bluuebunny/crossref_metadata_2025 huggingface dataset:
Meta-analysis of the prognostic value of long non-coding RNA PVT1 for cancer patients
Authors: Ma Chao , Nie Xing-Guo , Wang Yan-Li , Wu Da-Peng , Liang Qiu-dong
Published: December 2018

Background:

Plasmacytoma variant translocation 1 (PVT1) is reported to be dysregulated in various cancers. Therefore, this meta-analysis was performed to clarify its utility as a prognosis marker in malignant tumors.

Methods:

Electronic databases, including PubMed, OVID, Cochrane Library, and Web of Science databases, were retrieved from inception to December 16, 2017. Typically, hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated, so as to explore the relationship between PVT1 expression and patient survival. In addition, odds ratios (OR) were calculated to assess the association of PVT1 expression with pathological parameters.

Results:

A total of 23 studies involving 2350 patients were included in this meta-analysis. The pooled HR suggested that high PVT1 expression levels were correlated with poor overall survival (OS, HR = 1.99, 95% CI: 1.73–2.28), disease-free survival (DFS, HR = 1.76, 95% CI: 1.45–2.14), and recurrence-free survival (RFS, HR = 1.74, 95% CI: 1.26–2.39) in cancer patients without obvious heterogeneity. Moreover, high PVT1 expression levels were also correlated with larger tumor size (OR = 1.47, 95% CI: 1.02–2.11), poor differentiation grade (OR = 1.79, 95% CI: 1.39–2.30), advanced tumor stage (pooled OR = 3.28, 95% CI: 2.46–4.38), lymph node metastasis (OR = 2.67, 95% CI: 1.66–4.29) and distant metastasis (OR = 4.00, 95% CI: 1.39–11.50) in cancer patients.

Conclusions:

Findings of this meta-analysis suggest that a high PVT1 expression level may serve as a novel biomarker of poor prognosis in cancers.
Incidence of dysphagia and dysphonia after Hangman's fractures
Authors: Yang Yi , Dai Lijuan , Ma Litai , Gao Xinlin , Liu Hao
Published: December 2018

This research aims to explore the accurate incidence, severity and outcomes of dysphagia and dysphonia after Hangman fractures.

A total of 93 patients were included in this study and clinical data were reviewed. The Bazaz grading system (0-None; 1-Mild; 2-Moderate; 3-Severe) was used for dysphagia evaluation and the Voice Handicap Index-10 used to evaluate dysphonia. In all of the patients, evaluation of dysphagia and dysphonia was performed preoperatively and at 1 week, 1 month, 3, 6, and 12 months after surgery. SPSS 22.0 software (SPSS Inc, Chicago, IL) was used for all statistical analyses.

Posttraumatic immediate dysphagia was found in 8 patients and posttraumatic immediate dysphonia was observed in 3 patients. The incidence of dysphagia was 22.6% at the 1st week, 16.1% at the 1st month, and 9.7% at the 3rd month of follow-up. The incidence of dysphonia was 24.5% at the 1st week, 11.3% at the 1st month, and 3.8% at the 3rd month of follow-up.

Posttraumatic immediate dysphagia and dysphonia occurred and the anterior surgical approach was associated with a higher incidence of dysphagia compared to posterior surgery and nonoperative patients. Most dysphagia and dysphonia were mild and gradually decreased during the subsequent 3 months after surgery. Future prospective, randomized studies with larger sample sizes are required to validate these data.
Lambda-like ST-segment elevation in acute myocardial infarction triggered by coronary spasm may be a new risk predictor for lethal ventricular arrhythmia
Authors: Wang Guangqiang , Zhao Na , Zhang Chuanhuan , Zhong Shu , Li Xuexun
Published: December 2018

Rationale:

The lambda-like ST-elevation electrocardiography (ECG) pattern is extremely rare in patients with type 2 myocardial infarction (T2MI) triggered by coronary spasm. When this ECG pattern appears, sudden cardiac death (SCD) caused by lethal ventricular arrhythmia may occur because clinicians do not pay sufficient attention to this phenomenon.

Patient concerns:

We describe a 41-year-old man who presented with steep down-sloping ST-segment elevation, paroxysmal ventricular tachycardia, severe sinus bradycardia, and intermittent complete atrioventricular block on ECG during the sudden recurrence of clinical symptoms.

Diagnosis:

T2MI complicated with lethal arrhythmia and caused by coronary spasm.

Interventions:

The patient received an implantable cardioverter defibrillator (ICD) for SCD caused by lethal ventricular arrhythmia and received long-term calcium-blocker and nitroglycerin therapy.

Outcomes:

At a 3-month follow-up, no recurrence was noted.

Lessons:

The lambda-like ST-elevation pattern is identified with other ST-elevation patterns by geometry and may be a new risk predictor for lethal ventricular arrhythmia on ECG. When this pattern is identified, clinicians should adopt aggressive therapeutic strategies, including ICD implantation and etiological treatment.
Myocardial calcification found in Epstein–Barr viral myocarditis and rhabdomyolysis
Authors: Sui Mingliang , Tang Weibing , Wu Changjiang
Published: December 2018

Rationale:

The Epstein–Barr (EB) virus has rarely been reported as a cause of fulminant myocarditis. To our knowledge, the present case is the first report on myocardial calcification in EB viral myocarditis and rhabdomyolysis.

Patient concerns:

A 17-year-old man was admitted to the department with fever, chest tightness, and tachypnea that had been present for 2 days.

Diagnoses:

The initial investigation showed elevated liver enzyme levels, creatine kinase levels, creatine kinase isoenzyme levels, and elevated serum myoglobin. Echocardiography showed that left ventricular motion amplitude decreased. Test for immunoglobin M and immunoglobin G antibodies against Epstein–Barr virus were positive. These findings were consistent with fulminant myocarditis, cardiogenic shock, and rhabdomyolysis.

Interventions:

The patient was intensively treated with venoarterial extracorporeal membrane oxygenation (VA-ECMO), continuous renal replacement therapy (CRRT).

Outcomes:

Myocardial calcification was observed in the left ventricle walls on CT examination 10 days after the admission. Four months later, the patient is still alive and with adequate daily life.

Lessons:

This case indicates that this rare form of myocardial calcification may be associated with EB viral infection and rhabdomyolysis.
Brief Report: Pre-exposure Prophylaxis Awareness and Use Among Cisgender Women at a Sexually Transmitted Disease Clinic
Authors: Raifman Julia R. , Schwartz Sheree R. , Sosnowy Collette D. , Montgomery Madeline C. , Almonte Alexi , Bazzi Angela R. , Drainoni Mari-Lynn , Stein Michael D. , Willie Tiara C. , Nunn Amy S. , Chan Philip A.
Published: December 2018

Background:

Pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV transmission. Cisgender women (cis-women) constitute only a small proportion of PrEP users in the United States despite accounting for 19% of new HIV infections in 2016.

Setting:

The Rhode Island Sexually Transmitted Diseases (STD) Clinic from 2013 to 2016.

Methods:

We report on the demographic and behavioral characteristics of all HIV-negative, cis-women who presented to the Clinic and of those who met Centers for Disease Control and Prevention (CDC) indications for PrEP. In a logistic regression analysis, we evaluated PrEP awareness among cis-women by year and demographic characteristics. We compared PrEP awareness among cis-women with PrEP awareness among cisgender men who have sex with men and among cisgender men who inject drugs presenting to the Clinic.

Results:

Among 1431 HIV-negative cis-women, 84 (5.8%) met CDC indications for PrEP. PrEP awareness was significantly lower among Hispanic/Latina cis-women [11.0%; adjusted odds ratio (AOR): 0.46, 95% confidence interval (CI): 0.31 to 0.66] and non-Hispanic black cis-women (13.8%; AOR: 0.59, 95% CI: 0.39 to 0.89) relative to non-Hispanic white cis-women (20.7%). Men who have sex with men had significantly greater PrEP awareness (60.3%; AOR: 5.85, 95% CI: 3.35 to 10.23) than cis-women (22.9%). Only one woman reported PrEP use.

Conclusions:

Two-thirds of HIV-negative cis-women presenting for HIV/sexually transmitted disease testing and meeting CDC indications for PrEP were unaware of PrEP, and only one woman reported ever using PrEP. There is a critical need for public health professionals and health care providers to increase PrEP awareness and use among cis-women at risk for HIV.
Brief Report: Malignancies in Adults Living With HIV in Asia
Authors: Jiamsakul Awachana , Polizzotto Mark , Wen-Wei Ku Stephane , Tanuma Junko , Hui Eugenie , Chaiwarith Romanee , Kiertiburanakul Sasisopin , Avihingasanon Anchalee , Yunihastuti Evy , Kumarasamy Nagalingeswaran , Ly Penh Sun , Pujari Sanjay , Ditangco Rossana , Do Cuong Duy , Merati Tuti Parwati , Kantipong Pacharee , Zhang Fujie , Van Nguyen Kinh , Kamarulzaman Adeeba , Choi Jun Yong , Sim Benedict L.H. , Ng Oon Tek , Ross Jeremy , Wong Wingwai ,   on behalf of the TREAT Asia HIV Observational Database of IeDEA Asia-Pacific
Published: December 2018

Background:

Hematological malignancies have continued to be highly prevalent among people living with HIV (PLHIV). This study assessed the occurrence of, risk factors for, and outcomes of hematological and nonhematological malignancies in PLHIV in Asia.

Methods:

Incidence of malignancy after cohort enrollment was evaluated. Factors associated with development of hematological and nonhematological malignancy were analyzed using competing risk regression and survival time using Kaplan–Meier.

Results:

Of 7455 patients, 107 patients (1%) developed a malignancy: 34 (0.5%) hematological [0.08 per 100 person-years (/100PY)] and 73 (1%) nonhematological (0.17/100PY). Of the hematological malignancies, non-Hodgkin lymphoma was predominant (n = 26, 76%): immunoblastic (n = 6, 18%), Burkitt (n = 5, 15%), diffuse large B-cell (n = 5, 15%), and unspecified (n = 10, 30%). Others include central nervous system lymphoma (n = 7, 21%) and myelodysplastic syndrome (n = 1, 3%). Nonhematological malignancies were mostly Kaposi sarcoma (n = 12, 16%) and cervical cancer (n = 10, 14%). Risk factors for hematological malignancy included age >50 vs. ≤30 years [subhazard ratio (SHR) = 6.48, 95% confidence interval (CI): 1.79 to 23.43] and being from a high-income vs. a lower-middle-income country (SHR = 3.97, 95% CI: 1.45 to 10.84). Risk was reduced with CD4 351–500 cells/µL (SHR = 0.20, 95% CI: 0.05 to 0.74) and CD4 >500 cells/µL (SHR = 0.14, 95% CI: 0.04 to 0.78), compared to CD4 ≤200 cells/µL. Similar risk factors were seen for nonhematological malignancy, with prior AIDS diagnosis showing a weak association. Patients diagnosed with a hematological malignancy had shorter survival time compared to patients diagnosed with a nonhematological malignancy.

Conclusions:

Nonhematological malignancies were common but non-Hodgkin lymphoma was more predominant in our cohort. PLHIV from high-income countries were more likely to be diagnosed, indicating a potential underdiagnosis of cancer in low-income settings.
Novel Use of Responsive Neurostimulation (RNS System) in the Treatment of Super Refractory Status Epilepticus
Authors: Ernst Lia D. , Krause Katie L. , Kellogg Marissa A. , Raslan Ahmed M. , Spencer David C.
Published: December 2018

There are very few randomized controlled trials studying treatment of super refractory status epilepticus (SE), despite estimated occurrence in about 15% of SE cases and its association with high morbidity and mortality rates. Small case series and case reports have described use of neurostimulation, including vagal nerve stimulation, transcranial magnetic stimulation, and deep brain stimulation, to treat super refractory SE when medical interventions have failed. To our knowledge, this is the first reported case of responsive neurostimulation being used to successfully treat a case of super refractory SE. A 37-year-old man with refractory focal epilepsy and a known focal cortical dysplasia involving motor cortex was implanted with an RNS System device after being in super refractory SE for 20 days. Responsive neurostimulation strip and depth electrodes were placed targeting the cortical dysplasia. Detection and stimulation parameters were adjusted over a 14-day period, as medications were gradually weaned. Seizures abated 15 days after implant, 24 hours after stimulation parameters were configured to mimic seizure offset pattern. Seizure remission was sustained, allowing the patient to be weaned off sedating medications and discharged to a rehabilitation facility. At 6 weeks of follow-up, the patient was near his neurologic baseline with no focal deficits.
Where Do Women With Urinary Incontinence Find Information About Absorbent Products and How Useful Do They Find It?
Authors: Smith Nicholas , Hunter Kathleen F. , Rajabali Saima , Milsom Ian , Wagg Adrian
Published: December 2018

PURPOSE:

This study aimed to determine from what sources women with urinary and dual urinary and fecal incontinence sought and received information about incontinence and absorbent products. We also evaluated source utility.

DESIGN:

Descriptive, embedded, mixed-methods study with qualitative interviews nested into a survey design in a modified explanatory sequence.

SUBJECTS AND SETTING:

The target population was community-dwelling women in Canada who used containment products to manage urinary incontinence. Three hundred fifteen women completed the online survey, and 9 participated in interviews.

METHOD:

Quantitative data were collected using an online survey that was advertised in multiple locations, including continence and urogynecology clinics, non-for-profit health Web sites, and social media. Descriptive statistics were used for analysis. Using initial quantitative data results, a semistructured interview guide was designed to gain further insight. Local survey participants were invited to interviews at the end of the survey. Interview transcripts were coded using content analysis. The codes were then collapsed into categories and finally themes.

RESULTS:

The most common sources of information (n = 284/315) were retail outlets (43%) and television/radio (42%). The greatest percentages of “useful” or “very useful” resources were healthcare professionals (83%). Content analysis identified 5 themes: (1) using existing knowledge, (2) seeking knowledge, (3) finding the right pad, (4) being safe and secure, and (5) perceptions of healthcare professionals' roles. Product choice was made through trial and error; women drew information from a variety of sources, including product labels. Perceptions of helpfulness of experiences with healthcare professionals varied.

CONCLUSION:

Although women used multiple sources when selecting containment products, they did not receive information in a manner that suited their needs, resulting in a trial-and-error approach to product selection. Healthcare professionals should actively give information on containment products during their assessment of continence in patient encounters.
Robust and Structural Ergodicity Analysis and Antithetic Integral Control of a Class of Stochastic Reaction Networks
Authors: Briat Corentin , Khammash Mustafa
Published: December 2018

Controlling stochastic reactions networks is a challenging problem with important implications in various fields such as systems and synthetic biology. Various regulation motifs have been discovered or posited over the recent years, a very recent one being the so-called Antithetic Integral Control (AIC) motif [Briat, Gupta & Khammash, Cell Systems, 2016]. Several appealing properties for the AIC motif have been demonstrated for classes of reaction networks that satisfy certain irreducibility, ergodicity and output controllability conditions. Here we address the problem of verifying these conditions for large sets of reaction networks with time-invariant topologies, either from a robust or a structural viewpoint, using three different approaches. The first one adopts a robust viewpoint and relies on the notion of interval matrices. The second one adopts a structural viewpoint and is based on sign properties of matrices. The last one is a direct approach where the parameter dependence is exactly taken into account and can be used to obtain both robust and structural conditions. The obtained results lie in the same spirit as those obtained in [Briat, Gupta & Khammash, Cell Systems, 2016] where properties of reaction networks are independently characterized in terms of control theoretic concepts, linear programs, and graph-theoretic/algebraic conditions. Alternatively, those conditions can be cast as convex optimization problems that can be checked efficiently using modern optimization methods. Several examples are given for illustration.
PGC1α and Exercise Adaptations in Zebrafish
Authors: Parisi Alice , Blattmann Peter , Lizzo Giulia , Stutz Vivienne , Strohm Laura , Richard Joy , Civiletto Gabriele , Charpagne Aline , Raymond Frederic , Gobet Cedric , Weger Benjamin , Migliavacca Eugenia , Aebersold Ruedi , Spiegelman Bruce , Gut Philipp
Published: December 2018

Fish species display huge differences in physical activity ranging from lethargy to migration of thousands of miles, making them an interesting model to identify determinants of physical fitness. Here, we show a remarkable plasticity of zebrafish in response to exercise and induction of PGC1α (encoded byPPARGC1A), a dominant regulator of mitochondrial biogenesis. Forced expression of humanPPARGC1Ainduces mitochondrial biogenesis, an exercise-like gene expression signature, and physical fitness comparable to wild-type animals trained in counter-current swim tunnels. Quantifying transcriptional and proteomic changes in response to exercise or PGC1α, we identify conserved ‘exercise’ adaptations, including a stoichiometric induction of the electron transport chain (ETC) that re-organizes into respiratory supercomplexes in both conditions. We further show that ndufa4/ndufa4l, previously assigned to complex I, associates to free and supramolecular complex IVin vivo. Thus, zebrafish is a useful and experimentally tractable vertebrate model to study exercise biology, including ETC expression and assembly.

HIGHLIGHTS

PGC1α reprograms zebrafish skeletal muscle to a ‘red fiber’ phenotype and increases exercise performance

Zebrafish show a high molecular plasticity in response to PGC1α and exercise

SWATH-MS proteomics show a stoichiometric induction of the electron transport chain that organizes as supercomplexes in response to PGC1α and exercise

ndufa4/ndufa4l associate to free and supramolecular complex IVin vivo
Spontaneous mentalizing after early interpersonal trauma: Evidence for hypoactivation of the temporoparietal junction
Authors: Hudson Anna , Van Hamme Charlotte , Maeyens Lien , Brass Marcel , Mueller Sven
Published: December 2018

Experience of interpersonal trauma and violence alters self-other distinction (also known as theory of mind, or ToM), yet little is known about their neural correlates. This fMRI study assessed temporoparietal junction (TPJ) activation, an area strongly implicated in interpersonal processing, during spontaneous mentalizing in 35 adult women with histories of childhood physical, sexual, and/or emotional abuse (childhood abuse; CA) and 31 women without such experiences (unaffected comparisons, UC). Participants watched movies during which an agent formed true or false beliefs about the location of a ball, while participants always knew the true location of the ball. As hypothesized, right TPJ activation was greater for UC compared to CA for false versus true belief conditions. However, posttraumatic stress symptomatology (PTSS) appeared to play a role in driving the neural effect. In addition, CA showed increased functional connectivity relative to UC between the rTPJ and dorsomedial prefrontal cortex. Finally, the agent's false belief about the presence of the ball speeded participants' response (ToM indx), but without group differences. These findings highlight that experiencing early interpersonal trauma can alter brain areas involved in the neural processing of ToM and perspective-taking during adulthood.
Who is researching biodiversity hotspots in Eastern Europe? A case study on grasslands from Romania
Authors: Nita Andreea , Hartel Tibor , Manolache Steluta , Ciocanea Cristiana M. , Miu Iulia V. , Rozylowicz Laurentiu
Published: December 2018

Farming landscapes of Europe are vital arenas for social-ecological sustainability because of their significant coverage and potential to integrate food production with biodiversity conservation. Knowledge gathered by scientific research is a critical ingredient for developing and implementing socio-economically and ecologically sustainable grassland management strategies for grasslands. The quality of scientific knowledge and its potential to address grasslands as complex social-ecological systems is strongly dependent on the creativity and scientific ambition of the researcher, but also on the network (from academic and non-academic sectors) around the researcher. The goal of this paper is to map the research network around Romania’s grasslands. These systems have exceptional socio-cultural and economic values and are between the most biodiverse ecosystems of the world. Considering the multiple threats to these grasslands, it is an urgent need to understand the existing scientific knowledge profile around these systems. This paper aims at using bibliometrics analysis, a well-developed scientific domain that envisages network theory to analyze relationships between affiliations network, co-authorship network, and co-word analysis. The number of studies targeting grassland management in Romania is increasing mainly thanks to international involvement. However, the management of the grasslands is still deficient and the contribution of science to the process is virtually absent. The subject of research is mainly related to the biological and ecological characteristics of grasslands, a notable absence from internationally visible research being the management of grasslands, especially in the context of EU Common Agricultural Policies. To increase scientific performance, and better inform EU and local policies on grassland management, Romanian researchers should better capitalize on international collaborations and local academic leaders. Our findings can be used to identify research gaps and to improve collaboration and knowledge exchange between practitioners, scientists, policy makers, and stakeholders.
Wnt/β-catenin signaling is required for the development of multiple nephron segments
Authors: Deacon Patrick , Concodora Charles W , Chung Eunah , Park Joo-Seop
Published: December 2018

The nephron is composed of distinct segments that perform unique physiological functions to generate urine. Little is known about how multipotent nephron progenitor cells differentiate into different nephron segments. It is well known that Wnt/β-catenin signaling regulates the maintenance and commitment of mesenchymal nephron progenitors during kidney development. However, it is not fully understood how it regulates nephron patterning after nephron progenitors undergo mesenchymal-to-epithelial transition. To address this, we performed β-catenin loss-of-function and gain-of-function studies in epithelial nephron progenitors in the mouse kidney. Consistent with a previous report, the formation of the renal corpuscle was defective in the absence of β-catenin. Interestingly, we found that epithelial nephron progenitors lacking β-catenin were able to form presumptive proximal tubules but that they failed to further develop into differentiated proximal tubules, suggesting that Wnt/β-catenin signaling plays a critical role in proximal tubule development. We also found that epithelial nephron progenitors lacking β-catenin failed to form the distal tubules. Constitutive activation of Wnt/β-catenin signaling blocked the proper formation of all nephron segments, suggesting tight regulation of Wnt/β-catenin signaling during nephron patterning. This work shows that Wnt/β-catenin signaling regulates the patterning of multiple nephron segments along the proximo-distal axis of the mammalian nephron.
Resolving the insertion sites of polymorphic duplications reveals aHERC2haplotype under selection
Authors: Saitou M. , Gokcumen O.
Published: December 2018

Polymorphic duplications in humans have been shown to contribute to phenotypic diversity. However, the evolutionary forces that maintain variable duplications across the human genome are largely unexplored. To understand the haplotypic architecture of the derived duplications, we developed a linkage-disequilibrium based method to detect insertion sites of polymorphic duplications not represented in reference genomes. This method also allows resolution of haplotypes harboring the duplications. Using this approach, we conducted genome-wide analyses and identified the insertion sites of 22 common polymorphic duplications. We found that the majority of these duplications are intrachromosomal and only one of them is an interchromosomal insertion. Further characterization of these duplications revealed significant associations to blood and skin phenotypes. Based on population genetics analyses, we found that the partial duplication of a well-characterized pigmentation-related gene,HERC2, may be selected against in European populations. We further demonstrated that the haplotype harboring the partial duplication significantly affects the expression of theHERC2P9gene in multiple tissues. Our study sheds light onto the evolutionary impact of understudied polymorphic duplications in human populations and presents methodological insights for future studies.
Effect of diapause on cold-resistance in different life-stages of an aphid parasitoid wasp
Authors: Tougeron Kevin , Blanchet Leslie , van Baaren Joan , Le Lann Cecile , Brodeur Jacques
Published: December 2018

To overwinter, insects from mild temperate areas can either enter diapause or remain active. Both strategies involve costs and benefits depending on the environment. In the first case, the emerging individuals will resist winter but have a reduced fitness because diapause entails physiological and ecological costs. In the second case, individuals need to be cold-resistant enough to withstand winter temperatures during their immature and adult stages, but could avoid diapause-associated costs. In mild temperate areas, the cost-benefit balance between the diapause and the non-diapause strategy would likely change in response to climate warming. A trade-off between these two strategies should lead to reduction of diapause expression in some populations. We explored the importance of such trade-off through the comparison of cold resistance capacities among different life stages in diapause and non-diapause individuals in a population of the aphid parasitoid Aphidius ervi (Hymenoptera: Braconidae) originating from western France where a decrease of diapause incidence was recently observed. As a proxy measure of insect physiological cold resistance, the Super Cooling Point (SCP) was determined for non-diapausing and diapausing prepupae and adults that went through prepupal diapause or not. Diapausing and non-diapausing prepupae were equally cold-resistant (-24.20 ±0.30°C vs. -24.74 ±0.36°C, respectively), and overall more resistant than adults. Adults that went through diapause as prepupae were less cold resistant (-17.85 ±1.10°C) than adults that have not undergone through diapause (-21.10 ±0.54°C). We also found that diapausing prepupae and adults that have undergone diapause were lighter than their non-diapausing counterparts, at a comparable size, suggesting higher energetic expenses during diapause. These results suggest a trade-off between diapause expression in prepupae and cold resistance and life-history-traits in adults. We conclude that selection could favor insects that do not enter diapause and thus avoid its associated costs while taking advantage at exploiting the mild winter environment.
The genomic and proteomic landscape of the rumen microbiome revealed by comprehensive genome-resolved metagenomics
Authors: Stewart Robert D. , Auffret Marc D. , Warr Amanda , Walker Alan W. , Roehe Rainer , Watson Mick
Published: December 2018

Ruminants provide essential nutrition for billions of people worldwide. The rumen is a specialised stomach adapted to the breakdown of plant-derived complex polysaccharides, and collectively the rumen microbiota encode the thousands of enzymes responsible. Here we present a comprehensive analysis of over 6.5 terabytes of Illumina and Nanopore sequence data, including assembly of 4941 metagenome-assembled genomes, and several single-contig, whole-chromosome assemblies of novel rumen bacteria. We also present the largest dataset of predicted proteins from the rumen, and provide rich annotation against public datasets. Together these data will form an essential part of future studies of rumen microbiome structure and function.
Generating closed bacterial genomes from long-read nanopore sequencing of microbiomes
Authors: Moss Eli L. , Bhatt Ami S.
Published: December 2018

We present the first method for efficient recovery of complete, closed genomes directly from microbiomes using nanopore long-read sequencing and assembly. We apply our approach to three healthy human gut communities and compare results to short read and read cloud approaches. We obtain nine finished genomes including the first reported closed genome of Prevotella copri, an organism with highly repetitive genome structure prevalent in non-western human gut microbiomes.
Pseudozyma saprotrophic yeasts have retained a large effector arsenal, including functional Pep1 orthologs
Authors: Sharma Rahul , Ökmen Bilal , Doehlemann Gunther , Thines Marco
Published: December 2018

The basidiomycete smut fungi are predominantly plant parasitic, causing severe losses in some crops. Most species feature a saprotrophic haploid yeast stage, and several smut fungi are only known from this stage, with some isolated from habitats without suitable hosts, e.g. from Antarctica. Thus, these species are generally believed to be apathogenic, but recent findings that some of these might have a plant pathogenic sexual counterpart, casts doubts on the validity of this hypothesis. Here, four Pseudozyma genomes were re-annotated and compared to published smut pathogens and the well-characterised effector gene Pep1 from these species was checked for its ability to complement a Pep1 deletion strain of Ustilago maydis. It was found that 113 high-confidence putative effector proteins were conserved among smut and Pseudozyma genomes. Among these were several validated effector proteins, including Pep1. By genetic complementation we show that Pep1 homologs from the supposedly apathogenic yeasts restore virulence in Pep1-deficient mutants Ustilago maydis. Thus, it is concluded that Pseudozyma species have retained a suite of effectors. This hints at the possibility that Pseudozyma species have kept an unknown plant pathogenic stage for sexual recombination or that these effectors have positive effects when colonising plant surfaces.
Inhibition of Notch signaling rescues cardiovascular development in Kabuki Syndrome
Authors: de los Angeles Serrano Maria , Demarest Bradley L. , Tone-Pah-Hote Tarlynn , Tristani-Firouzi Martin , Yost H. Joseph
Published: December 2018

Kabuki Syndrome patients have a spectrum of congenital disorders, including congenital heart defects, the primary determinant of mortality. Seventy percent of Kabuki Syndrome patients have mutations in the histone methyl-transferase KMT2D. However, the underlying mechanisms that drive these congenital disorders are unknown. Here, we generated and characterized a zebrafish kmt2d null mutant that recapitulates the cardinal phenotypic features of Kabuki Syndrome, including microcephaly, palate defects, abnormal ear development and cardiac defects. The cardiovascular defects consist of abnormal aortic arches and hypoplastic ventricle, driven by previously unknown aberrant endocardial and endothelial vasculogenesis. We identify a regulatory link between the Notch pathway and Kmt2d during vasculogenesis and show that pharmacological inhibition of Notch signaling rescues the cardiovascular phenotype in zebrafish Kabuki Syndrome. Taken together these findings demonstrate that Kmt2d regulates vasculogenesis, provide evidence for interactions between Kmt2d and Notch signaling in Kabuki Syndrome, and suggest future directions for clinical research.
Geometry alone influences stem cell differentiation in a precision 3D printed stem cell niche:
Authors: Prina Elisabetta , Sidney Laura , Tromayer Maximilian , Moore Jonathan , Liska Robert , Bertolin Marina , Ferrari Stefano , Hopkinson Andrew , Dua Harminder , Yang Jing , Wildman Ricky , Rose Felicity RAJ
Published: December 2018

Stem cells within epithelial tissues reside in anatomical structures known as crypts that are known to contribute to the mechanical and chemical milieu important for function. To date, epithelial stem cell therapies have largely ignored the niche and focussed solely on the cell population to be transplanted. Our aim was to recreate the precise geometry of the epithelial stem cell niche using two photon polymerisation and to determine the influence of this structure alone on stem cell phenotype. We were able to recreate crypt structures and following cell seeding, a zonation in cell phenotype along the z-axis emerged. This illustrates that geometry alone, without the use of exogenous signalling molecules, influences cell response. Understanding the role of geometry in the regulation of the stem cell niche will enable significant advances in our ability to influence stem cell behaviour to expedite cellular therapies to the clinic.
Cellular multifunctionality in the muscle activity ofHydra vulgaris
Authors: Szymanski John , Yuste Rafael
Published: December 2018

As a cnidarian,Hydrahas an anatomically simple neuromuscular system likely similar to those of ancestral species, and its study could provide insights on the design logic and function of animal body plans throughout evolution. Here we have used calcium imaging to map the activity of the entire epitheliomuscular system of livingHydrain mounted preparations. We find seven basic spatiotemporal patterns of activation, with fast and slow kinetics of initiation and propagation. Contrary to previous assumptions, both endodermal and ectodermal epitheliomuscular tissues are systematically activated jointly during contractions, in spite of their muscle fibers being orthogonally arranged. We also find that individual cells surprisingly participate in multiple patterns, using different kinetics of activation. Our results reveal thatHydra’sepitheliomuscular tissue is a multifunctional system that can be flexibly reconfigured to generate different spatiotemporal activity patterns, enabling a structurally simple design to implement a varied behavior output.
Genome-wide recombination map construction from single individuals using linked-read sequencing
Authors: Dréau Andreea , Venu Vrinda , Gaspar Ludmila , Jones Felicity C.
Published: December 2018

Meiotic recombination is a major molecular mechanism generating genomic diversity. Recombination rates vary across the genome, often involving localized crossover “hotspots” and “coldspots”. Studying the molecular basis and mechanism underlying this variation within and among individuals has been challenging due to the high cost and effort required to construct individualized genome-wide maps of recombination crossovers. In this study we introduce a new method to detect recombination crossovers across the genome from sperm DNA using Illumina sequencing of linked-read libraries produced using 10X Genomics technology. We leverage the long range information provided by the linked short reads to phase and assign haplotype states to each DNA molecule. When applied to DNA from gametes of a diploid organism, the majority of linked-read molecules can be used to faithfully reconstruct an individual’s two haplotypes present at each location in the genome. A valuable rare fraction of molecules that span meiotic crossovers between the two chromosome haplotypes can then be isolated from the broader population of nonrecombinant molecules. Our pipeline, called ReMIX, allows us to characterize the genomic location and intensity of meiotic crossovers in a single individual and faithfully detects previously described recombination hotspots discovered by studies using mapping panels in mice. With a median crossover resolution of the mouse and stickleback being 15kb and 23kb respectively, ReMIX provides a powerful, high-throughput, low-cost approach to quantify recombination variation across the genome opening up numerous opportunities to study recombination variation with high genomic resolution in multiple individuals. ReMIX source code is available at athttps://github.com/adreau/ReMIX.
Type-I myosins promote actin polymerization to drive membrane bending in endocytosis
Authors: Manenschijn Hetty E , Picco Andrea , Mund Markus , Ries Jonas , Kaksonen Marko
Published: December 2018

Clathrin-mediated endocytosis in budding yeast requires the formation of a dynamic actin network that produces the force to invaginate the plasma membrane against the intracellular turgor pressure. The type-I myosins Myo3 and Myo5 are important for endocytic membrane reshaping, but mechanistic details of their function remain scarce. Here, we studied the function of Myo3 and Myo5 during endocytosis using quantitative live-cell imaging and genetic perturbations. We show that the type-I myosins promote, in a dose-dependent way, the growth and expansion of the actin network, which controls the speed of membrane and coat internalization. We found that this myosin-activity is independent of the actin nucleation promoting activity of myosins, and cannot be compensated for by increasing actin nucleation. Our results suggest a new mechanism for type-I myosins to produce force by promoting actin filament polymerization.
Automated detection of the HER2 gene amplification status in Fluorescencein situhybridization images for the diagnostics of cancer tissues
Authors: Zakrzewski Falk , Back Walter de , Weigert Martin , Wenke Torsten , Zeugner Silke , Mantey Robert , Sperling Christian , Friedrich Katrin , Roeder Ingo , Aust Daniela E. , Baretton Gustavo , Hönscheid Pia
Published: December 2018

The human epidermal growth factor receptor 2 (HER2) gene amplification status is a crucial marker for evaluating clinical therapies of breast or gastric cancer. We propose a deep learning-based pipeline for the detection, localization and classification of interphase nuclei depending on their HER2 gene amplification state in Fluorescence in situ hybridization (FISH) images. Our pipeline combines two RetinaNet-based object localization networks which are trained (1) to detect and classify interphase nuclei into distinct classes normal, low-grade and high-grade and (2) to detect and classify FISH signals into distinct classes HER2 or centromere of chromosome 17 (CEN17). By independently classifying each nucleus twice, the two-step pipeline provides both robustness and interpretability for the automated detection of the HER2 amplification status. The accuracy of our deep learning-based pipeline is on par with that of three pathologists and FISH images on a set of 57 validation images containing several hundreds of nuclei are accurately classified. The automatic pipeline is a first step towards assisting pathologists in evaluating the HER2 status of tumors using FISH images, for analyzing FISH images in retrospective studies, and for optimizing the documentation of each tumor sample by automatically annotating and reporting of the HER2 gene amplification specificities.
The distribution of epistasis on simple fitness landscapes
Authors: Fraïsse Christelle , Welch John J.
Published: December 2018

Fitness interactions between mutations can influence a population’s evolution in many different ways. While epistatic effects are difficult to measure precisely, important information about the overall distribution is captured by the mean and variance of log fitnesses for individuals carrying different numbers of mutations. We derive predictions for these quantities from simple fitness landscapes, based on models of optimizing selection on quantitative traits. We also explore extensions to the models, including modular pleiotropy, variable effects sizes, mutational bias, and maladaptation of the wild-type. We illustrate our approach by reanalysing a large data set of mutant effects in a yeast snoRNA. Though characterized by some strong epistatic interactions, these data give a good overall fit to the non-epistatic null model, suggesting that epistasis might have little effect on the evolutionary dynamics in this system. We also show how the amount of epistasis depends on both the underlying fitness landscape, and the distribution of mutations, and so it is expected to vary in consistent ways between new mutations, standing variation, and fixed mutations.
Smart computational exploration of stochastic gene regulatory network models using human-in-the-loop semi-supervised learning
Authors: Wrede Fredrik , Hellander Andreas
Published: December 2018

Discrete stochastic models of gene regulatory network models are indispensable tools for biological inquiry since they allow the modeler to predict how molecular interactions give rise to nonlinear system output. Model exploration with the objective of generating qualitative hypotheses about the workings of a pathway is usually the first step in the modeling process. It involves simulating the gene network model under a very large range of conditions, due to the the large uncertainty in interactions and kinetic parameters. This makes model exploration highly computational demanding. Furthermore, with no prior information about the model behavior, labour-intensive manual inspection of very large amounts of simulation results becomes necessary. This limits systematic computational exploration to simplistic models. We address this by developing an interactive, smart workflow for model exploration based on semi-supervised learning and human-in-the-loop labeling of data. The proposed methodology lets a modeler rapidly discover ranges of interesting behaviors predicted by a model. Utilizing the notion that similar simulation output is in proximity of each other in feature space, the modeler can focus on informing the system about what behaviors are more interesting than others instead of configuring and analyzing simulation results. This large reduction in time-consuming manual work by the modeler early in a modeling project can substantially reduce the time needed to go from an initial model to testable predictions and downstream analysis.
Arp2/3 complex-driven spatial patterning of the BCR enhances immune synapse formation, BCR signaling and cell activation
Authors: Bolger-Munro Madison , Choi Kate , Scurll Joshua , Abraham Libin , Chappell Rhys , Sheen Duke , Dang-Lawson May , Wu Xufeng , Priatel John J , Coombs Daniel , Hammer John A , Gold Michael R
Published: December 2018

When B cells encounter antigens on the surface of an antigen-presenting cell (APC), B cell receptors (BCRs) are gathered into microclusters that recruit signaling enzymes. These microclusters then move centripetally and coalesce into the central supramolecular activation cluster of an immune synapse. The mechanisms controlling BCR organization during immune synapse formation, and how this impacts BCR signaling, are not fully understood. We show that this coalescence of BCR microclusters depends on the actin-related protein 2/3 (Arp2/3) complex, which nucleates branched actin networks. Moreover, in murine B cells this dynamic spatial reorganization of BCR microclusters amplifies proximal BCR signaling reactions and enhances the ability of membrane-associated antigens to induce transcriptional responses and proliferation. Our finding that Arp2/3 complex activity is important for B cell responses to spatially-restricted membrane-bound antigens, but not for soluble antigens, highlights a critical role for Arp2/3 complex-dependent actin remodelling in B cell responses to APC-bound antigens.
A Chemical Kinetic Basis for Measuring Translation Initiation and Elongation Rates from Ribosome Profiling data
Authors: Sharma Ajeet K. , Sormanni Pietro , Ahmed Nabeel , Ciryam Prajwal , Friedrich Ulrike A. , Kramer Guenter , O’Brien Edward P.
Published: December 2018

Analysis methods based on simulations and optimization have been previously developed to estimate relative translation rates from next-generation sequencing data. Translation involves molecules and chemical reactions; hence, bioinformatics methods consistent with the laws of chemistry and physics are more likely to produce accurate results. Here, we derive simple equations based on chemical kinetic principles to measure the translation-initiation rate, transcriptome-wide elongation rate, and individual codon translation rates from ribosome profiling experiments. Our methods reproduce the known rates from ribosome profiles generated from detailed simulations of translation. Applying our methods to data from S. cerevisiae and mouse embryonic stem cells we find that the extracted rates reproduce expected correlations with various molecular properties. A codon can exhibit up to 26-fold variability in its translation rate depending upon its context within a transcript. This broad distribution means that the average translation rate of a codon is not representative of the rate at which most instances of that codon are translated. We also find that mouse embryonic stem cells have a global translation speed of 5.2 AA/s, is similar to what has been previous reported using another analysis method. This large variability in translation rates suggests that translational regulation might be used by cells to a greater degree than previously thought.
Dynamic design: manipulation of millisecond timescale motions on the energy landscape of Cyclophilin A
Authors: Juárez-Jiménez Jordi , Gupta Arun A. , Karunanithy Gogulan , Mey Antonia S. J. S. , Georgiou Charis , Ioannidis Harris , De Simone Alessio , Barlow Paul N. , Hulme Alison N. , Walkinshaw Malcolm D. , Baldwin Andrew J. , Michel Julien
Published: December 2018

Proteins need to interconvert between many conformations in order to function, many of which are formed transiently, and sparsely populated. Particularly when the lifetimes of these states approach the millisecond timescale, identifying the relevant structures and the mechanism by which they inter-convert remains a tremendous challenge. Here we introduce a novel combination of accelerated MD (aMD) simulations and Markov State modelling (MSM) to explore these ‘excited’ conformational states. Applying this to the highly dynamic protein CypA, a protein involved in immune response and associated with HIV infection, we identify five principally populated conformational states and the atomistic mechanism by which they interconvert. A rational design strategy predicted that the mutant D66A should stabilise the minor conformations and substantially alter the dynamics whereas the similar mutant H70A should leave the landscape broadly unchanged. These predictions are confirmed using CPMG and R1ρ solution state NMR measurements. By accurately and reliably exploring functionally relevant, but sparsely populated conformations with milli-second lifetimesin silico, our aMD/MSM method has tremendous promise for the design of dynamic protein free energy landscapes for both protein engineering and drug discovery.