bluuebunny/crossref_metadata_2025 huggingface dataset:
Current trends in the clinical trial landscape for amyotrophic lateral sclerosis
Authors: van Eijk Ruben P.A. , Kliest Tessa , van den Berg Leonard H.
Published: August 2020

Purpose of review

To review the current developments in the design and conduct of clinical trials for amyotrophic lateral sclerosis (ALS), illustrated by a critical appraisal of ClinicalTrials.gov.

Recent findings

In total, 63 clinical trials were included in the analysis, of which 13 phase 1, 35 phase 2 and 15 phase 3. Virtually all phase 3 clinical trials can be classified as randomized, placebo controlled, whereas this is only true for 57% of the phase 2 clinical trials. There are promising developments in the routes of drug administration, eligibility criteria, efficacy endpoints and overall trial design. Some of these innovative approaches may, however, not fulfil clinical trial guidelines or regulatory requirements. This could delay the development of effective therapy or hamper our ability to determine whether a treatment is truly (in)effective. The initiation of trial consortia comprising patient organizations, academia, industry and funding bodies may significantly strengthen the future clinical trial landscape for ALS.

The ALS clinical trial landscape is currently highly active with several promising innovative developments and therapeutic options. By further refinement of evidence-based guidelines, and alignment of our current endeavours, we may soon be able to positively impact the lives of people living with ALS.
Total cost of carbon capture and storage implemented at a regional scale: northeastern and midwestern United States
Authors: Schmelz William J. , Hochman Gal , Miller Kenneth G.
Published: August 2020

We model the costs of carbon capture and storage (CCS) in subsurface geological formations for emissions from 138 northeastern and midwestern electricity-generating power plants. The analysis suggests coal-sourced CO
2
emissions can be stored in this region at a cost of $52–$60 ton
−1
, whereas the cost to store emission from natural-gas-fired plants ranges from approximately $80 to $90. Storing emissions offshore increases the lowest total costs of CCS to over $60 per ton of CO
2
for coal. Because there apparently is sufficient onshore storage in the northeastern and midwestern United States, offshore storage is not necessary or economical unless there are additional costs or suitability issues associated with the onshore reservoirs. For example, if formation pressures are prohibitive in a large-scale deployment of onshore CCS, or if there is opposition to onshore storage, offshore storage space could probably store emissions at an additional cost of less than $10 ton
−1
. Finally, it is likely that more than 8 Gt of total CO
2
emissions from this region can be stored for less $60 ton
−1
, slightly more than the $50 ton
−1
Section 45Q tax credits incentivizing CCS.
Forest policy and management approaches for carbon dioxide removal
Authors: vonHedemann Nicolena , Wurtzebach Zachary , Timberlake Thomas J. , Sinkular Emily , Schultz Courtney A.
Published: August 2020

Forests increasingly will be used for carbon dioxide removal (CDR) as a natural climate solution, and the implementation of forest-based CDR presents a complex public policy challenge. In this paper, our goal is to review a range of policy tools in place to support use of forests for CDR and demonstrate how concepts from the policy design literature can inform our understanding of this domain. We explore how the utilization of different policy tools shapes our ability to use forests to mitigate and adapt to climate change and consider the challenges of policy mixes and integration, taking a close look at three areas of international forest policy, including the Kyoto Protocol's Clean Development Mechanism, Reducing Emissions from Deforestation and Forest Degradation (REDD+) and voluntary carbon offset markets. As it is our expertise, we then examine in detail the case of the USA as a country that lacks aggressive implementation of national climate policies but has potential to increase CDR through reforestation and existing forest management on both public and private land. For forest-based CDR to succeed, a wide array of policy tools will have to be implemented in a variety of contexts with an eye towards overcoming the challenges of policy design with regard to uncertainty in policy outcomes, policy coherence around managing forests for carbon simultaneously with other goals and integration across governance contexts and levels.
Effects of 1-MCP and calcium chloride treatments on quality maintenance of full-ripe cherry tomatoes
Authors: Thwin Yan Wunna , Chang Min Sun , Hong Yoonpyo , Lim Sooyeon
Published: August 2020

This study aims to elucidate the effects of separate or combined 1-methylcyclopropene (1-MCP) and calcium chloride (CaCl2) treatment on the post-harvest quality of full-ripe cherry tomatoes (TY high Q cultivar). Full-ripe cherry tomatoes were exposed to 500 ppb 1-MCP (14 h), 2% CaCl2 (2 min), or a combination of both. After treatment, the fruit were evaluated based on the changes in their physicochemical factors, antioxidant activities, lycopene contents, and insoluble pectin contents during storage at 10°C over 17 days. All chemical treatments prevented weight loss and reductions in the insoluble pectin contents over the 17 days period, and also over an additional distribution period of 4 days, when compared to the control fruit. Interestingly, the full-ripe cherry tomatoes treated 1-MCP with CaCl2 exhibited a delay in discoloration until 13 days after treatment compared to the control. In addition, the synergetic effect of 1-MCP and CaCl2 was revealed by following their lycopene levels and antioxidant activities during storage. Furthermore, the insoluble pectin contents of the cherry tomatoes subjected to the combined treatment were higher than those recorded for the separate treatments. These results suggest that treatment with a combination of 1-MCP and CaCl2 can be useful as a post-harvest technique to improve both the post-harvest quality and the beneficial properties of cherry tomatoes even when the fruit is approaching the full-ripe stage.
Effects of different cultivated regions on bioactive compound content and antioxidant activity of aronia (Aronia melanocarpa)
Authors: Hwang Eun-Sun , Lee You Ji
Published: August 2020

This study aimed to compare the bioactive substances and antioxidant activities of aronia grown in Korea and Poland, and thus to provide basic data for its future use as a processed food. The powders of three types of aronia, each from Korea and Poland, were extracted with distilled water and 80% ethanol at 25°C and 80°C, respectively, and the total polyphenol, flavonoid, and anthocyanin contents were evaluated. Additionally, the antioxidant activities were compared with DPPH and ABTS radical scavenging activities and reducing power depending on the extraction temperature and extraction solvent. The total polyphenol content was higher in the 80% ethanol extracts than the water extracts, in the six samples from Korea and Poland. The total polyphenols and flavonoids were higher in water extracts at 80°C than at 25°C, and at 80°C in 80% ethanol. The anthocyanin content in the other five samples showed a similar tendency except for sample E, which had the highest anthocyanin content, based on 80% ethanol extract. The 80% ethanol extract showed higher antioxidant activity than water extract and in the aronia water extract, the antioxidant activity of the sample extracted at 80°C was higher than that of the 25°C extract at the same concentration. Based on these findings, it was confirmed that the antioxidative activity of Korea aronia was either similar to that of the Polish variant or was slightly higher.
Antioxidant, anti-inflammatory, and α-amylase inhibitory activities of Ulva lactuca extract
Authors: Tong Tao , Liu Ya-Juan , Zhang Ping , Kang Seong-Gook
Published: August 2020

In this study, an extract of Ulva lactuca was investigated for its in vitro antioxidant activities (2,2-diphenyl1-picrylhydrazyl radical, hydroxyl radical, and superoxide anion radical scavenging activity, and reducing power) and enzyme inhibitory activities (α-amylase and α-glucosidase). The anti-inflammatory effect of U. lactuca extract was evaluated in lipopolysaccharide-stimulated RAW 264.7 cells, a widely used macrophage cell line. We observed that U. lactuca extract contained a relatively high total phenolic content (7.72 mg of gallic acid equivalents/g of extract) and exhibited multiple antioxidant activities including the scavenging of 2,2-diphenyl-1-picrylhydrazyl radical, hydroxyl, and superoxide anion radicals as well as reducing power. Simultaneously, we found that U. lactuca extract exhibited anti-inflammatory activity as evidenced by the reduction of nitric oxide in the U. lactuca extract-treated RAW 264.7 cells. Moreover, U. lactuca extract had a moderate inhibitory effect on α-amylase, although it showed no obvious inhibitory effect on α-glucosidase at the concentration tested. Collectively, our results demonstrated that the phenolic-enriched U. lactuca extract exhibited antioxidant and anti-inflammatory activities, and inhibited enzyme (α-amylase) relevant to hyperglycemia. Further research is required to determine the potential of developing the U. lactuca extract as a nutraceutical or pharmaceutical ingredient.
Factors Associated with Disease Severity and Mortality among Patients with Coronavirus Disease 2019: A Systematic Review and Meta-Analysis
Authors: Chidambaram Vignesh , Tun Nyan Lynn , Haque Waqas Z , Majella Marie Gilbert , Sivakumar Ranjith Kumar , Kumar Amudha , Hsu Angela Ting-Wei , Ishak Izza A , Nur Aqsha A , Ayeh Samuel K , Salia Emmanuella L , Zil-E-Ali Ahsan , Saeed Muhammad A , Sarena Ayu PB , Seth Bhavna , Ahmadzada Muzzammil , Haque Eman F , Neupane Pranita , Wang Kuang-Heng , Pu Tzu-Miao , Ali Syed MH , Arshad Muhammad A , Wang Lin , Baksh Sheriza , Karakousis Petros C , Galiatsatos Panagis
Published: August 2020

Background

Understanding the factors associated with disease severity and mortality in Coronavirus disease (COVID-19) is imperative to effectively triage patients. We performed a systematic review to determine the demographic, clinical, laboratory and radiological factors associated with severity and mortality in COVID-19.

Methods

We searched PubMed, Embase and WHO database for English language articles from inception until May 8, 2020. We included Observational studies with direct comparison of clinical characteristics between a) patients who died and those who survived or b) patients with severe disease and those without severe disease. Data extraction and quality assessment were performed by two authors independently.

Results

Among 15680 articles from the literature search, 109 articles were included in the analysis. The risk of mortality was higher in patients with increasing age, male gender (RR 1.45, 95%CI 1.23–1.71), dyspnea (RR 2.55, 95%CI 1.88–2.46), diabetes (RR 1.59, 95%CI 1.41–1.78), hypertension (RR 1.90, 95%CI 1.69–2.15). Congestive heart failure (OR 4.76, 95%CI 1.34–16.97), hilar lymphadenopathy (OR 8.34, 95%CI 2.57–27.08), bilateral lung involvement (OR 4.86, 95%CI 3.19–7.39) and reticular pattern (OR 5.54, 95%CI 1.24–24.67) were associated with severe disease. Clinically relevant cut-offs for leukocytosis(>10.0 ×109/L), lymphopenia(< 1.1 ×109/L), elevated C-reactive protein(>100mg/L), LDH(>250U/L) and D-dimer(>1mg/L) had higher odds of severe disease and greater risk of mortality.

Conclusion

Knowledge of the factors associated of disease severity and mortality identified in our study may assist in clinical decision-making and critical-care resource allocation for patients with COVID-19.

Primary Funding Source

None.
Face masks release water vapour but where does it go? An early observational study
Authors: Stubington T.J. , Sahota R.S. , Mottacki N. , Johnston M.N. , Judd O.
Published: August 2020

Objectives

The aim of this observational study was to demonstrate the behaviour and trajectory of exhaled material from an individual wearing an FFP3 mask. Valves allow material release, but we theorised that valve design may direct material downwards towards patient and surrounding environment.

Limiting transmission of diseases with aerosolised spread is a current and serious concern within healthcare worldwide. Filtering face piece masks (FFP) are an essential piece of protective equipment when treating patients with ongoing infection. However, valved masks in other settings such as elective theatre and by the general public may have unforeseen negative effects.

Design

A heating coil-based vaporiser was used to produce visible water vapour. A healthy test subject was filmed wearing a variety of different masks and exhaling the water vapour.

Results

Flexible pleated and solid-shell FFP masks direct exhaled material downwards in plumes exceeding 25 cm. Duckbill-shaped masks appear to direct exhaled vapour laterally, with a smaller plume. The effect is influenced by mask design and type of valve. Fluid repellent surgical masks reduce material directed downwards, and when used in conjunction with an FFP3 mask, appear to reduce the size and density of the exhaled vapour plume. The use of a visor was ineffective in reducing plume expulsion.

Interpretation

A properly fit-tested FFP3-rated protective mask may only moderately limit expulsion of aerosolised particles from asymptomatic healthcare workers to patients, particularly in cases where procedures are being performed in close proximity to patients or in cases where mucosal surfaces are exposed. Further research in this area is needed.
A city-level analysis of air pollution, climate and COVID-19 early spread during the Spanish lockdown
Authors: Briz-Redón Álvaro , Belenguer-Sapiña Carolina , Serrano-Aroca Ángel
Published: August 2020

The COVID-19 outbreak has escalated into the worse pandemic of the present century. The fast spread of the new SARS-CoV-2 coronavirus has caused devastating health and economic crises all over the world, with Spain being one of the worst affected countries in terms of confirmed COVID-19 cases and deaths per inhabitant. In this situation, the Spanish Government declared the lockdown of the country. The variations of air pollution in terms of fine particulate matter (PM2.5) levels in seven cities of Spain are analyzed here considering the effect of meteorology during the national lockdown. The possible associations of PM2.5pollution and climate with COVID-19 accumulated cases were also analyzed. While the epidemic curve was flattened, the results of the analysis show that the 4-week Spanish lockdown significantly reduced the PM2.5levels in only one of the cities despite the drastically reduced human activity in good agreement with our previous study of changes in air quality in terms of CO, SO2, PM10, O3and NO2levels. Furthermore, no associations between either PM2.5exposure or environmental conditions and COVID-19 transmission were found during the early spread of the pandemic.
Transmission heterogeneities, kinetics, and controllability of SARS-CoV-2
Authors: Sun Kaiyuan , Wang Wei , Gao Lidong , Wang Yan , Luo Kaiwei , Ren Lingshuang , Zhan Zhifei , Chen Xinghui , Zhao Shanlu , Huang Yiwei , Sun Qianlai , Liu Ziyan , Litvinova Maria , Vespignani Alessandro , Ajelli Marco , Viboud Cécile , Yu Hongjie
Published: August 2020

A long-standing question in infectious disease dynamics is the role of transmission heterogeneities, particularly those driven by demography, behavior and interventions. Here we characterize transmission risk between 1,178 SARS-CoV-2 infected individuals and their 15,648 close contacts based on detailed contact tracing data from Hunan, China. We find that 80% of secondary transmissions can be traced back to 14% of SARS-CoV-2 infections, indicating substantial transmission heterogeneities. Regression analysis suggests a marked gradient of transmission risk scales positively with the duration of exposure and the closeness of social interactions, after adjusted for demographic and clinical factors. Population-level physical distancing measures confine transmission to families and households; while case isolation and contact quarantine reduce transmission in all settings. Adjusted for interventions, the reconstructed infectiousness profile of a typical SARS-CoV-2 infection peaks just before symptom presentation, with ~50% of transmission occurring in the pre-symptomatic phase. Modelling results indicate that achieving SARS-CoV-2 control would require the synergistic efforts of case isolation, contact quarantine, and population-level physical distancing measures, owing to the particular transmission kinetics of this virus.
Germline mutations in hereditary breast cancer genes are associated with early age at diagnosis and family history in Guatemalan breast cancer
Authors: Ren Megan , Orozco Anali , Shao Kang , Albanez Anaseidy , Ortiz Jeremy , Cao Boyang , Wang Lusheng , Barreda Lilian , Alvarez Christian S. , Garland Lisa , Wu Dongjing , Chung Charles , Wang Jiahui , Frone Megan , Ralon Sergio , Argueta Victor , Orozco Roberto , Gharzouzi Eduardo , Dean Michael
Published: August 2020

Background

Mutations in hereditary breast cancer genes play an important role in the risk for cancer, however, little is known of the type and frequency of mutations in Central American populations, including Guatemala.

Methods

Two separate panels of known cancer susceptibility genes were used to sequence blood DNA from 664 unselected breast cancer cases from two large hospitals in Guatemala. Variants were annotated with ClinVar and VarSome. Data from a structured questionnaire was used to compare mutation carriers of medium and high penetrance genes.

Results

A total of 73 out of 664 subjects (11%) had a variant classified as pathogenic in a gene with known high or medium penetrance for inherited breast cancer. The most frequently mutated genes were BRCA1 (37/664, 5.6%) followed by BRCA2 (15/664, 2.3%), PALB2 (5/664, 0.8%) and TP53 (5/664, 0.8%). Pathogenic variants were also detected in the moderate penetrance genes ATM, BARD1, CHEK2, and MSH6, and rare pathogenic variants detected in the low penetrance genes AXIN2, FH, MLH1, MSH2, MUTYH, NF1, and SDHB. The high ratio of BRCA1/BRCA2 mutations is due to the presence of two potential founder mutations, BRCA1 c.212+1G>A splice mutation (15 cases) and BRCA1 c.799delT (9 cases). Compared to all others, cases with pathogenic mutations had a significantly earlier age at diagnosis (45 vs 51 years, P<0.001), more likely to have had diagnosis before menopause, and a higher percentage had a relative with any cancer (51% vs 37%, P=0.038) or breast cancer (33% vs 15%, P<0.001). Mammography usage was less frequent in lower SES women indicating this group is less likely to be screened for breast cancer (p < 0.001).

Conclusions

Guatemalan women have rates of hereditary breast cancer mutations similar to other populations, and these women are more likely to have early age at diagnosis and family history. This data supports the use of genetic testing in breast cancer patients and those at high risk as part of a strategy to reduce breast cancer mortality in Guatemala.
The Mean Unfulfilled Lifespan (MUL): A new indicator of the impact of mortality shocks on the individual lifespan, with application to global 2020 quarterly mortality from COVID-19
Authors: Heuveline Patrick
Published: August 2020

Declines in period life expectancy at birth (PLEB) provide intuitive indicators of the impact of a cause of death on the individual lifespan. Derived under the assumption that future mortality conditions will remain indefinitely those observed during a reference period, however, the intuitive interpretation of a PLEB becomes problematic when that period conditions reflect a temporary mortality “shock”, resulting from a natural disaster or the diffusion of a new epidemic in the population for instance.

Rather than to make assumptions about future mortality, I propose measuring the difference between a period average age at death and the average expected age at death of the same individuals (death cohort): the Mean Unfulfilled Lifespan (MUL). For fine-grained tracking of the mortality impact of an epidemic, I also provide an empirical shortcut to MUL estimation for small areas or short periods.

For illustration, quarterly MUL values in 2020 are derived from estimates of COVID-19 deaths in 159 national populations and 122 sub-national populations in Italy, Mexico, Spain and the US. The highest quarterly values in national populations are obtained for Ecuador (5.12 years, second quarter) and Peru (4.56 years, third quarter) and, in sub-national populations, for New York (5.52 years), New Jersey (5.56 years, second quarter) and Baja California (5.19 years, fourth quarter). Using a seven-day rolling window, the empirical shortcut suggests the MUL peaked at 9.12 years in Madrid, 9.20 years in New York, and 9.15 years in Baja California, and in Guayas (Ecuador) it even reached 12.6 years for the entire month of April.

Based on reported COVID-19 deaths that might substantially underestimate overall mortality change in affected populations, these results nonetheless illustrate how the MUL tracks the mortality impact of the pandemic, or any mortality shock, retaining the intuitive metric of differences in PLEB, without their problematic underlying assumptions.
Drug Response Pharmacogenetics for 200,000 UK Biobank Participants
Authors: McInnes Gregory , Altman Russ B
Published: August 2020

Pharmacogenetics studies how genetic variation leads to variability in drug response. Guidelines for selecting the right drug and right dose to patients based on their genetics are clinically effective, but are still widely unused. For some drugs, the normal clinical decision making process may lead to the optimal dose of a drug that minimizes side effects and maximizes effectiveness. Without measurements of genotype, physicians and patients may observe and adjust dosage in a manner that reflects the underlying genetics. The emergence of genetic data linked to longitudinal clinical data in large biobanks offers an opportunity to confirm known pharmacogenetic interactions as well as discover novel associations by investigating outcomes from normal clinical practice. Here we use the UK Biobank to search for pharmacogenetic interactions among 200 drugs and 9 genes among 200,000 participants. We identify associations between pharmacogene phenotypes and drug maintenance dose as well as side effect incidence. We find support for several known drug-gene associations as well as novel pharmacogenetic interactions.
Cumulative survival profiling: a new PAP-based method for detecting heteroresistance in staphylococcal clinical isolates
Authors: Alsallaq Ramzi A. , Dao Tina H. , Rosch Jason W. , Margolis Elisa
Published: August 2020

The area under the population analysis profile (PAP) is used in the gold standard method for detecting heteroresistance in staphylococci. We tested the hypothesis that the initial inoculum strongly influences the area under the population analysis profile. We sought to interpret this dependence and develop a new metric that lacks this dependence to retrospectively detect heteroresistance to vancomycin in coagulase-negative staphylococcal (CoNS) isolates.

We tested our hypothesis on 20 PAPs from the heteroresistant positive control isolate (Mu3) and 7 PAPs from one CoNS isolate which is associated with poor clinical response. The area under the PAP depended linearly (p<0.001) on the initial inoculum. We interpreted the slope to be the cumulative survival under vancomycine concentration gradient. The statistical distribution of the cumulative survival for Mu3 and the CoNS isolate constituted the cumulative survival profiles for each. The profiles reflect ed spectrum of response under vancomycine gradient with the left-tail of CoNS isolate profile located near the median of Mu3 profile indicating the heteroresistance of the CoNS isolate and that the most resistant in the spectrum are likely to be associated with poor clinical response. We estimated that about two-third of the CoNS from unique participants are heteroresistant with 80% of heteroresistant isolates may be associated with a poor clinical response.
Fine-tuned Forecasting Techniques for COVID-19 Prediction in India
Authors: Gola Abhinav , Arya Ravi Kumar , Animesh  , Dugh Ravi , Khan Zuber
Published: August 2020

Estimation of statistical quantities plays a cardinal role in handling of convoluted situations such as COVID-19 pandemic and forecasting the number of affected people and fatalities is a major component for such estimations. Past researches have shown that simplistic numerical models fare much better than the complex stochastic and regression-based models when predicting for countries such as India, United States and Brazil where there is no indication of a peak anytime soon. In this research work, we present two models which give most accurate results when compared with other forecasting techniques. We performed both short-term and long-term forecasting based on these models and present the results for two discrete durations.
Bias and precision of parameter estimates from models using polygenic scores to estimate environmental and genetic parental influences
Authors: Kim Yongkang , Balbona Jared V. , Keller Matthew C.
Published: August 2020

In a companion paper (Balbona et al. (2020)), we introduced a series of causal models that use polygenic scores from transmitted and nontransmitted alleles, the offspring trait, and parental traits to estimate the variation due to the environmental influences the parental trait has on the offspring trait (vertical transmission) as well as additive genetic effects. These models also estimate and account for the gene-gene and gene-environment covariation that arises from assortative mating and vertical transmission respectively. In the current study, we simulated polygenic scores and phenotypes of parents and offspring under genetic and vertical transmission scenarios, assuming two types of assortative mating. We instantiated the models from our companion paper in the OpenMx software, and compared the true values of parameters to maximum likelihood estimates from models fitted on the simulated data to quantify the bias and precision of estimates. We show that parameter estimates from these models are unbiased when assumptions are met, but as expected, they are biased to the degree that assumptions are unmet. Standard errors of the estimated variances due to vertical transmission and to genetic effects decrease with increasing sample sizes and with increasingr2values of the polygenic score. Even when the polygenic score explains a modest amount of trait variation (r2= .05), standard errors of these standardized estimates were reasonable (< .05) forn= 16Ktrios, and smaller sample sizes (e.g., down to 4K) when the polygenic score is more predictive. These causal models offer a novel approach for understanding how parents influence their offspring, but their use requires polygenic scores on relevant traits that are modestly predictive (e.g.,r2> .025) as well as datasets with genomic and phenotypic information on parents and offspring. The utility of polygenic scores for elucidating parental influences should thus serve as additional motivation for large genomic biobanks to perform GWAS’s on traits that may be relevant to parenting and to oversample close relatives, particularly parents and offspring.
Understanding transformation tolerant visual object representations in the human brain and convolutional neural networks
Authors: Xu Yaoda , Vaziri-Pashkam Maryam
Published: August 2020

Forming transformation-tolerant object representations is critical to high-level primate vision. Despite its significance, many details of tolerance in the human brain remain unknown. Likewise, despite the ability of convolutional neural networks (CNNs) to exhibit human-like object categorization performance, whether CNNs form tolerance similar to that of the human brain is unknown. Here we provide the first comprehensive documentation and comparison of three tolerance measures in the human brain and CNNs. We measured fMRI responses from human ventral visual areas to real-world objects across both Euclidean and non-Euclidean feature changes. In single fMRI voxels in higher visual areas, we observed robust object response rank-order preservation across feature changes. This is indicative of functional smoothness in tolerance at the fMRI meso-scale level that has never been reported before. At the voxel population level, we found highly consistent object representational structure across feature changes towards the end of ventral processing. Rank-order preservation, consistency, and a third tolerance measure, cross-decoding success (i.e., a linear classifier’s ability to generalize performance across feature changes) showed an overall tight coupling. These tolerance measures were lower for Euclidean than non-Euclidean feature changes in lower visual areas, but increased over the course of ventral processing in most cases. These characteristics of tolerance, however, were absent in eight CNNs pretrained with ImageNet images with varying network architecture, depth, the presence/absence of recurrent processing, or whether a network was pretrained with the original or stylized ImageNet images that encouraged shape processing. Most notably, CNNs do not show increased representational consistency across feature changes at the higher layers. CNNs thus do not appear to develop the same kind of tolerance as the human brain over the course of visual processing.

Significant Statement

Perceiving object identity among changes in non-identity features and forming transformation-tolerant object representations is essential to high-level primate vision. Here we provide a comprehensive documentation and comparison of three tolerance measures between the human brain and CNNs pretrained for object classification. While all three measures show increased tolerance in the human brain across four types of feature changes towards the end of ventral visual processing, CNNs fail to develop the same kind of tolerance with visual processing.
PCNA monoubiquitination is regulated by diffusion of Rad6/Rad18 complexes along RPA filaments
Authors: Li Mingjie , Sengupta Bhaswati , Benkovic Stephen J. , Lee Tae Hee , Hedglin Mark
Published: August 2020

Translesion DNA synthesis (TLS) enables DNA replication through damaging modifications to template DNA and requires monoubiquitination of the PCNA sliding clamp by the Rad6/Rad18 complex. This posttranslational modification is critical to cell survival following exposure to DNA damaging agents and is tightly regulated to restrict TLS to damaged DNA. RPA, the major single strand DNA (ssDNA) binding protein, forms filaments on ssDNA exposed at TLS sites and plays critical yet undefined roles in regulating PCNA monoubiquitination. Here, we utilize kinetic assays and single molecule FRET microscopy to monitor PCNA monoubiquitination and Rad6/Rad18 complex dynamics on RPA filaments, respectively. Results reveal that a Rad6/Rad18 complex is recruited to an RPA filament via Rad18•RPA interactions and randomly translocates along the filament. These translocations promote productive interactions between the Rad6/Rad18 complex and the resident PCNA, significantly enhancing monoubiquitination. These results illuminate critical roles of RPA in the specificity and efficiency of PCNA monoubiquitination.
Development and application of aerobic, chemically defined media forDysgonomonas
Authors: Bridges Charles M. , Gage Daniel J.
Published: August 2020

Members ofDysgonomonasare Gram-negative, non-motile, facultatively anaerobic coccobacilli originally described in relation to their isolation stool and wounds of human patients (CDC group DF-3). More recentlyDysgonomonashave been found to be widely distributed in terrestrial environments and are particularly enriched in insect systems. Their prevalence in xylophagous insects such as termites and wood-feeding cockroaches, as well as in soil-fed microbial fuel cells, elicit interest in lignocellulose degradation and biofuel production, respectively. Their prevalence in mosquito and fruit fly have implications relating to symbiosis, host immunology and developmental biology. Additionally, their prevalence in termite, mosquito and nematode present novel opportunities for pest and vector control. Currently, the absolute growth requirements ofDysgonomonasare unknown, and they are cultured solely under anaerobic conditions on complex media containing blood, peptones, tryptones, and yeast, plant or meat extracts. Restrictive & undefined culturing conditions preclude physiological and genetic studies, and thus further understanding of metabolic potential. Here we describe the requirements for growth of termite-derivedDysgonomonasisolates and create parallel defined, minimal and complex media that permit vigorous and reliable aerobic growth. Furthermore, we show that these media can be used to easily enrich forDysgonomonasisolates from complex and microbially-diverse environmental samples.

Impact Statement

Members of the genusDysgonomonasare increasingly prevalent in ecological, medical and biotechnological contexts. To the best of our knowledge, there are currently no formulations for chemically defined or minimal media forDysgonomonas, and limited complex formulations that allow aerobic growth, particularly on solid media. We have created three parallel media formulations (complex, defined & minimal) that permit robust aerobic and anaerobic growth in liquid and agar-solidified media. These formulations remove the necessity for animal blood and expensive equipment such as anaerobic chambers, which can inhibit basic research by groups with biosafety and resource limitations.
MultiPaths: a Python framework for analyzing multi-layer biological networks using diffusion algorithms
Authors: Marín-Llaó Josep , Mubeen Sarah , Perera-Lluna Alexandre , Hofmann-Apitius Martin , Picart-Armada Sergio , Domingo-Fernández Daniel
Published: August 2020

High-throughput screening yields vast amounts of biological data which can be highly challenging to interpret. In response, knowledge-driven approaches emerged as possible solutions to analyze large datasets by leveraging prior knowledge of biomolecular interactions represented in the form of biological networks. Nonetheless, given their size and complexity, their manual investigation quickly becomes impractical. Thus, computational approaches, such as diffusion algorithms, are often employed to interpret and contextualize the results of high-throughput experiments. Here, we present MultiPaths, a framework consisting of two independent Python packages for network analysis. While the first package, DiffuPy, comprises numerous state-of-the-art diffusion algorithms applicable to any generic network, the second, DiffuPath, enables the application of these algorithms on multi-layer biological networks. To facilitate its usability, the framework includes a command line interface, reproducible examples, and documentation. To demonstrate the framework, we conducted several diffusion experiments on three independent multi-omicsdatasets over disparate networks generated from pathway databases, thus, highlighting the ability of multi-layer networks to integrate multiple modalities. Finally, the results of these experiments demonstrate how the generation of harmonized networks from disparate databases can improve predictive performance with respect to individual resources.

Availability

DiffuPy and DiffuPath are publicly available under the Apache License 2.0 athttps://github.com/multipaths.

Contact

sergi.picart@upc.eduanddaniel.domingo.fernandez@scai.fraunhofer.de
Characterization of a newLeishmania majorisolate for use in a controlled human infection model
Authors: Ashwin Helen , Sadlova Jovana , Vojtkova Barbora , Becvar Tomas , Lypaczewski Patrick , Schwartz Eli , Greensted Elizabeth , Van Bocxlaer Katrien , Pasin Marion , Lipinski Kai S. , Parkash Vivak , Matlashewski Greg , Layton Alison M. , Lacey Charles J. , Jaffe Charles L. , Volf Petr , Kaye Paul M.
Published: August 2020

Leishmaniasis is widely regarded as a vaccine-preventable disease, but the costs required to reach pivotal Phase 3 studies and uncertainty about which candidate vaccines should be progressed into human studies significantly limits progress in vaccine development for this neglected tropical disease. Controlled human infection models (CHIM) provide a pathway for accelerating vaccine development and to more fully understand disease pathogenesis and correlates of protection. Here, we describe the isolation, characterization and GMP manufacture of a new clinical isolate ofLeishmania major. Two fresh isolates ofL. majorfrom Israel were initially compared by genome sequencing,in vivoinfectivity and drug sensitivity in mice, and development and transmission competence in sand flies, allowing one (L. major_MRC-02) to be selected for GMP production. This study addresses a major roadblock in the development of vaccines for leishmaniasis, providing a key resource for CHIM studies of sand fly transmitted cutaneous leishmaniasis.
Wine terroir and the soil microbiome: an amplicon sequencing–based assessment of the Barossa Valley and its sub-regions
Authors: Zhou Jia , Cavagnaro Timothy R. , De Bei Roberta , Nelson Tiffanie M. , Stephen John R. , Metcalfe Andrew , Gilliham Matthew , Breen James , Collins Cassandra , Rodríguez López Carlos M.
Published: August 2020

Soil is an important factor that contributes to the uniqueness of a wine produced by vines grown in specific conditions. Recent data shows that the composition, diversity and function of soil microbial communities may play important roles in determining wine quality and indirectly affect its economic value. Here, we evaluated the impact of environmental variables on the soil microbiomes of 22 Barossa Valley vineyard sites based on the 16S rRNA gene hypervariable region 4. In this study, we report that environmental heterogeneity (soil plant-available P content, elevation, rainfall, temperature, spacing between row and spacing between vine) caused more microbial dissimilarity than geographic distance. Vineyards located in cooler and wetter regions showed lower beta diversity and a higher ratio of dominant taxa. Differences in microbial community composition were significantly associated with differences in fruit traits and in wine chemical and metabolomic profiles, highlighting the potential influence of microbial communities on the phenotype of grapevines. Our results suggest that environmental factors affect wine terroir, and this may be mediated by changes in microbial structure, thus providing a basic understanding of how growing conditions affect interactions between plants and their soil microbiomes.
Reference genes for gene expression analysis in the fungal pathogenNeonectria ditissimaand their use demonstrating expression up-regulation of candidate virulence genes
Authors: Florez Liz M. , Scheper Reiny W. A. , Fisher Brent M. , Sutherland Paul W. , Templeton Matthew D. , Bowen Joanna K.
Published: August 2020

European canker, caused by the necrotrophic fungal phytopathogenNeonectria ditissima, is one of the most damaging apple diseases worldwide. An understanding of the molecular basis ofN. ditissimavirulence is currently lacking. Identification of genes with an up-regulation of expression during infection, which are therefore probably involved in virulence, is a first step towards this understanding. Real-time quantitative reverse transcription PCR (qRT-PCR) can be used to identify these candidate virulence genes, but relies on the use of reference genes for relative gene expression data normalisation. However, no report that addresses selecting appropriate fungal reference genes for use in theN. ditissima-apple pathosystem has been published to date. In this study, eightN. ditissimagenes were selected as candidate qRT-PCR reference genes for gene expression analysis. A subset of the primers (six) designed to amplify regions from these genes were specific forN. ditissima, failing to amplify PCR products with template from other fungal pathogens present in the apple orchard. The efficiency of amplification of these six primer sets was satisfactory, ranging from 81.8 to 107.53%. Analysis of expression stability when a highly pathogenicN. ditissimaisolate was cultured under 10 regimes, using the statistical algorithms geNorm, NormFinder and BestKeeper, indicated thatactinandmyo-inositol-1-phosphate synthase(mips), or their combination, could be utilised as the most suitable reference genes for normalisation ofN. ditissimagene expression. As a test case, these reference genes were used to study expression of three candidate virulence genes during a time course of infection. All three, which shared traits with fungal effector genes, had up-regulated expressionin plantacompared toin vitrowith expression peaking between five and six weeks post inoculation (wpi). Thus, these three genes may well be involved inN. ditissimapathogenicity and are priority candidates for further functional characterization.
CAP1 and cofilin1 cooperate in neuronal actin dynamics, growth cone function and neuron connectivity
Authors: Schneider Felix , Duong Thuy-An , Metz Isabell , Winkelmeier Jannik , Hübner Christian A. , Endesfelder Ulrike , Rust Marco B.
Published: August 2020

Neuron connectivity depends on growth cones that navigate axons through the developing brain. Growth cones protrude and retract actin-rich structures to sense guidance cues. These cues control local actin dynamics and steer growth cones towards attractants and away from repellents, thereby directing axon outgrowth. Hence, actin binding proteins (ABPs) moved into the focus as critical regulators of neuron connectivity. We found cyclase-associated protein 1 (CAP1), an ABP with unknown brain function, abundant in growth cones. Super-resolution microscopy and live cell imaging combined with pharmacological approaches on hippocampal neurons from gene-targeted mice revealed a crucial role for CAP1 in actin dynamics that is critical for growth cone morphology and function. Growth cone defects in mutant neurons compromised neuron differentiation and was associated with impaired neuron connectivity in CAP1 mutant brains. Mechanistically, we found that CAP1 and cofilin1 synergistically control growth cone actin dynamic and morphology. Together, we identified CAP1 as a novel actin regulator in growth cone that is relevant for neuron connectivity.
IL-27 enhances the lymphocyte mediated innate resistance to primary hookworm infection in the lungs
Authors: Noon Jason B. , Sharma Arjun , Platten Johannes , Quinton Lee J. , Reinhardt Christoph , Bosmann Markus
Published: August 2020

Interleukin-27 (IL-27) is a heterodimeric cytokine of the IL-12 family, formed by non-covalent association of the promiscuous EBI3 subunit and selective p28 subunit. IL-27 is produced by mononuclear phagocytes and unfolds pleiotropic immune-modulatory functions through high affinity ligation to IL-27 receptor alpha (IL-27RA). While IL-27 is known to contribute to immunity and to end inflammation following numerous types of infections, its relevance for host defense against multicellular parasites is still poorly defined. Here, we investigated the role of IL-27 during infection with the soil-transmitted hookworm,Nippostrongylus brasiliensis,in its early intrapulmonary life cycle. IL-27(p28) was detectable in broncho-alveolar lavage fluids of C57BL/6J wild type mice on day 1 after subcutaneousN. brasiliensisinoculation. The expression of IL-27RA was most abundant on lung invading γδ T cells followed by CD8+T cells, CD4+T cells and NK cells. IL-27RA was weakly present on CD19+B cells and absent on neutrophils, alveolar macrophages and eosinophils. Il27ra−/−mice showed increased parasite burden together with aggravated pulmonary hemorrhage and higher alveolar albumin leakage as a surrogate for disruption of the epithelial/vascular barrier. Conversely, recombinant mouse IL-27 injections of wild type mice reduced parasite burdens and lung injury. In multiplex screens, we identified higher airway accumulations of IL-6, TNFα and MCP-3 (CCL7) in Il27ra−/−mice, while rmIL-27 treatment showed a reciprocal effect. Finally, γδ T cell infiltration of the airways required endogenous IL-27 expression. In summary, this report demonstrates protective functions of IL-27 to control the early larval stage of hookworm infection in the lungs.
A dynamic gradient architecture generates brain activity states
Authors: Brown Jesse A. , Lee Alex J. , Pasquini Lorenzo , Seeley William W.
Published: August 2020

A central goal of systems neuroscience is to determine the functional-anatomical basis of brain-wide activity dynamics. While brain activity patterns appear to be low-dimensional and guided by spatial gradients, the set of gradients remains provisional and their mode of interaction is unclear. Here we applied deep learning-based dimensionality reduction to task-free fMRI images to derive an intrinsic latent space of human brain activity. Each dimension represented a discrete, dynamically fluctuating spatial activity gradient. The principal dimension was a novel unipolar sensory-association gradient underlying the global signal. A small set of gradients appeared to underlie key functional connectomics phenomena. Different task activation patterns were generated by gradients adopting task-specific configurations. Dynamical systems modelling revealed that gradients interact via state-specific coupling parameters, allowing accurate forecasts and simulations of task-specific brain activity. Together, these findings indicate that a small set of dynamic, interacting gradients create the repertoire of possible brain activity states.
Plasma membrane nano-organization specifies phosphoinositide effects on Rho-GTPases and actin dynamics in tobacco pollen tubes
Authors: Fratini Marta , Krishnamoorthy Praveen , Stenzel Irene , Riechmann Mara , Bacia Kirsten , Heilmann Mareike , Heilmann Ingo
Published: August 2020

Pollen tube growth requires coordination of cytoskeletal dynamics and apical secretion. The regulatory phospholipid, phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) is enriched in the subapical plasma membrane of pollen tubes and can influence both actin dynamics and secretion. How alternative PtdIns(4,5)P2-effects are specified is unclear. Spinning disc microscopy (SD) reveals dual distribution of a fluorescent PtdIns(4,5)P2-reporter in dynamic plasma membrane nanodomains vs. apparent diffuse membrane labelling, consistent with spatially distinct coexisting pools of PtdIns(4,5)P2. Several PI4P 5-kinases (PIP5Ks) can generate PtdIns(4,5)P2in pollen tubes. Despite localizing to one membrane region, AtPIP5K2 and NtPIP5K6 display distinctive overexpression effects on cell morphologies, respectively related to altered actin dynamics or membrane trafficking. When analyzed by SD, AtPIP5K2-EYFP associated with nanodomains, whereas NtPIP5K6-EYFP localized diffusely. Chimeric AtPIP5K2 and NtPIP5K6 variants with reciprocally swapped membrane-associating domains evoked reciprocally shifted effects on cell morphology upon overexpression. Overall, PI4P 5-kinase variants targeted to nanodomains stabilized actin, suggesting a specific function of PtdIns(4,5)P2-nanodomains. A distinct role of nanodomain-associated AtPIP5K2 in actin regulation is further supported by proximity to and interaction with the Rho-GTPase NtRac5, and by functional interplay with elements of ROP-signalling. Plasma membrane nano-organization may thus aid the specification of PtdIns(4,5)P2-functions to coordinate cytoskeletal dynamics and secretion in pollen tubes.