bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE)
Authors: Cloughesy Timothy F , Brenner Andrew , de Groot John F , Butowski Nicholas A , Zach Leor , Campian Jian L , Ellingson Benjamin M , Freedman Laurence S , Cohen Yael C , Lowenton-Spier Noa , Rachmilewitz Minei Tamar , Fain Shmueli Shifra ,   GLOBE Study Investigators, Wen Patrick Y , Avgeropoulos Nicholas , Beck Joseph , Benkers Tara , Bokstein Felix , Brenner Andrew , Burton Eric , Butowski Nicholas , Campian Jian , Carrillo Jose , Cloughesy Timothy , de Groot John , De Robles Paula , Drappatz Jan , Dunbar Irine , Fink Karen , Groves Morris , Han Xiaosi , Adila Hormigo , Jensen Randy , Kowalska Agnieszka , Kumthekar Pyriya , Lee Mijung , Lesser Glenn , Lossos Alexander , Lukas Rimas , Macdonald David , Mammoser Aaron , Mechtler Laszlo , Mohile Nimish , Nagpal Seema , Nicholas Garth , Kreisl Teri , Pan Edward , Peak Scott , Pearlman Michael , Perry James , Peterson Richard , Piccioni David , Robins Henry , Ronan Lara , Salacz Michael , Schiff David , Tran David , Zach Leor , Tzuk-Shina Tzahala , Walbert Tobias , Wen Patrick , Youst Shlomit
Published: December 2019

Background

Ofranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab.

Methods

This pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS).

Results

Enrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91–1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3–5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction.

Conclusions

In this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results.

Clinical trials registration

NCT02511405
The Diagnostic Laboratory Hub: A New Health Care System Reveals the Incidence and Mortality of Tuberculosis, Histoplasmosis, and Cryptococcosis of PWH in Guatemala
Authors: Samayoa B , Aguirre L , Bonilla O , Medina N , Lau-Bonilla D , Mercado D , Moller A , Perez J C , Alastruey-Izquierdo A , Arathoon E , Denning D W , Rodríguez-Tudela J L ,   “Fungired”, López Pérez Oscar Eduardo , Ortiz Barrientos Brenan , Reyes Muñoz Vilma Alejandrina , Sajché Aguilar Gladys , Méndez Andrade Aura Marina , de León Luis Roberto Santa Marina , Gómez Alcázar Ana Lucía , González Eduardo Celada , Quiñónez M Gustavo A , Cuyuch Sontay Germán Orlando , Contreras Marín Alba Virtud , Fong Araujo María de Lourdes , Mazariegos L Claudia , Guzmán Brenda
Published: December 2019

Background

A Diagnostic Laboratory Hub (DLH) was set up in Guatemala to provide opportunistic infection (OI) diagnosis for people with HIV (PWH).

Methods

Patients newly presenting for HIV, PWH not receiving antiretrovirals (ARVs) for >90 days but returned to care (Return/Restart), and PWH on ARVs with symptoms of OIs (ARV treatment) were prospectively included. Screening for tuberculosis, nontuberculous mycobacteria (NTM), histoplasmosis, and cryptococcosis was done. Samples were couriered to the DLH, and results were transmitted electronically. Demographic, diagnostic results, disease burden, treatment, and follow-up to 180 days were analyzed.

Results

In 2017, 1953 patients were included, 923 new HIV infections (an estimated 44% of all new HIV infections in Guatemala), 701 on ARV treatment, and 315 Return/Restart. Three hundred seventeen (16.2%) had an OI: 35.9% tuberculosis, 31.2% histoplasmosis, 18.6% cryptococcosis, 4.4% NTM, and 9.8% coinfections. Histoplasmosis was the most frequent AIDS-defining illness; 51.2% of new patients had <200 CD4 cells/mm3 with a 29.4% OI incidence; 14.3% of OIs in new HIV infections occurred with CD4 counts of 200–350 cells/mm3. OIs were the main risk factor for premature death for new HIV infections. At 180 days, patients with OIs and advanced HIV had 73-fold greater risk of death than those without advanced disease who were OI-free.

Conclusions

The DLH OI screening approach provides adequate diagnostic services and obtains relevant data. We propose a CD4 screening threshold of <350 cells/mm3. Mortality remains high, and improved interventions are required, including expansion of the DLH and access to antifungal drugs, especially liposomal amphotericin B and flucytosine.
TREATMENT OF INTERNAL CAROTID ANEURYSMS USING PIPELINE EMBOLIZATION DEVICES: MEASURING THE RADIATION DOSE OF THE PATIENT AND DETERMINING THE FACTORS AFFECTING IT
Authors: Kawauchi Satoru , Chida Koichi , Moritake Takashi , Hamada Yusuke , Matsumaru Yuji , Tsuruta Wataro , Sato Masayuki , Hosoo Hisayuki , Sun Lue
Published: December 2019

The purpose of this study was to measure the peak skin dose (PSD) and bilateral lens doses using radiophotoluminescence glass dosimeters and to determine the factors influencing the radiation dose in cases of cerebral aneurysm treated with pipeline embolization devices (PEDs). The cumulative dose, PSD and right and left lens doses were 3818.1 ± 1604.6, 1880.0 ± 723.0, 124.8 ± 49.2 and 180.7 ± 124.8 mGy, respectively. Using multivariate analysis, body mass index (p < 0.01; odds ratio (OR) = 1.806; 95% confidence interval (CI) = 1.007–3.238) and deployment time of PED (p < 0.05; OR = 1.107; 95% CI = 1.001–1.224) were found to be the independent predictors of PSD exceeding 2 Gy. Measures such as collimation of the radiation field and optimization of radiation dose should be taken to reduce the radiation to the patient.
High frequency of Exon 20 S768I EGFR mutation detected in malignant pleural effusions: a poor prognosticator of NSCLC?
Authors: D’Souza George , Dhar Chirag , Kyalanoor Vishal , Yadav Lokendra , Sharmra Mugdha , Nawaz S Mohammad , Srivastava Sweta
Published: December 2019

Lung cancer is the cause of a fourth of all cancer-related deaths. About a third of all lung adenocarcinoma tumours harbour mutations on exons 18, 19, 20 and 21 of the epidermal growth factor receptor (EGFR) gene. Detection of these mutations allows for targeted therapies in the form of EGFR Tyrosine kinase inhibitors. In our study, we utilized malignant pleural effusions (MPEs) as “liquid biopsies” to detect EGFR mutations when tissue biopsies were unavailable. We showed that a direct sequencing approach was likely to miss SNVs in MPEs. We then optimized an EGFR mutant-specific quantitative polymerase chain reaction-based assay and piloted it on n=10 pleural effusion samples (1 non-malignant pleural effusion as a negative control). 5/9 (55.55%) samples harboured EGFR mutations with 2/9 (22.22%) being exon 19 deletions and 3/9 (33.33%) had the S768I exon 20 mutation. The frequency of the S768I SNV in our study was significantly higher than that observed in other studies (∼0.3%). Utilizing publicly available cBioPortal data, we report that patients with the S768I SNV had a shorter median survival time, progression-free survival time and lower tumor mutation count compared to patients with other EGFR mutations. These data suggest that this point mutation predicts poor prognosis as a result of aggressive disease, though studies in larger cohorts are necessary to confirm these findings. The high frequency of S768I mutations seen in our study also suggests that cancer cells harbouring these mutations may be superior in their ability to migrate, home or reside in pleural fluid.
Whole exome-trio analysis reveals rare variants associated with Congenital Pouch Colon
Authors: Gupta Sonal , Mathur Praveen , Mishra Ashwani Kumar , Medicherla Krishna Mohan , Suravajhala Prashanth
Published: December 2019

Anorectal malformations (ARM) are individually common but Congenital Pouch Colon (CPC), a rare anorectal anomaly causes a dilated pouch in genitourinary tract. We have earlier attempted to understand the clinical genetic makeup of CPC and identified genes responsible for the disease using whole exome sequencing (WES). Here we report our studies of CPC, by identifying de novo heterozygous missense mutations in 16 proband-parent trios and further discover variants of unknown significance which could provide insights into CPC manifestation and its etiology. Our study confirms candidate mutations in genes, viz. C7orf57, C10orf120, C9orf84 and MUC16, CTC1 particularly emphasizing the role of hypothetical genes or open reading frames causing this developmental disorder. Variant validation revealed disease causing mutations associated with CPC and genitourinary diseases which could close the gaps of surgery in bringing intervention in therapies.
Using the Bayesian credible subgroups method to identify populations benefiting from treatment: An application to the Look AHEAD trial
Authors: Coonan Anna , Forbes John , Schnell Patrick , Smith Joel
Published: December 2019

Traditionally, subgroup analyses are used to assess whether patient characteristics moderate treatment effectiveness with general disregard for issues of multiplicity. Using data from The Action for Health in Diabetes (Look AHEAD) trial in the United States, we aim to identify a subgroup where all of its types of members experience a treatment benefit defined as reducing the likelihood of a major cardiovascular event under an intensive lifestyle and weight-loss intervention. We apply the credible subgroups method to a Bayesian logistic model with a conservative prior that is sceptical of large treatment effect heterogeneity. The covariate profiles for which there is sufficient evidence of treatment benefit are, coarsely, middle-aged women, in poor subjective general health and with moderately to poorly controlled diabetes. There is at least 80% posterior probability that the conditional average treatment effect is positive for all covariate profiles fitting this description, which account for 0.5% of trial participants. Conversely, the covariate profiles that are likely to be associated with no benefit are middle aged and older men in excellent subjective general health, with well-controlled diabetes. These profiles apply to less than 2% of trial participants. More information is required to determine treatment benefit or no benefit for the remainder of the trial population.
Assessment and Utilization of Patient-Reported Outcomes Measures to Improve Cardiovascular Disease Prevention
Authors: Finneran Phoebe A , Sanborn Tinamarie , Guo Xiao , Traynor Kate C , Jaff Michael R. , Natarajan Pradeep
Published: December 2019

Background

The American Heart Association’s Life’s Simple 7 (LS7) consist of clinical factors and health-related behaviors associated with cardiovascular health. The prevalence of these health factors among patients seeking specialized cardiovascular care is unknown. We sought to quantify patient-reported cardiovascular risk among those seeking specialized cardiovascular care and implement tailored quality improvement interventions.

Methods and Results

Patients cared for by cardiovascular specialists at an academic medical center were surveyed with a modified LS7. We compared the prevalence of optimal health factors by atherosclerotic cardiovascular disease (ASCVD) status. Recent smokers or patients with ASCVD reporting non-adherence to antiplatelets/statins were contacted.

Surveys for 5,950 patients were collected during 2014 to 2016. The mean (SD) age was 64 (15) years, 2613 (44%) were women, and 3478 (58%) had ASCVD. Only 34 (0.6 %) achieved ideal status for all 7 factors, which did not differ by ASCVD status (P=0.48). Of 404 (6.8%) reporting recent smoking, 94/404 (23.3%) were successfully contacted, and 71/404 (17.6%) accepted support. Among those with ASCVD, 84 (2.4%) reported not taking a statin or antiplatelet without contraindications.

Conclusions

The prevalence of optimal health factors, including health-related behaviors, among patients cared for by cardiovascular specialists remains low. Assessment of patient-reported outcomes facilitates scalable interventions to improve cardiovascular disease prevention.
Localization of the signal of dystonia-associated protein torsinA near the Golgi apparatus in cultured central neurons
Authors: Iwabuchi Sadahiro , Kawano Hiroyuki , Harata N. Charles
Published: December 2019

A single in-frame deletion of a codon for a glutamic acid residue within theTOR1Agene is linked to the autosomal-dominant movement disorder DYT1 dystonia, a condition characterized by involuntary muscle contractions that cause abnormal posture. This gene encodes the protein torsinA, and the functions of both wild-type and mutant (ΔE-torsinA) forms remain poorly understood. Previous studies based on overexpression systems indicated that wild-type torsinA resides mainly in the endoplasmic reticulum but that ΔE-torsinA is localized to the nuclear envelope or intracellular inclusions. This mutation-associated mis-localization has been proposed to underlie at least a part of the pathophysiology of DYT1 dystonia. However, the subcellular localization of torsinA has not been extensively studied when expressed at the endogenous level. Here we report an immunocytochemical analysis of torsinA proteins in cultured mouse neurons from a ΔE-torsinA knock-in model of DYT1 dystonia, where torsinA proteins are not upregulated. In all examined neurons of wild-type, heterozygous and homozygous mice, torsinA signal was found mainly near the Golgi apparatus, and only weakly in the endoplasmic reticulum and nuclear envelope. These results suggest that, in the absence of overexpression, torsinA proteins are localized near the Golgi apparatus and may influence cellular function involving the organelle.
Retrospective Assessment of Deep Neural Networks for Skin Tumor Diagnosis
Authors: Han Seung Seog , Moon Ik Jun , Na Jung-Im , Kim Myoung Shin , Park Gyeong Hun , Kim Seong Hwan , Kim Kiwon , Lee Ju Hee , Chang Sung Eun
Published: December 2019

BACKGROUND

The aim of this study was to validate the performance of algorithm (http://rcnn.modelderm.com) for the diagnosis of benign and malignant skin tumors.

METHODS

With external validation dataset (43 disorders; 40,331 clinical images from 10,426 patients; January 1, 2008 – March 31, 2019), we compared the prediction of algorithm with the clinical diagnosis of 65 attending physicians at the time of biopsy request.

RESULTS

For binary-task classification of determining malignancy, the AUC of the algorithm was 0.863(95% CI 0.852-0.875) with unprocessed clinical photographs. The sensitivity/specificity of the algorithm at the predefined high-sensitivity and high-specificity threshold were 79.1%(76.9-81.4)/76.9%(76.1-77.8) and 62.7%(59.9- 65.5)/90.0%(89.4-90.6), respectively. The sensitivity/specificity calculated by the clinical diagnosis of attending physicians were 88.1%/83.8%(Top-3) and 70.2%/95.6%(Top-1), which were superior to those of algorithm.

For multi-task classification, the mean Top-1,2,3 accuracies of the algorithm were 42.6±20.7%, 56.1±22.8%, 61.9±22.9%, and those of clinical diagnosis were 65.4±17.7%, 73.9±16.6%, 74.7±16.6%, respectively.

In the reader test with images from 30-patients batches, the sensitivity / specificity of the algorithm at the predefined threshold were 66.9%±30.2% / 87.4%±16.5%. The sensitivity / specificity derived from the first diagnosis of 44 the participants were 65.8%±33.3% / 85.7%±11.0%, which were comparable with those of the algorithm (Wilcoxon signed-rank test; P=0.61 / 0.097).

CONCLUSIONS

Our algorithm could diagnose skin tumors at dermatologist-level when diagnosis was made solely with photographs, demonstrating its potential as a mass screening tool in telemedicine setting. However, due to limited data relevancy, the performance was inferior to that of actual medical examination. Clinical information should be integrated with imaging information to achieve more accurate predictions.
Temporal trends in public mass shootings: high-capacity magazines significantly increase fatality counts, and are becoming more prevalent
Authors: Towers Sherry , Wallace Danielle , Hemenway David
Published: December 2019

Background

There has been disagreement in the literature regarding whether public mass shootings are becoming more frequent, or more deadly, and whether high-capacity magazine (HCM) weaponry is associated with increased fatalities.

Objective

We examined the 85 non-felony- and non-gang-related mass shootings with at least four people shot and killed that occurred in public places between 1995 to 2018 to examine the frequency and deadliness of public mass shootings, as well as the role of HCM weaponry in fatalities.

Findings

The per-capita rate of public mass shootings with at least four people killed has not significantly increased since 1995 (Negative Binomial linear regression p=0.20), but public mass shootings with at least six people killed have been increasing by 6.9% per year (p=0.01). Public mass shootings are becoming significantly more deadly, with fatalities per incident increasing by 4.5% per year (truncated Negative Binomial log-linear regression p<0.001).

Use of HCM weaponry banned during the 1994 to 2004 Federal Assault Weapons Ban (FAWB) increased fatality counts on average by 1.9 times, and total number shot by 3.3 times (non-parametric bootstrap comparison of means (NPBCM), p < 0.001 in both cases). In these incidents, HCM pistols were as deadly as assault rifles. The fraction of firearms involving HCMs used by perpetrators more than doubled after the lapse of the federal ban, from 25% during the ban to 59% after (Binomial factor regression, p<0.001).

Our online visual analytics application, https://mass-shooting-analytics.shinyapps.io/mass_shootings/, allows interested parties to examine and download our data, replicate our analysis results and explore the analysis with alternate selections.

Policy recommendations

A re-instatement of the federal ban on high-capacity magazines in pistols and rifles, or special taxes on such weaponry, may reduce public mass shooting fatalities.
Integrated Bioinformatic Approach to Identify Potential Biomarkers against Idiopathic Pulmonary Fibrosis
Authors: Ullah Md. Asad , Sarkar Bishajit , Araf Yusha , Islam Prottoy Md. Nazmul , Saha Ananna , Jahan Tanjila , Boby Aisha Siddiqua , Islam Md. Shariful
Published: December 2019

Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive lung disease that leads to gradual decline in lung function. The molecular mechanism and risk factors of this disease are still obscure. Poorly understood etiology of this disease is the major obstacle in the identification of potential biomarkers and drug targets. In this study, microarray gene expression data of normal and IPF patient has been utilized for the statistical analysis of differentially expressed genes (DEGs) with a view to identifying potential molecular signatures using network-based system. Then their functional enrichment analysis revealed their predominant involvement in transcription, protein acetylation, extracellular matrix organization, apoptic process, inflammatory response etc. Protein-Protein Interaction (PPI) network revealed (UBC, PTEN, SOS1, PTK2, FGFR1, YAP1, FOXO1, RACK1, BMP4 and CD44) as hub proteins in IPF. Subsequent regulatory network analysis suggested (E2F1, STAT3, PPARG, MEF2A, FOXC1, GATA3, YY1, GATA2, NFKB1, and FOXL1) as the best regulatory transcriptional signatures and (hsa-mir-155-5p, hsa-mir-16-5p, hsa-mir-17-5p, hsa-mir-19a-3p, hsa-mir-192-5p, hsa-mir-92a-3p, hsa-mir-26b-5p, hsa-mir-335-5p, hsa-mir-124-3p, and hsa-let-7b-5p) as the best post-transcriptional signatures. This study represents proteome and RNA signatures of IPF which might be useful to uphold the present efforts in the discovery of potential biomarkers and treatments of this disease.
Screening of Diabetes and Hypertension Based on Retinal Fundus Photographs Using Deep Learning
Authors: Dai Guangzheng , Zhang Chenguang , He Wei
Published: December 2019

Purpose

The aim of this study was to use deep learning to screen for hypertension and diabetes based on retinal fundus images.

Methods

We collected 1160 retinal photographs which included 580 from patients with a diagnosis of hypertension or diabetes and 580 from normotensive and non-diabetic control. We divided this image dataset into (i) a development dataset to develop model and (ii) test dataset which were not present during the training process to assess model’s performance. A binary classification model was trained by fine-tuning the classifier and the last convolution layer of deep residual network. Precision, recall, the area under the ROC (AUC), and the area under the Precision-Recall curve (AUPR) were used to evaluate the performance of the learned model.

Results

When we used 3-channel color retinal photographs to train and test model, its prediction precision for diabetes or hypertension was 65.3%, the recall was 82.5%, the AUC was 0.745, and the AUPR was 0.742. When we used grayscale retinal photographs to train and test model, its prediction precision was 70.0%, the recall was 87.5%, the AUC was 0.803, and the AUPR was 0.779.

Conclusions

Our study shows that trained deep learning model based on the retinal fundus photographs alone can be used to screen for diabetes and hypertension, although its current performance was not ideal.
Type 2 diabetes risks and determinants in 2nd generation migrants and mixed ethnicity people of South Asian and African Caribbean descent in the UK
Authors: Farmaki Aliki-Eleni , Garfield Victoria , Eastwood Sophie V. , Farmer Ruth E. , Mathur Rohini , Patalay Praveetha , Sattar Naveed , Hughes Alun , Bhaskaran Krishnan , Smeeth Liam , Chaturvedi Nish
Published: December 2019

Background

Type 2 diabetes mellitus (T2DM) risk is markedly higher in UK South Asians (SA) and African Caribbeans (AC) compared to Europeans. Explanations for this excess are unclear. We therefore compared risks and determinants of T2DM in first- and second-generation (born in the UK) migrants, and in those of mixed ethnicity populations.

Methods

Data from the UK Biobank, a large population-based cohort of volunteers aged 40-69, were used. T2DM was assigned using self-report and glycated haemoglobin. Ethnicity was self-assigned. Using logistic regression and mediation analysis, we compared T2DM between first- and second-generation migrants, and between mixed European/South Asians (MixESA), or mixed European/African Caribbeans (MixEAC) with both Europeans and SA or AC respectively.

Results

T2DM prevalence was three to five times higher in SA and AC compared with Europeans [OR (95%CI): 4·80(3·60,6·40) and 3·30(2·70,4·10) respectively]. T2DM was 20-30% lower in second versus first generation SA and AC migrants [0·78(0·60,1·01) and 0·71(0·57,0·87) respectively]. T2DM in mixed populations was lower than comparator ethnic minority groups [MixESA versus SA 0·29(0·21,0·39), MixEAC versus AC 0·48(0·37,0·62)] and higher than Europeans, in MixESA 1·55(1·11, 2·17), and in MixEAC 2·06 (1·53, 2·78). Improved adiposity patterns in second generation migrants made an important contribution to risk reduction. Greater socioeconomic deprivation accounted for 17% and 42% of the excess risk of T2DM in MixESA and MixEAC compared to Europeans, respectively.

Conclusion

Excess T2DM risks in South Asians and African Caribbeans compared with Europeans in the UK are attenuated by ∼20% in second-generation migrants, demonstrating the marked benefits of favourable changes in environmental risk factors. T2DM prevalence in people of mixed ethnicity was also raised compared with Europeans, but considerably less than in the ethnic minority group; persistent socioeconomic disadvantage accounted for some of the residual excess.
Survey of Public Assay Data: Opportunities and Challenges to Understanding Antimicrobial Resistance
Authors: Agarwal Akshay , Nayar Gowri , Kaufman James
Published: December 2019

Computational learning methods allow researchers to make predictions, draw inferences, and automate generation of mathematical models. These models are crucial to solving real world problems, such as antimicrobial resistance, pathogen detection, and protein evolution. Machine learning methods depend upon ground truth data to achieve specificity and sensitivity. Since the data is limited in this case, as we will show during the course of this paper, and as the size of available data increases super-linearly, it is of paramount importance to understand the distribution of ground truth data and the analyses it is suited and where it may have limitations that bias downstream learning methods. In this paper, we focus on training data required to model antimicrobial resistance (AR). We report an analysis of bacterial biochemical assay data associated with whole genome sequencing (WGS) from the National Center for Biotechnology Information (NCBI), and discuss important implications when making use of assay data, utilizing genetic features as training data for machine learning models. Complete discussion of machine learning model implementation is outside the scope of this paper and the subject to a later publication.

The antimicrobial assay data was obtained from NCBI BioSample, which contains descriptive information about the physical biological specimen from which experimental data is obtained and the results of those experiments themselves.[1] Assay data includes minimum inhibitory concentrations (MIC) of antibiotics, links to associated microbial WGS data, and treatment of a particular microorganism with antibiotics.

We observe that there is minimal microbial data available for many antibiotics and for targeted taxonomic groups. The antibiotics with the highest number of assays have less than 1500 measurements each. Corresponding bias in available assays makes machine learning problematic for some important microbes and for building more advanced models that can work across microbial genera. In this study we focus, therefore, on the antibiotic with most assay data (tetracycline) and the corresponding genus with the most available sequence (Acinetobacterwith 14000 measurements across 49 antibiotic compounds). Using this data for training and testing, we observed contradictions in the distribution of assay outcomes and report methods to identify and resolve such conflicts. Per antibiotic, we find that there can be up to 30% of (resolvable) conflicting measurements. As more data becomes available, automated training data curation will be an important part of creating useful machine learning models to predict antibiotic resistance.

CCS CONCEPTS

• Applied computing → Computational biology; Computational genomics; Bioinformatics;
The urinary microbiota composition remains stable over time and under various storage conditions
Authors: Bundgaard-Nielsen Caspar , Ammitzbøll Nadia , Isse Yusuf Abdi , Muqtar Abdisalam , Jensen Ann-Maria , Leutscher Peter , Arenholt Louise Thomsen Schmidt , Hagstrøm Søren , Sørensen Suzette
Published: December 2019

Background

New sensitive techniques have revealed a large population of bacteria in the human urinary tract, challenging the perception of the urine of healthy humans being sterile. While the role of this urinary microbiota is unknown, dysbiosis has been linked to disorders like urgency urinary incontinence and interstitial cystitis. When comparing studies it is crucial to account for possible confounders introduced due to methodological differences. Here we investigated whether storage condition or time of collection, had any impact on the urinary microbial composition.

Results

For comparison of different storage conditions, urine was collected from five healthy adult female donors, and analyzed by 16S rRNA gene sequencing. Using the same methods, the daily or day-to-day variation in urinary microbiota was investigated in nineteen healthy donors, including four women, five men, five girls, and five boys. With the exception of two male adult donors, none of the tested conditions gave rise to significant differences in alpha and beta diversities between individuals.Conclusion: The composition of the urinary microbiota was found to be highly resilient to changes introduced by storage temperature and duration. In addition, we did not observe any intrapersonal daily or day-to-day variations in microbiota composition in women, girls or boys.

Together our study supports flexibility in study design, when conducting urinary microbiota studies.

Author summary

The discovery of bacteria native to the urinary tract in healthy people, a location previously believed to be sterile, has prompted research into the clinical potential of these bacteria. However, methodological weaknesses can significantly influence such studies, and thus development of robust techniques for investigating these bacteria are needed. In the present study, we investigated whether differences in storage following collection, could affect the bacterial composition of urine samples. Next, we investigated if this composition exhibited daily or day-to-day variations.

Firstly, we found, that the bacterial composition of urine could be maintained by storage at −80 °C, −20 °C, or refrigerated at 4 °C. Secondly, the bacterial composition of urine remained stable over time. Overall, the results of this study provide information important to study design in future investigations into the clinical implications of urinary bacteria.
Estimating densities of larval Salmonflies (Pteronarcys californica) through multiple pass removal of post-emergent exuvia in Colorado rivers
Authors: Heinold Brian D. , Kowalski Dan A. , Nehring R. Barry
Published: December 2019

Traditional methods of collecting and sorting benthic macroinvertebrate samples are useful for stream biomonitoring and ecological studies; however, these methods are time consuming, expensive, and require taxonomic expertise. Estimating larval densities through collection of post-emergent exuvia can be a practical and time efficient alternative. We evaluated the use of multiple pass depletion techniques of the post-emergent exuvia ofPteronarcys californicato estimate larval densities at ten sites in three Colorado rivers. Exuvia density was highly correlated with both final-instar larval density (R2= 0.90) and total larval density (R2= 0.88) and the multiple pass removal technique performed well. Exuvia surveys foundP. californicaat three low density sites where benthic sampling failed to detect it. At moderate and high density sites the exuvia surveys always produced lower density estimates than benthic surveys. Multiple pass depletion estimates of exuvia proved to be an accurate and efficient technique at estimating larval densities and provided an effective alternative for traditional benthic sampling when objectives are monitoringP. californicaand detecting populations, especially at low density sites.
RosettaGPCR: Multiple Template Homology Modeling of GPCRs with Rosetta
Authors: Bender Brian Joseph , Marlow Brennica , Meiler Jens
Published: December 2019

G-protein coupled receptors (GPCRs) represent a significant target class for pharmaceutical therapies. However, to date, only about 10% of druggable GPCRs have had their structures characterized at atomic resolution. Further, because of the flexibility of GPCRs, alternative conformations remain to be modeled, even after an experimental structure is available. Thus, computational modeling of GPCRs is a crucial component for understanding biological function and to aid development of new therapeutics. Previous single- and multi-template homology modeling protocols in Rosetta often generated non-native-like conformations of transmembrane α-helices and/or extracellular loops. Here we present a new Rosetta protocol for modeling GPCRs that is improved in two critical ways: Firstly, it uses a blended sequence- and structure-based alignment that now accounts for structure conservation in extracellular loops. Secondly, by merging multiple template structures into one comparative model, the best possible template for every region of a target GPCR can be used expanding the conformational space sampled in a meaningful way. This new method allows for accurate modeling of receptors using templates as low as 20% sequence identity, which accounts for nearly the entire druggable space of GPCRs. A model database of all non-odorant GPCRs is made available atwww.rosettagpcr.org.

Author Summary

Structure-based drug discovery is among the new technologies driving the development of next generation therapeutics. Inherent to this process is the availability of a protein structure for virtual screening. The most heavily drugged protein family, G-protein coupled receptors (GPCRs), however suffers from a lack of experimental structures that could hinder drug development. Technical challenges prevent the determination of every protein structure, so we turn to computational modeling to predict the structures of the remaining proteins. Again, traditional techniques fail due to the high divergence of this family. Here, we build on available methods specifically for the challenge of modeling GPCRs. This new method outperforms other methods and allows for the ability to accurately model nearly 90% of the entire GPCR family. We therefore generate a model database of all GPCRs (www.rosettagpcr.org) for use in future drug development.
Visualization of two architectures in class-II CAP-dependent transcription activation
Authors: Shi Wei , Jiang Yanan , Deng Yibin , Dong Zigang , Liu Bin
Published: December 2019

Transcription activation by cyclic AMP receptor protein (CAP) is the classic paradigm of transcription regulation in bacteria. CAP was suggested to activate transcription on class-II promoters via a recruitment and isomerization mechanism. However, whether and how it modifies RNA polymerase (RNAP) to initiate transcription remains unclear. Here we report cryo-EM structures of an intactE. coliclass-II CAP-dependent transcription activation complex (TAC) with and withoutde novoRNA transcript. The structures reveal two distinct architectures of TAC and show that CAP-binding induces substantial conformational changes in all the subunits of RNAP and consequently widens the main cleft of RNAP considerably to facilitate DNA promoter entering and formation of initiation open complex. These structural changes vanish during further RNA transcript synthesis. The observations in this study suggest a unique activation mechanism on class-II promoters that CAP activates transcription by first remodeling RNAP conformation and then stabilizing initiation complex.
Intellectual disability-associated factor Zbtb11 cooperates with NRF-2/GABP to control mitochondrial function
Authors: Wilson Brooke C. , Boehme Lena , Annibali Ambra , Hodgkinson Alan , Carroll Thomas S. , Oakey Rebecca J. , Seitan Vlad C.
Published: December 2019

Zbtb11 is a conserved transcription factor mutated in families with hereditary intellectual disability. Its precise molecular and cellular functions are currently unknown, precluding our understanding of the aetiology of this disease. Using a combination of functional genomics, genetic and biochemical approaches here we show that Zbtb11 plays essential roles in maintaining the homeostasis of mitochondrial function. Mechanistically, we find Zbtb11 facilitates the recruitment of Nuclear Respiratory Factor 2 (NRF-2) to its target promoters, activating a subset of nuclear genes with roles in the biogenesis of respiratory complex I and the mitoribosome. Genetic inactivation ofZbtb11resulted in a severe complex I assembly defect, impaired mitochondrial respiration, mitochondrial depolarisation, and ultimately proliferation arrest and cell death. Experimental modelling of the pathogenic human mutations showed these have a destabilising effect on the protein, resulting in reduced Zbtb11 dosage, down-regulation of its target genes, and impaired complex I biogenesis. Our study establishes Zbtb11 as a novel essential mitochondrial regulator, improves our understanding of the transcriptional mechanisms of nuclear control over mitochondria, and provides a rationale for the aetiology of Zbtb11-associated intellectual disability.
TGFβ superfamily signaling regulates the state of human stem cell pluripotency and competency to create telencephalic organoids
Authors: Watanabe Momoko , Haney Jillian R. , Vishlaghi Neda , Turcios Felix , Buth Jessie E. , Gu Wen , Collier Amanda J. , Miranda Osvaldo A. , Chen Di , Sabri Shan , Clark Amander T. , Plath Kathrin , Christofk Heather R. , Gandal Michael J. , Novitch Bennett G.
Published: December 2019

Telencephalic organoids generated from human pluripotent stem cells (hPSCs) are emerging as an effective system to study the distinct features of the developing human brain and the underlying causes of many neurological disorders. While progress in organoid technology has been steadily advancing, many challenges remain including rampant batch-to-batch and cell line-to-cell line variability and irreproducibility. Here, we demonstrate that a major contributor to successful cortical organoid production is the manner in which hPSCs are maintained prior to differentiation. Optimal results were achieved using fibroblast-feeder-supported hPSCs compared to feeder-independent cells, related to differences in their transcriptomic states. Feeder-supported hPSCs display elevated activation of diverse TGFβ superfamily signaling pathways and increased expression of genes associated with naïve pluripotency. We further identify combinations of TGFβ-related growth factors that are necessary and together sufficient to impart broad telencephalic organoid competency to feeder-free hPSCs and enable reproducible formation of brain structures suitable for disease modeling.

HIGHLIGHTS

hPSC maintenance conditions influence outcomes in cortical organoid formation

Identification of an intermediate pluripotency state optimal for cortical organoids

Feeder support involves activation of diverse TGFβ signaling pathways

The organoid-promoting effects of feeders can be mimicked by a TGFβ factor mixture
Broccoli: combining phylogenetic and network analyses for orthology assignment
Authors: Derelle Romain , Philippe Hervé , Colbourne John K.
Published: December 2019

Orthology assignment is a key step of comparative genomic studies, for which many bioinformatic tools have been developed. However, all gene clustering pipelines are based on the analysis of protein distances, which are subject to many artefacts. In this paper we introduce Broccoli, a user-friendly pipeline designed to infer, with high precision, orthologous groups and pairs of proteins using a phylogeny-based approach. Briefly, Broccoli performs ultra-fast phylogenetic analyses on most proteins and builds a network of orthologous relationships. Orthologous groups are then identified from the network using a parameter-free machine learning algorithm. Broccoli is also able to detect chimeric proteins resulting from gene-fusion events and to assign these proteins to the corresponding orthologous groups. Tested on two benchmark datasets, Broccoli outperforms current orthology pipelines. In addition, Broccoli is scalable, with runtimes similar to those of recent distance-based pipelines. Given its high level of performance and efficiency, this new pipeline represents a suitable choice for comparative genomic studies.

Broccoli is freely available athttps://github.com/rderelle/Broccoli.
Pull-Push Neuromodulation of Cortical Plasticity Enables Rapid Bi-Directional Shifts in Ocular Dominance
Authors: Hong Su Z. , Huang Shiyong , Severin Daniel , Kirkwood Alfredo
Published: December 2019

Neuromodulatory systems are essential for remodeling glutamatergic connectivity during experience-dependent cortical plasticity. This permissive/enabling function of neuromodulators has been associated with their capacity to facilitate the induction of Hebbian forms of long-term potentiation (LTP) and depression (LTD) by affecting cellular and network excitability.In vitrostudies indicate that neuromodulators can also affect the expression of Hebbian plasticity in a pull-push manner: receptors coupled to the G-protein Gs promote the expression of LTP at the expense of LTD, and Gq-coupled receptors promote LTD at the expense of LTD. Here we show that the pull-push mechanism can be recruitedin vivoby pairing brief monocular stimulation with pharmacological or chemogenetical activation of Gs- or Gq-coupled receptors to respectively enhance or reduce visual cortical responses. These changes were stable, can be induced in adults after the termination of the critical period for juvenile ocular dominance plasticity, and can rescue deficits induced by prolonged monocular deprivation.
Multiomic and quantitative label-free microscopy-based analysis ofex vivoculture and TGFbeta1 stimulation of human precision-cut lung slices
Authors: Khan Muzamil Majid , Poeckel Daniel , Halavatyi Aliaksandr , Stein Frank , Vappiani Johanna , Sevin Daniel C. , Tischer Christian , Zinn Nico , Eley Jess D , Gudmann Natasja Stæhr , Muley Thomas , Winter Hauke , Fisher Andrew J , Nanthakumar Carmel B. , Bergamini Giovanna , Pepperkok Rainer
Published: December 2019

Fibrosis can affect any organ resulting in the loss of tissue architecture and function with often life-threatening consequences. Pathologically, fibrosis is characterised by expansion of connective tissue due to excessive deposition of extracellular matrix proteins (ECM), including the fibrillar forms of collagen. A significant hurdle for discovering cures for fibrosis is the lack of suitable models and techniques to quantify mature collagen deposition in tissues. Here we have extensively characterized an ex-vivo cultured human lung derived, precision-cut lung slices model (hPCLS) using live fluorescence light microscopy as well as mass spectrometry-based techniques to obtain a proteomic and metabolomic fingerprint. Using an integrated approach of multiple readouts such as quantitative label-free Second Harmonic Generation (SHG) imaging to measure fibrillar collagen in the extracellular matrix and ELISA-based methods to measure soluble ECM biomarkers, we investigated TGFbeta1-mediated pro-fibrotic signalling in hPCLS. We demonstrate that hPCLS are viable and metabolically active with mesenchymal, epithelial, endothelial, and immune cells surviving for at least two weeks in ex vivo culture. Analysis of hPCLS-conditioned supernatants showed strong induction of ECM synthesis proteins P1NP and fibronectin upon TGFb stimulation. Importantly, this effect translated into an increased deposition of fibrillar collagen in ECM of cultured hPCLS as measured by a novel quantitative SHG-based imaging method only following addition of a metalloproteinase inhibitor (GM6001). Together the data show that an integrated approach of measuring soluble pro-fibrotic markers and quantitative SHG-based analysis of fibrillar collagen is a valuable tool for studying pro-fibrotic signalling and testing anti-fibrotic agents.
Molecular basis of CTCF binding polarity in genome folding
Authors: Nora Elphège P. , Caccianini Laura , Fudenberg Geoffrey , Kameswaran Vasumathi , Nagle Abigail , Uebersohn Alec , So Kevin , Hajj Bassam , Le Saux Agnès , Coulon Antoine , Mirny Leonid A. , Pollard Katherine S. , Dahan Maxime , Bruneau Benoit G.
Published: December 2019

Current models propose that boundaries of mammalian topologically associating domains (TADs) arise from the ability of the CTCF protein to stop extrusion of chromatin loops by cohesin proteins (Merkenschlager & Nora, 2016; Fudenberg, Abdennur, Imakaev, Goloborodko, & Mirny, 2017). While the orientation of CTCF motifs determines which pairs of CTCF sites preferentially stabilize DNA loops (de Wit et al., 2015; Guo et al., 2015; Rao et al., 2014; Vietri Rudan et al., 2015), the molecular basis of this polarity remains mysterious. Here we report that CTCF positions cohesin but does not control its overall binding or dynamics on chromatin by single molecule live imaging. Using an inducible complementation system, we found that CTCF mutants lacking the N-terminus cannot insulate TADs properly, despite normal binding. Cohesin remained at CTCF sites in this mutant, albeit with reduced enrichment. Given that the orientation of the CTCF motif presents the CTCF N-terminus towards cohesin as it translocates from the interior of TADs, these observations provide a molecular explanation for how the polarity of CTCF binding sites determines the genomic distribution of chromatin loops.
Therapy without a prescription: buprenorphine/naloxone diversion and the therapeutic assemblage in Taiwan
Authors: Chen Jia‐shin
Published: December 2019

Buprenorphine/naloxone (B/N) therapy is a prescription pharmacotherapy for opioid dependence. For certain health service providers, when B/N escapes supervision and diverts into the hands of people for whom it is unintended, it can pose serious risks even if it may still have therapeutic benefits. The line between therapy and diversion is thus a problematic one. By qualitatively analysing archival review and in‐depth interviews, this study uses the concept of a therapeutic assemblage to understand the relationships among government, knowledge, and professionals that surround the regulation of B/N in Taiwan. The therapeutic assemblage is characterised by the partitioning of administration, the loose regulation of prescription, the exclusion of addiction treatment from National Health Insurance (NHI), and the materiality and technicality of therapies. These elements contribute to the therapeutic assemblage's different territorial modes as reflected in the substance schedules that allow for diversion. This is the first grounded work in Asia that empirically examines and theoretically explains the diversion of B/N from an assemblage perspective. It suggests establishing new associations by incorporating addiction treatment into NHI. Lastly, it addresses the analytic purchase of the assemblage approach in unveiling and problematising unintended outcomes of an intervention.