft, and number of digits injured. Patients were matched 1:2 by propensity score to create 2 groups with similar risks of receiving anticoagulation postoperatively. Generalized estimating equation logistic model was used to determine differences in digit failure between groups.

Results

Digit replantation or revascularization was performed on 282 patients (92% male; median age, 43 years). Postoperative anticoagulation was administered in 69 (24%) patients, with continuous IV heparin in 34 patients and intravenous heparin with dextran in 35 patients. Digit failure occurred in 88 patients overall, representing 38% of patients receiving anticoagulation and 29% of those not. Major complications were higher among the anticoagulated patients (13% vs 3.3%). After propensity score matching, use of anticoagulation was not associated with digit failure (odds ratio, 0.79; 95% confidence interval, 0.47–1.32).

Conclusions

Among DRR patients with similar predisposing characteristics for postoperative therapeutic heparin or dextran, the use of therapeutic anticoagulation does not have a protective effect against digit failure. Studies are needed to define the role of postoperative IV anticoagulation in DRR and to justify the risk of its administration.
Anatomical and Clinical Comparison of Small Free Flaps for Repairing Finger Skin Defects
Authors: He Bo , Liu Jianghui , Pang Vincent , Zhu Lei , Huang Yongjun , Wang Zengtao , Xu Yangbin , Zhu Zhaowei , Wang Kun
Published: June 2019

The reconstruction of finger defects requires improved functional outcomes and acceptable esthetic outcomes, and small free flaps present a good alternative technique for repairing finger skin defects. From January 2006 to December 2018, we investigated the number and diameter of proximal digital artery perforators, medial plantar artery perforators, and peroneal proper plantar digital arteries of the hallux by dissection and then transplanted free digital arterial perforator flaps, free medial plantar flaps, and free peroneal flaps from the hallux to repair small finger skin defects. The number (SD) of perforators from the medial plantar artery was approximately 2.2 (0.5), and these perforators measured 0.53 (0.20) mm in diameter. The diameter (SD) of the first metatarsal dorsal artery was approximately 1.16 (0.30) mm. A total of 25 patients were included in this study. The transplantation times (SD) for free digital arterial perforator flaps, free medial plantar flaps, and free peroneal flaps from the hallux were 3.5 (0.5) hours, 3.2 (0.7) hours, and 2.0 (0.4) hours, respectively. The follow-up period ranged from 8 to 15 months. All flaps survived and were appropriately shaped. The donor site was either covered with a free flap or directly sutured. Among these 3 types of small flaps, the free peroneal flap from the hallux can be recommended for clinical use because of the large diameter of the contributing vessels, the short operative time, the ease of access, and the improved appearance of the donor site.
TEO-Transanal Intersphincteric Intramesorectal and Laparoscopic Approach in Proctosigmoidectomy for Benign Disease
Authors: Serra-Aracil Xavier , Pascua-Solé Mireia , Serra-Pla Sheila , Mora-López Laura , Pallisera-Lloveras Anna , Calvet Xavier , Navarro-Soto Salvador
Published: June 2019

Purpose:

Completion proctectomy is the traditional approach in the rectal stump remaining after subtotal colectomy for benign disease. It is associated with high morbidity and urinary and sexual dysfunction. To reduce this risk, a minimally invasive approach is presented, intersphincteric intramesorectal proctosigmoidectomy by transanal endoscopic operation and laparoscopy.

Patients and Methods:

Patients who had undergone total or subtotal colectomy for benign disease, those with a rectosigmoid stump who had rejected intestinal reconstruction and with refractory symptoms or risk of degeneration were selected. The technique proposed and the morbidity outcomes are described.

Results:

Three patients underwent this minimally invasive approach, operative time was 130 to 150 minutes. The median postoperative hospital stay was 6.6 days. Genitourinary and sexual tests performed in the male patient showed no dysfunction.

Conclusions:

This minimally invasive technique, with intersphincteric resection and dissection close to the rectal wall, theoretically reduces morbidity and the damage to the autonomic pelvic nerves.
A novel mode of communication between blood and the germline for the inheritance of paternal experiences
Authors: van Steenwyk Gretchen , Gapp Katharina , Jawaid Ali , Germain Pierre-Luc , Manuella Francesca , Tanwar Deepak K. , Zamboni Nicola , Gaur Niharika , Efimova Anastasiia , Thumfart Kristina , Miska Eric A. , Mansuy Isabelle M.
Published: June 2019

In many species, environmental stimuli can affect the germline and contribute to phenotypic changes in the offspring, without altering the genetic code1–5. So far, little is known about which biological signals can link exposure to germ cells. Using a mouse model of postnatal trauma with transgenerational effects, we show that exposure alters lipid-based metabolites in blood of males and their non-exposed offspring. Comparable alterations are validated in serum and saliva of orphan children exposed to trauma. Peroxisome proliferator-activated receptor (PPAR) is identified as mediating the effects of metabolites alterations. Mimicking PPAR activation with a dual PPARα/γ agonist in vivo induces changes in the sperm transcriptome similarly to trauma, and reproduces metabolic phenotypes in the offspring. Injecting serum collected from adult males exposed to postnatal trauma into controls recapitulates metabolic phenotypes in the offspring. These results suggest conserved effects of early life adversity on blood metabolites, and causally involve paternal blood factors and PPAR nuclear receptor in phenotype heritability.
Staufen blocks autophagy in neurodegeneration
Authors: Paul Sharan , Dansithong Warunee , Gandelman Mandi , Figueroa Karla P. , Zu Tao , Ranum Laura P.W. , Scoles Daniel R. , Pulst Stefan M.
Published: June 2019

Objective

The mechanistic target of rapamycin (mTOR) kinase is one of the master coordinators of cellular stress responses, regulating metabolism, autophagy, and apoptosis. We recently reported that Staufen1 (STAU1), a stress granule (SG) protein, was overabundant in fibroblast cell lines from patients with spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis, frontotemporal degeneration, Huntington’s, Alzheimer’s, and Parkinson’s diseases as well as animal models, and patient tissues. STAU1 overabundance is associated with mTOR hyperactivation and links SG formation with autophagy. Our objective was to determine the mechanism of mTOR regulation by STAU1.

Methods

We determined STAU1 abundance with disease- and chemical-induced cellular stressors in patient cells and animal models. We also used RNA binding assays to contextualize STAU1 interaction with MTOR mRNA.

Results

STAU1 and mTOR were overabundant in BAC-C9orf72, ATXN2Q127, and Thy1-TDP-43 transgenic mouse models. Reducing STAU1 levels in these mice normalized mTOR levels and activity and autophagy-related marker proteins. We also saw increased STAU1 levels in HEK293 cells transfected to express C9orf72-relevant dipeptide repeats (DPRs). Conversely, DPR accumulations were not observed in cells treated by STAU1 RNAi. Overexpression of STAU1 in HEK293 cells increased mTOR levels through direct MTOR mRNA interaction, activating downstream targets and impairing autophagic flux. Targeting mTOR by rapamycin or RNAi normalized STAU1 abundance in a SCA2 cellular model.

Interpretation

STAU1 interaction with mTOR drives its hyperactivation and inhibits autophagic flux in multiple models of neurodegeneration. Staufen, therefore, constitutes a novel target to modulate mTOR activity, autophagy, and for the treatment of neurodegenerative diseases.
Stochastic Yield Catastrophes and Robustness in Self-Assembly
Authors: Gartner Florian M. , Graf Isabella R. , Wilke Patrick , Geiger Philipp M. , Frey Erwin
Published: June 2019

A guiding principle in self-assembly is that, for high production yield, nucleation of structures must be significantly slower than their growth. However, details of the mechanism that impedes nucleation are broadly considered irrelevant. Here, we analyze self-assembly into finite-sized target structures employing mathematical modeling. We investigate two key scenarios to delay nucleation: (i) by introducing a slow activation step for the assembling constituents and, (ii) by decreasing the dimerization rate. These scenarios have widely different characteristics. While the dimerization scenario exhibits robust behavior, the activation scenario is highly sensitive to demographic fluctuations. These demographic fluctuations ultimately disfavor growth compared to nucleation and can suppress yield completely. The occurrence of this stochastic yield catastrophe does not depend on model details but is generic as soon as number fluctuations between constituents are taken into account. On a broader perspective, our results reveal that stochasticity is an important limiting factor for self-assembly and that the specific implementation of the nucleation process plays a significant role in determining the yield.
Adaptive and maladaptive genetic diversity in small populations; insights from the Brook Charr (Salvelinus fontinalis)case study
Authors: Ferchaud Anne-Laure , Leitwein Maeva , Laporte Martin , Boivin-Delisle Damien , Bougas Bérénice , Hernandez Cécilia , Normandeau Éric , Thibault Isabel , Bernatchez Louis
Published: June 2019

Investigating the relative importance of neutralversusselective processes governing the accumulation of genetic variants is a key goal in evolutionary biology. This is particularly true in the context of small populations, where genetic drift can counteract the effect of selection. In this study, we investigated the accumulation of putatively beneficial and harmful variations using 7,950 high-quality filtered SNPs among 36 lacustrine, seven riverine and seven anadromous Brook Charr (Salvelinus fontinalis) populations (n = 1,193) from Québec, Canada. Using the Provean algorithm, we observed an accumulation of deleterious mutations that tend to be more prevalent in isolated lacustrine and riverine populations than the more connected anadromous populations. In addition, the absence of correlation between the occurrence of putative beneficial nor deleterious mutations and local recombination rate supports the hypothesis that genetic drift might be the main driver of the accumulation of such variants. Despite the effect of pronounced genetic drift and limited gene flow in non-anadromous populations, several loci representing biological functions of potential adaptive significance were associated with environmental variables, and particularly with temperature. We also identified genomic regions associated with anadromy. We also observed an overrepresentation of transposable elements associated with variation in environmental variables, thus supporting the importance of transposable elements in adaptation.
The drug-induced phenotypic landscape of colorectal cancer organoids
Authors: Betge Johannes , Rindtorff Niklas , Sauer Jan , Rauscher Benedikt , Dingert Clara , Gaitantzi Haristi , Herweck Frank , Srour-Mhanna Kauthar , Miersch Thilo , Valentini Erica , Hauber Veronika , Gutting Tobias , Frank Larissa , Belle Sebastian , Gaiser Timo , Buchholz Inga , Jesenofsky Ralf , Härtel Nicolai , Zhan Tianzuo , Fischer Bernd , Breitkopf-Heinlein Katja , Burgermeister Elke , Ebert Matthias P. , Boutros Michael
Published: June 2019

Patient derived organoids resemble the biology of tissues and tumors, enablingex vivomodeling of human diseases from primary patient samples. Organoids can be used as models for drug discovery and are being explored to guide clinical decision making. Patient derived organoids can have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we used high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with more than 500 small molecules. Integration of data using a joint multi-omics modelling framework identified organoid size and cystic vs. solid organoid architecture as axes of morphological variation across organoids. Mechanistically, we found that organoid size was linked to IGF1 receptor signaling, while a cystic organoid architecture was associated with an LGR5+ stemness program. Treatment-induced organoid morphology reflected organoid viability, drug mechanism of action, and was biologically interpretable using joint modelling. Inhibition of MEK led to cystic reorganization of organoids and increased expression of LGR5, while inhibition of mTOR induced IGF1 receptor signaling. In conclusion, we identified shared axes of variation for colorectal cancer organoid morphology, their underlying biological mechanisms, and pharmacological interventions with the ability to move organoids along them. Image-based profiling of patient derived organoids coupled with multi-omics integration facilitates drug discovery by linking drug responses with underlying biological mechanisms.
Seizure pathways change on circadian and slower timescales in individual patients with focal epilepsy
Authors: Schroeder Gabrielle M , Diehl Beate , Chowdhury Fahmida A , Duncan John S , de Tisi Jane , Trevelyan Andrew J , Forsyth Rob , Jackson Andrew , Taylor Peter N , Wang Yujiang
Published: June 2019

Personalised medicine requires that treatments adapt to not only the patient, but changing factors within each individual. Although epilepsy is a dynamic disorder that is characterised by pathological fluctuations in brain state, surprisingly little is known about whether and how seizures vary in the same patient. We quantitatively compared within-patient seizure network dynamics using intracranial recordings of over 500 seizures from 31 patients with focal epilepsy (mean 16.5 seizures/patient). In all patients, we found variability in seizure paths through the space of possible network dynamics, producing either a spectrum or clusters of different dynamics. Seizures with similar pathways tended to occur closer together in time, and a simple model suggested that seizure pathways change on circadian and/or slower timescales in the majority of patients. These temporal relationships occurred independent of whether the patient underwent antiepileptic medication reduction. Our results suggest that various modulatory processes, operating at different timescales, shape within-patient seizure dynamics, leading to variable seizure pathways that may require tailored treatment approaches.
Sensor localization using magnetic dipole-like coils: A method for highly accurate co-registration in on-scalp MEG
Authors: Pfeiffer Christoph , Ruffieux Silvia , Andersen Lau M. , Kalabukhov Alexei , Winkler Dag , Oostenveld Robert , Lundqvist Daniel , Schneiderman Justin F.
Published: June 2019

Source modelling in magnetoencephalography (MEG) requires precise co-registration of the sensor array and the anatomical structure of the measured individual’s head. In conventional MEG, positions and orientations of the sensors relative to each other are fixed and known beforehand, requiring only localization of the head relative to the sensor array. Since the sensors in on-scalp MEG are positioned on the scalp, locations of the individual sensors depend on the subject’s head shape and size. The positions and orientations of on-scalp sensors must therefore be measured at every recording. This can be achieved by inverting conventional head localization, localizing the sensors relative to the head - rather than the other way around.

In this study we present a practical method for localizing sensors using magnetic dipole-like coils attached to the subject’s head. We implement and evaluate the method in a set of on-scalp MEG recordings using a 7-channel on-scalp MEG system based on high critical temperature superconducting quantum interference devices (high-Tc SQUIDs). The method provides accurate estimates of individual sensor positions and orientations with short averaging time (≤ 2 mm and < 3 degrees, respectively, with 1-second averaging), enabling continuous sensor localization. Calibrating and jointly localizing the sensor array can further improve the localization accuracy (< 1 mm and < 2.5 degrees, respectively, with 1-second coil recordings).

We demonstrate source localization of on-scalp recorded somatosensory evoked activity based on co-registration with our method. Equivalent current dipole fits of the evoked responses corresponded well (within 5.3 mm) with those based on a commercial, whole-head MEG system.
Functional and comparative genomic analysis of integrated prophage-like sequences inCandidatus Liberibacter asiaticus
Authors: Dominguez-Mirazo Marian , Jin Rong , Weitz Joshua S.
Published: June 2019

Huanglongbing (HLB; yellow shoot disease) is a severe worldwide infectious disease for citrus family plants. The pathogenCandidatus Liberibacter asiaticus(CLas) is an alphapro-teobacterium of theRhizobiaceaefamily that has been identified as the cause. The virulence of CLas has been attributed, in part, to prophage encoded genes. Prophage and prophage like elements have been identified in 12 of the 15 CLas available genomes, and are classified into three prophage types. Here, we re-examined all 15 CLas genomes using ade novoprediction approach and expanded the number of prophage like elements from 16 to 33. Further, we find that all CLas contain at least one prophage-like sequence. Comparative analysis reveals a prevalent, albeit previously unknown, prophage-like sequence type that is a remnant of an integrated prophage. Notably, this remnant prophage is found in the Ishi-1 CLas strain that had previously been reported as lacking prophages. Our findings provide both a resource and new insights into the evolutionary relationship between phage and CLas pathogenicity.
Effect of accelerated ageing on seed membrane integrity and chemical composition of Tetrapleura tetraptera (schum. & thonn.)
Authors: Sossou H. S. , Asomaning J. M. , Gaveh E. A. , Sodedji A. F. K. , Agoyi E. E. , Sarkodie-Addo J. , Assogbadjo A. E.
Published: June 2019

Seed ageing is one of the major issues in the storage of seeds. Accelerated ageing test has shown great potential for studying the mechanism of ageing and associated deterioration processes of seeds. This study was conducted to evaluate the effects of accelerated ageing process on seed membrane integrity and chemical composition of Tetrapleura tetraptera (schum. & thonn.). Seeds were subjected to traditional accelerated ageing (100% RH at 38 and 41°C for 48, 72 and 96 h) and salt-saturated accelerated ageing (76% RH at 38 and 41°C for 48, 72 and 96 h) tests and the aged seeds were tested for moisture content, leachate conductivity and chemical composition. Results showed that the accelerated ageing process led to an increase in seed moisture content, carbohydrate, fat, ash and crude fibre content and a reduction in crude protein content in the aged seeds. Also, the leachate conductivity test revealed a loss in membrane integrity of T. tetraptera seed indicating that the accelerated ageing process triggered the seed coat dormancy release in T. tetraptera seed and led to the leaching of the mineral constituent of the seed. The accelerated ageing test combined with a storage experiment could therefore be a promising technique for estimating the storage potential of T tetraptera seed but further investigations including the enzyme activity, are required to standardize the appropriate testing conditions for the species.
Elucidating the molecular determinants of Aβ aggregation with deep mutational scanning
Authors: Gray Vanessa E. , Sitko Katherine , Kameni Floriane Z. Ngako , Williamson Miriam , Stephany Jason J. , Hasle Nicholas , Fowler Douglas M.
Published: June 2019

Despite the importance of Aβ aggregation in Alzheimer’s disease etiology, our understanding of the sequence determinants of aggregation is sparse and largely derived from in vitro studies. For example, in vitro proline and alanine scanning mutagenesis of Aβ40 proposed core regions important for aggregation. However, we lack even this limited mutagenesis data for the more disease-relevant Aβ42. Thus, to better understand the molecular determinants of Aβ42 aggregation in a cell-based system, we combined a yeast DHFR aggregation assay with deep mutational scanning. We measured the effect of 791 of the 798 possible single amino acid substitutions on the aggregation propensity of Aβ42. We found that ~75% of substitutions, largely to hydrophobic residues, maintained or increased aggregation. We identified 11 positions at which substitutions, particularly to hydrophilic and charged amino acids, disrupted Aβ aggregation. These critical positions were similar but not identical to critical positions identified in previous Aβ mutagenesis studies. Finally, we analyzed our large-scale mutagenesis data in the context of different Aβ aggregate structural models, finding that the mutagenesis data agreed best with models derived from fibrils seeded using brain-derived Aβ aggregates.
Bacterial survival in microscopic droplets
Authors: Grinberg Maor , Orevi Tomer , Steinberg Shifra , Kashtan Nadav
Published: June 2019

Plant leaves constitute a huge microbial habitat of global importance. How microorganisms survive the dry daytime on leaves and avoid desiccation is not well-understood. There is evidence that microscopic wetness in the form of thin films and micrometer-sized droplets, invisible to the naked eye, persists on leaves during daytime due to deliquescence – the absorption of water until dissolution – of hygroscopic aerosols. Here we study how such microscopic wetness affects cell survival. We show that, on surfaces drying under moderate humidity, stable microdroplets form around bacterial aggregates due to deliquescence and capillary pinning. Notably, droplet-size increases with aggregate-size and the survival of cells is higher the larger the droplet. This phenomenon was observed for 13 different bacterial species, two of which –Pseudomonas fluorescensandP. putida– were studied in depth. Microdroplet formation around aggregates are likely key to bacterial survival in a variety of unsaturated microbial habitats, including leaf surfaces.
Analyzing effect of altitudinal variation in Enzymatic antioxidants ofColeus forskohliifrom Uttarakhand, India
Authors: Rana Pawan Singh , Saklani Pooja
Published: June 2019

Enzymatic antioxidant activity of the five populations of the medicinal plantColeus forskohliifrom five locations of varied altitudes was assayed to analyze the effect of altitude on the enzymatic antioxidant potential. The various enzymes assayed were SOD, CAT, POD, PPO, APX and GR. Highest activity for all the enzymes was observed at higher altitudes. Strong positive correlation was observed between the protein content, enzyme activities and altitude. CAT, POD and GR activity increases significantly with the altitude while SOD was least affected. APX and PPO shows positive correlation. High activity of all these enzymes seems to be to combat the high oxidative stress at higher altitudes. Results of the present study suggest thatColeus forskohliipopulation growing at a higher altitude has higher antioxidant potential than those at lower altitude. Thus, the population ofColeus forskohliifrom a higher altitude can be used as a source of antioxidants and for commercial propagation.
Evolution at two time-frames: ancient and common origin of two structural variants involved in local adaptation of the European plaice (Pleuronectes platessa)
Authors: Le Moan Alan , Bekkevold Dorte , Hemmer-Hansen Jakob
Published: June 2019

Changing environmental conditions can lead to population diversification through differential selection on standing genetic variation. Structural variant (SV) polymorphisms provide examples of ancient alleles that in time become associated with novel environmental gradients. The European plaice (Pleuronectes platessa) is a marine flatfish showing large allele frequency differences at two putative SVs associated with environmental variation. In this study, we explored the contribution of these SVs to population structure across the North East Atlantic. We compared genome wide population structure using sets of RAD sequencing SNPs with the spatial structure of the SVs. We found that in contrast to the rest of the genome, the SVs were only weakly associated with an isolation-by-distance pattern. Indeed, both SVs showed important allele frequency differences associated with two different environmental gradients, with the same allele increasing both along the salinity gradient of the Baltic Sea, and the latitudinal gradient along the Norwegian coast. Nevertheless, both SVs were found to be polymorphic across most sampling sites, even in the Icelandic population inferred to originate from a different glacial refuge than the remaining populations from the European continental shelf. Phylogenetic analyses suggested that the SV alleles are much older than the age of the Baltic Sea itself. These results suggest that the SVs are older than the age of the environmental gradients with which they currently co-vary. Interestingly, both SVs shared similar phylogenetic and genetic diversity, suggesting that they have a common origin. Altogether, our results suggest that the plaice SVs were shaped by evolutionary processes occurring at two time-frames, firstly following their common origin and secondly related to their current association with more recent environmental gradients such as those found in the North Sea − Baltic Sea transition zone.
Improvement of baculovirus as protein expression vector and as biopesticide by CRISPR/Cas9 editing
Authors: Pazmiño-Ibarra Verónica , Mengual Adriá , Targovnik Alexandra , Herrero Salvador
Published: June 2019

The CRISPR (Clustered Regularly Interspaced Short Palindromic repeats) system associated Cas9 endonuclease is a molecular tool that enables specific sequence edition with high efficiency. The edition using CRISPR/Cas9 system has been successfully reported in small and large viral genomes. In this study, we have explored the use of CRISPR/Cas9 system for the edition of the baculovirus genome. We have shown that the delivering of Cas9-sgRNA ribonucleoprotein (RNP) complex with or without DNA repair template into Sf21 insect cells through lipofection might be efficient to produce knocks-out as well as knocks-in into the baculovirus. To evaluate potential application of our CRISPR/Cas9 method to improve baculovirus as protein expression vector and as biopesticide, we attempted to knock-out several genes from a recombinant AcMNPV form used in the baculovirus expression system as well as in a natural occurring viral isolate from the same virus. We have additionally confirmed the adaptation of this methodology for the generation of viral knocks-in specific regions of the viral genome. Analysis of the generated mutants revealed that the edition efficiency and the type of changes was variable but relatively high. Depending on the targeted gene, the rate of edition ranged from 10% to 40%. This study established the first report revealing the potential of CRISPR/Cas9 for the edition of baculovirus contributing to the engineering of baculovirus as protein expression vector as well as a biological control agent.