bluuebunny/crossref_metadata_2025 huggingface dataset:
First Report of Shot-Hole on Flowering Cherry Caused by Burkholderia contaminans and Pseudomonas syringae pv. syringae
Authors: Han Viet-Cuong , Yu Nan Hee , Park Ae Ran , Yoon Hyeokjun , Son Youn Kyoung , Lee Byoung-Hee , Kim Jin-Cheol
Published: June 2021

Shot-hole disease (SH) is one of the most common and important diseases affecting flowering cherry (FC; Prunus × yedoensis Matsumura; Somei-yoshino) trees in South Korea every year, resulting in premature defoliation and reduced flowering in the following year. However, pathogens associated with the disease remain unknown, which has rendered disease management challenging. Here, the pathogens associated with SH, their biochemical characteristics, and their host range were elucidated. Detached-leaf and in planta assays revealed that two biofilm-forming bacteria—namely, Burkholderia contaminans and Pseudomonas syringae pv. syringae—caused SH of FC trees. These pathogens were recorded for the first time as the causes of SH of FC trees in South Korea. Additionally, the two pathogens induced similar disease symptoms in several stone fruit belonging to the genus Prunus, including peach (Prunus persica), plum (P. salicina), and apricot (P. mume), with peach being the most susceptible. These results indicate that B. contaminans and P. syringae pv. syringae caused SH on FC trees and presented a broad spectrum of hosts. Furthermore, Xanthomonas arboricola pv. pruni, the causative agent of leaf spot on stone fruit, incited brown spots and shot holes on FC leaves. Therefore, FC trees are susceptible to infections by various pathogenic bacteria, including B. contaminans, P. syringae pv. syringae, and X. arboricola pv. pruni. These findings will be of great importance as a reference for effective management of SH in the face of possible cross-infection between Prunus spp. in the future.
Aggressiveness and Mycotoxin Production by Fusarium meridionale Compared with F. graminearum on Maize Ears and Stalks in the Field
Authors: Machado Franklin. J. , de Barros Aline V. , McMaster Nicole , Schmale David G. , Vaillancourt Lisa J. , Del Ponte Emerson M.
Published: June 2021

Fusarium meridionale and F. graminearum both cause Gibberella ear rot (GER) and Gibberella stalk rot (GSR) of maize in Brazil, but the former is much more common. Recent work with two isolates of each from maize suggested this dominance could be caused by greater aggressiveness and competitiveness of F. meridionale on maize. We evaluated pathogenicity and toxigenicity of 16 isolates of F. graminearum and 24 isolates of F. meridionale recovered from both wheat and maize. Strains were individually inoculated into ears of four maize hybrids in field trials. GER severity varied significantly between isolates within each species. Although ranges overlapped, the average GER severity induced by F. meridionale (25.2%) was two times as high overall as that induced by F. graminearum (12.8%) for isolates obtained from maize but was similar for those isolated from wheat (19.9 and 21.4%, respectively). In contrast, severity of GSR was slightly higher for F. graminearum (22.2%) than for F. meridionale (19.8%), with no effect of the host of origin. Deoxynivalenol and its acetylated form 15ADON were the main mycotoxins produced by F. graminearum (7/16 strains), and nivalenol toxin was produced by F. meridionale (17/24 strains). Six isolates of F. graminearum and three of F. meridionale also produced zearalenone. Results confirmed that F. meridionale from maize is, on average, more aggressive on maize but also suggested greater complexity related to diversity among the isolates within each species and their interactions with different hybrids. Further studies involving other components of the disease cycle are needed to more fully explain observed patterns of host dominance.
The endocannabinoid system, cannabis, and cannabidiol: Implications in urology and men's health
Authors: Capodice Jillian L. , Kaplan Steven A.
Published: June 2021

Background:

The endocannabinoid system is a neuromodulatory system responsible for partial regulation of cognitive and emotional processes in the human central nervous system such as behavior, mood disorders, and neurologic disorders such as epilepsy. The endocannabinoid system is also prevalent throughout the peripheral nervous system and human body and its receptors and signaling pathways are present and active in areas including the male and female reproductive tracts and organ systems such as the urologic and gastrointestinal system.

The purpose of this article is to provide the reader with a brief background on the endocannabinoid system and to discuss the implications of the endocannabinoid system in urology as it applies to the male reproductive system, risk of urologic malignancy, and impact on the lower urinary tract, voiding, and urologic pain. It also summaries and discusses the epidemiology and research on cannabis and cannabidiol products.

Key message:

The endocannabinoid system affects the urologic and reproductive systems. Cannabis products and inhibitors targeting endocannabinoid pathways are being studied for their potential use as treatments for lower urinary tract symptoms and other urologic symptoms. Cannabis use adversely affects spermatogenesis and semen parameters and may be a risk factor for testicular germ cell tumors, however, it may be useful as a potential treatment for urologic symptoms. Cannabidiol products are popular in the consumer marketplace but there is still a paucity of scientific data on their potential medicinal use.
Pediatric Emergency Department Discharge Instructions for Spanish-Speaking Families
Authors: Isbey Sarah , Badolato Gia , Kline Jaclyn
Published: June 2021

Objectives

Patients who speak Spanish are less likely to comply with discharge instructions, adhere to appointments, and take medications than English-speaking patients. However, adherence is improved when discharge instructions are provided in Spanish. This study was designed to assess the frequency of providing written discharge instructions in Spanish to patients who speak Spanish and request interpretation services, and to determine factors associated with receiving written discharge instructions in the preferred language in a pediatric emergency department (ED).

Methods

This was a retrospective cross-sectional study of all discharges of Spanish-speaking patients who requested an interpreter in 1 year from a large urban pediatric ED and an associated community ED. Multivariable logistic regression was used to identify patient and visit level characteristics associated with receiving written discharge instructions in Spanish.

Results

Sixty-one percent of 11,545 patient encounters where a Spanish interpreter was requested received written discharge instructions in Spanish. Patients aged 1 to 3 years (adjusted odds ratio [aOR], 2.87; 95% CI, 2.18–3.77) and aged 4 to 12 years (aOR, 2.06; 95% CI, 1.6–2.65), those seen without a trainee (aOR, 1.37; 95% CI, 1.25–1.5), and those with low acuity triage levels (aOR, 1.6; 95% CI, 1.29–1.97) were more likely to receive discharge instruction in Spanish. Female patients were less likely to receive Spanish discharge instructions (aOR, 0.9; 95% CI, 0.83–0.97).

Conclusions

Discharged pediatric ED patients often do not receive written instructions in the preferred language. Patient and provider factors are associated with receiving written instructions in Spanish. Quality improvement efforts are needed to ensure appropriate language discharge education.
Racial/Ethnic Differences in Pediatric Emergency Department Wait Times
Authors: Johnson Tiffani J. , Goyal Monika K. , Lorch Scott A. , Chamberlain James M. , Bajaj Lalit , Alessandrini Evaline A. , Simmons Timothy , Casper T. Charles , Olsen Cody S. , Grundmeier Robert W. , Alpern Elizabeth R.
Published: June 2021

Objectives

Wait time for emergency care is a quality measure that affects clinical outcomes and patient satisfaction. It is unknown if there is racial/ethnic variability in this quality measure in pediatric emergency departments (PEDs). We aim to determine whether racial/ethnic differences exist in wait times for children presenting to PEDs and examine between-site and within-site differences.

Methods

We conducted a retrospective cohort study for PED encounters in 2016 using the Pediatric Emergency Care Applied Research Network Registry, an aggregated deidentified electronic health registry comprising 7 PEDs. Patient encounters were included among all patients 18 years or younger at the time of the ED visit. We evaluated differences in emergency department wait time (time from arrival to first medical evaluation) considering patient race/ethnicity as the exposure.

Results

Of 448,563 visits, median wait time was 35 minutes (interquartile range, 17–71 minutes). Compared with non-Hispanic White (NHW) children, non-Hispanic Black (NHB), Hispanic, and other race children waited 27%, 33%, and 12% longer, respectively. These differences were attenuated after adjusting for triage acuity level, mode of arrival, sex, age, insurance, time of day, and month [adjusted median wait time ratios (95% confidence intervals): 1.11 (1.10–1.12) for NHB, 1.12 (1.11–1.13) for Hispanic, and 1.05 (1.03–1.06) for other race children compared with NHW children]. Differences in wait time for NHB and other race children were no longer significant after adjusting for clinical site. Fully adjusted median wait times among Hispanic children were longer compared with NHW children [1.04 (1.03–1.05)].

Conclusions

In unadjusted analyses, non-White children experienced longer PED wait times than NHW children. After adjusting for illness severity, patient demographics, and overcrowding measures, wait times for NHB and other race children were largely determined by site of care. Hispanic children experienced longer within-site and between-site wait times compared with NHW children. Additional research is needed to understand structures and processes of care contributing to wait time differences between sites that disproportionately impact non-White patients.
The ripple effect of evidence implementation: a descriptive evaluation of JBI's Evidence-based Clinical Fellowship Program
Authors: McArthur Alexa , Munn Zachary , Lizarondo Lucylynn , Porritt Kylie , Stephenson Matthew , Stern Cindy , Lockwood Craig , Moola Sandeep , Pearson Alan , Jordan Zoe
Published: June 2021

Background:

Across healthcare there are acknowledged gaps in the translation of evidence into clinical practice. Undertaking a structured implementation program may assist clinicians to achieve this in their clinical practice setting.

Aims/Methods:

The current study descriptively evaluates and analyzes the impact of JBI's (formerly known as the Joanna Briggs Institute) Evidence-based Clinical Fellowship program, since its inception in 2005.

Results:

Since its inception the JBI Evidence-based Clinical Fellowship Program has trained over 560 Clinical Fellows. The program consists of two 1-week intensive training workshops at JBI, collaborating with a JBI Research Fellow facilitator, with each participant then conducting a workplace evidence implementation project over the intervening 6 months in their own clinical setting. A ‘train-the-trainer’ program was established to provide accredited trainers to run the program through established JBI Collaborating Entities.

Conclusion:

Implementation of research evidence into the clinical setting is challenging for health professionals. A pragmatic approach adopted through the JBI Evidence-based Clinical Fellowship Program ensures that the Clinical Fellow remains central as the program leader, but has direction and support from their team of various stakeholders, and ongoing collaboration with a JBI facilitator. This ensures increased capacity for engagement and ongoing sustainability of future implementation programs.
Barriers and facilitators for implementation of a patient prioritization tool in two specialized rehabilitation programs
Authors: Déry Julien , Ruiz Angel , Routhier François , Gagnon Marie-Pierre , Côté André , Ait-Kadi Daoud , Bélanger Valérie , Lamontagne Marie-Eve
Published: June 2021

Introduction and aims:

Prioritization tools aim to manage access to care by ranking patients equitably in waiting lists based on determined criteria. Patient prioritization has been studied in a wide variety of clinical health services, including rehabilitation contexts. We created a web-based patient prioritization tool (PPT) with the participation of stakeholders in two rehabilitation programs, which we aim to implement into clinical practice. Successful implementation of such innovation can be influenced by a variety of determinants. The goal of this study was to explore facilitators and barriers to the implementation of a PPT in rehabilitation programs.

Methods:

We used two questionnaires and conducted two focus groups among service providers from two rehabilitation programs. We used descriptive statistics to report results of the questionnaires and qualitative content analysis based on the Consolidated Framework for Implementation Research.

Results:

Key facilitators are the flexibility and relative advantage of the tool to improve clinical practices and produce beneficial outcomes for patients. Main barriers are the lack of training, financial support and human resources to sustain the implementation process.

Conclusion:

This is the first study that highlights organizational, individual and innovation levels facilitators and barriers for the implementation of a prioritization tool from service providers’ perspective.
Individual Reference Intervals for Personalized Interpretation of Clinical and Metabolomics Measurements
Authors: Pusparum Murih , Ertaylan Gökhan , Thas Olivier
Published: June 2021

The Population Reference Interval (PRI) refers to the range of outcomes that are expected in a healthy population for a clinical or a diagnostic measurement. This interval is widely used in daily clinical practice and is essential for assisting clinical decision making in diagnosis and treatment. In this study, we demonstrate that each individual indeed has a range for a given variable depending on personal biological traits. This Individual Reference Intervals (IRI) can be calculated and be utilized in clinical practice, in combination with the PRI for improved decision making where multiple data points are present per variable. As calculating IRI requires several data points from the same individual to determine a personal range, here we introduce novel methodologies to obtain the correct estimates of IRI. We use Linear Quantile Mixed Models (LQMM) and Penalized Joint Quantile Models (PJQM) to estimate the IRI’s upper and lower bounds. The estimates are obtained by considering both the within and between subjects’ variations. We perform a simulation study designed to benchmark both methods’ performance under different assumptions, resulted in PJQM giving a better empirical coverage than LQMM. Finally, both methods were evaluated on real-life data consisting of eleven clinical and metabolomics parameters from the VITO IAM Frontier study. The PJQM method also outperforms LQMM on its predictive accuracy in the real-life data setting. In conclusion, we introduce the concept of IRI and demonstrate two methodologies for calculating it to complement PRIs in clinical decision making.
Working in a care home during the COVID-19 pandemic: How has the pandemic changed working practices?
Authors: Giebel Clarissa , Hanna Kerry , Cannon Jacqueline , Shenton Justine , Mason Stephen , Tetlow Hilary , Marlow Paul , Rajagopal Manoj , Gabbay Mark
Published: June 2021

The aim of this research was to explore the impact of COVID-19 on the working practices of care home staff, caring for people living with dementia. Remote qualitative, semi-structured interviews were conducted with care home staff caring for people living with dementia (PLWD) in the UK. Participants were recruited to the larger programme of research via convenience sampling. Interviews were conducted via telephone or online platforms. This research employed inductive thematic analysis. Sixteen care home staff were included in this study. Three overarching themes were developed from the analysis that conveyed changes to the everyday working practices of the care home workforce and the impact such changes posed to staff wellbeing: (1) Practical implications of working in a care home during the COVID-19 pandemic; (2); Staff values and changes to the staff roles (3): Impact to the care home staff and concerns for the care sector. The COVID-19 pandemic has significantly disrupted the daily working practices of care home staff, with staff forced to adopt additional roles on top of increased workloads to compensate for the loss of external agencies and support. Support and guidance must be offered urgently to inform care home staff on how to best adapt to their new working practices, ensuring that they are adequately trained.
Social networking service, patient-generated health data, and population health informatics: patterns and implications for using digital technologies to support mental health
Authors: Ye Jiancheng , Wang Zidan , Hai Jiarui
Published: June 2021

Objective

To describe and compare characteristics of the population with and without mental health issues (depression or anxiety disorder), including physical health, sleep, and alcohol use. We also examined the patterns of social networking service use, patient-generated health data on the digital platforms, and health information sharing attitudes and activities.

Methods

We drew data from the National Cancer Institute’s 2019 Health Information National Trends Survey (HINTS). Participants were divided into two groups by mental health status. Then, we described and compared the characteristics of social determinants of health, health status, sleeping and drinking behaviors, and patterns of social networking service use and health information data sharing between the two groups. Multivariable logistic regression models were applied to assess the predictors of mental health. All analyses were weighted to provide nationally representative estimates.

Results

Participants with mental health issues are significantly more likely to be younger, White, female, have a lower income, have a history of chronic diseases, less capable of taking care of their own health; regarding behavioral health, they sleep less than six hours on average, have worse sleep quality, consume more alcohol; meanwhile, they are more likely to visit and share health information on social networking sites, write online diary blogs, participate online forum or support groups, watch health-related videos.

Discussion and Conclusion

This study illustrates that individuals with mental health issues have inequitable social determinants of health, poor physical health, and behavioral health. However, they are more likely to use social network platforms and services, share their health information, and have active engagements with patient-generated health data (PGHD). Leveraging these digital technologies and services could be beneficial to develop tailored and effective strategies for self-monitoring and self-management, thus supporting mental health.
Hepatitis E in Bangladesh: Insights from a National Serosurvey
Authors: Azman Andrew S , Paul Kishor Kumar , Bhuiyan Taufiqur Rahman , Koyuncu Aybüke , Salje Henrik , Qadri Firdausi , Gurley Emily S
Published: June 2021

Background

Hepatitis E virus, typically genotypes 1 and 2, is a major cause of avoidable morbidity and mortality in South Asia. Although case fatality risk among pregnant women can reach as high as 25%, a lack of population-level disease burden data has been cited as a primary factor in key global policy recommendations against the routine use of licensed hepatitis E vaccines, one of the only effective tools available for preventing disease and death.

Methods

We tested serum from a nationally-representative serosurvey in Bangladesh for anti-HEV IgG. We estimated the proportion of the population with evidence of historical HEV infection and used Bayesian geostatistical models to generate high-resolution national maps of seropositivity. We examined variability in seropositivity by individual-level, household-level, and community-level risk factors using spatial logistic regression.

Results

We tested serum samples from 2924 individuals from 70 communities representing all divisions of Bangladesh and estimated a national seroprevalence of hepatitis E of 20% (95% CI 17-24%). Seropositivity increased with age and male sex (OR: 2.2, 95% CI: 1.8–2.8). Community-level seroprevalence ranged from 0-78% with the seroprevalence in urban areas being higher, including Dhaka, the capital, with 3-fold (95%CrI 2.3-3.7) higher seroprevalence than the rest of the country.

Conclusion

Hepatitis E infections are common throughout Bangladesh, though 90% of women reach reproductive age without any evidence of previous exposure to the virus, thus likely susceptible to infection and disease. Strengthening clinical surveillance for hepatitis E, especially in urban areas may help generate additional evidence needed to appropriately target interventions like vaccines to the populations most likely to benefit.
Gender Balance and Readability of COVID-19 Scientific Publishing: A Quantitative Analysis of 90,000 Preprint Manuscripts
Authors: Celi Leo Anthony , Charpignon Marie-Laure , Ebner Daniel K. , Kaufman Aaron R. , McCoy Liam G. , Millado Maria Cecilia , Park Joel , Salciccioli Justin , Situ Julia
Published: June 2021

Releasing preprints is a popular way to hasten the speed of research but may carry hidden risks for public discourse. The COVID-19 pandemic caused by the novel SARS-CoV-2 infection highlighted the risk of rushing the publication of unvalidated findings, leading to damaging scientific miscommunication in the most extreme scenarios. Several high-profile preprints, later found to be deeply flawed, have indeed exacerbated widespread skepticism about the risks of the COVID-19 disease – at great cost to public health. Here, preprint article quality during the pandemic is examined by distinguishing papers related to COVID-19 from other research studies. Importantly, our analysis also investigated possible factors contributing to manuscript quality by assessing the relationship between preprint quality and gender balance in authorship within each research discipline. Using a comprehensive data set of preprint articles from medRxiv and bioRxiv from January to May 2020, we construct both a new index of manuscript quality including length, readability, and spelling correctness and a measure of gender mix among a manuscript’s authors. We find that papers related to COVID-19 are less well-written than unrelated papers, but that this gap is significantly mitigated by teams with better gender balance, even when controlling for variation by research discipline. Beyond contributing to a systematic evaluation of scientific publishing and dissemination, our results have broader implications for gender and representation as the pandemic has led female researchers to bear more responsibility for childcare under lockdown, inducing additional stress and causing disproportionate harm to women in science.
Analysis of the Second COVID-19 Wave in India and the United Kingdom Using a Birth-Death Model
Authors: Viswanath Narayanan C.
Published: June 2021

Several countries have witnessed multiple waves of the COVID-19 pandemic between 2020 and 21. The method in [8] is applied here to analyze the COVID-19 waves in India and the UK. For this, a birth-death model is fitted to the active and total cases data for 30 days periods called windows starting from 16th March 2020 up to 10th May 2021. Peculiarities of the parameters suggested a classification of the above windows into three categories: (i) whose fitted parameters predicted a rise in the number of active cases before a fall to zero, (ii) which predicted a decrease, without rising, in the active cases to zero and (iii) which predicted an increase in the active cases until the entire susceptible population gets infected. It follows that some of the type (iii) windows are of the same or lesser concern when compared to some type (i) windows. Further analysis of the type (iii) windows leads to the identification of those which could be indicators of the start of a new wave of the pandemic. The study thus proposes a method for using the present data for identifying pandemic waves in the near future.
A personalized network framework reveals predictive axis of anti-TNF response across diseases
Authors: Gerassy-Vainberg Shiran , Starosvetsky Elina , Gaujoux Renaud , Blatt Alexandra , Maimon Naama , Gorelik Yuri , Pressman Sigal , Alpert Ayelet , Bar-Yoseph Haggai , Dubovik Tania , Perets Benny , Katz Adir , Milman Neta , Chowers Yehuda , Shen-Orr Shai S.
Published: June 2021

Personalized treatment of complex diseases has been mostly predicated on biomarker identification of one drug-disease combination at a time. Here, we used a novel computational approach termed Disruption Networks to generate a new data type, contextualized by cell-centered individual-level networks, that captures biology otherwise overlooked when performing standard statistics. The new data-type extends beyond the ‘feature level space’, to the ‘relations space’, by quantifying individual-level breaking or rewiring of cross-feature relations. Applying disruption network to dissect high-dimensional blood data, we discover and validate that the RAC1-PAK1 axis is predictive of anti-TNF response in inflammatory bowel disease. Intermediate monocytes, which correlate with the inflammatory state, play a key role in the RAC1-PAK1 responses, supporting their modulation as a therapeutic target. This axis also predicts response in rheumatoid arthritis, validated in three public cohorts. Our findings support blood-based drug response diagnostics across immune-mediated diseases, implicating common mechanisms of non-response.
Structural organization of the C1b projection within the ciliary central apparatus
Authors: Cai Kai , Zhao Yanhe , Zhao Lei , Phan Nhan , Witman George B. , Nicastro Daniela
Published: June 2021

‘9+2’ motile cilia contain 9 doublet microtubules and a central apparatus (CA) composed of two singlet microtubules with associated projections. The CA plays crucial roles in regulating ciliary motility. Defects in CA assembly or function usually result in motility-impaired or paralyzed cilia, which in humans causes disease. Despite their importance, the protein composition and functions of most CA projections remain largely unknown. Here, we combined genetic approaches and quantitative proteomics with cryo-electron tomography and subtomogram averaging to compare the CA of wild-type Chlamydomonas with those of two CA mutants. Our results show that two conserved proteins, FAP42 and FAP246, are localized to the L-shaped C1b projection of the CA. We also identified another novel CA candidate protein, FAP413, which interacts with both FAP42 and FAP246. FAP42 is a large protein that forms the peripheral ‘beam’ of the C1b projection, and the FAP246-FAP413 subcomplex serves as the ‘bracket’ between the beam (FAP42) and the C1b ‘pillar’ that attaches the projection to the C1 microtubule. The FAP246-FAP413-FAP42 complex is essential for stable assembly of both the C1b and C1f projections, and loss of any of these proteins leads to ciliary motility defects. Our results provide insight into the subunit organization and 3D structure of the C1b projection, suggesting that the FAP246-FAP413-FAP42 subcomplex is part of a large interconnected CA-network that provides mechanical support and may play a role in mechano-signaling between the CA and radial spokes to regulate dynein activity and ciliary beating.

Summary Statement

The present work provides insight into the subunit organization and 3D structure of the C1b projection of CA and the mechanism by which it regulates dynein activity and ciliary beating.
Single Cell Transcriptomics Reveals Global Markers of Transcriptional Diversity Across Different Forms of Cellular Senescence
Authors: Evans Shane A. , Teo Yee Voan , Clark Kelly , Ito Takahiro , Sedivy John M. , Neretti Nicola
Published: June 2021

Cellular Senescence is a state of irreversible cell cycle arrest, and the accumulation of senescent cells contributes to age- related organismal decline. The detrimental effects of cellular senescence are due to the senescence associated secretory phenotype (SASP), an array of signaling molecules and growth factors secreted by senescent cells that contribute to the sterile inflammation associated with aging tissues. Recent studies, both in vivo and in vitro, have highlighted the heterogeneous nature of the senescence phenotype. In particular, single cell transcriptomics has revealed that Oncogene Induced Senescence (OIS) is characterized by the presence of subpopulations of cells expressing different SASP profiles. We have generated a comprehensive dataset via single-cell transcriptional profiling of genetically homogenous clonal cell lines from different forms of senescence, including OIS, Replicative Senescence (RS), and DNA Damage Induced Senescence (DDIS). We identified subpopulations of cells that are common to all three major forms of senescence and show that the expression profiles of these subpopulations are driven by markers formerly identified in individual forms of senescence. These common signatures are characterized by chromatin modifiers, inflammation, extracellular matrix remodeling, and Ribosomal protein expression. The expression patterns of these subpopulations recapitulate primary and secondary senescence, a phenomenon where a preexisting (primary) senescent cell induces senescence in a neighboring (secondary) cell through cell-to-cell contact. Since it is still unclear what type of senescence occurs in-vivo with age, it is important to know that the formation of primary and secondary populations is common to multiple types of senescence since this mechanism could help explain how senescent cells accumulate in aged organisms. Finally, we show that these subpopulations show differential susceptibility to the senolytic agent Navitoclax, suggesting that senolytic agents targeting the apoptotic pathways may be clearing only a subset of senescent cells based on their inflammatory profiles in-vivo.
Accurate Protein Function Prediction via Graph Attention Networks with Predicted Structure Information
Authors: Lai Boqiao , Xu Jinbo
Published: June 2021

Experimental protein function annotation does not scale with the fast-growing sequence databases. Only a tiny fraction (<0.1%) of protein sequences in UniProtKB has experimentally determined functional annotations. Computational methods may predict protein function in a high-throughput way, but its accuracy is not very satisfactory. Based upon recent breakthroughs in protein structure prediction and protein language models, we develop GAT-GO, a graph attention network (GAT) method that may substantially improve protein function prediction by leveraging predicted inter-residue contact graphs and protein sequence embedding.

Our experimental results show that GAT-GO greatly outperforms the latest sequence- and structure-based deep learning methods. On the PDB-mmseqs testset where the train and test proteins share <15% sequence identity, GAT-GO yields Fmax(maximum F-score) 0.508, 0.416, 0.501, and AUPRC(area under the precision-recall curve) 0.427, 0.253, 0.411 for the MFO, BPO, CCO ontology domains, respectively, much better than homology-based method BLAST (Fmax 0.117,0.121,0.207 and AUPRC 0.120, 0.120, 0.163). On the PDB-cdhit testset where the training and test proteins share higher sequence identity, GAT-GO obtains Fmax 0.637, 0.501, 0.542 for the MFO, BPO, CCO ontology domains, respectively, and AUPRC 0.662, 0.384, 0.481, significantly exceeding the just-published graph convolution method DeepFRI, which has Fmax 0.542, 0.425, 0.424 and AUPRC 0.313, 0.159, 0.193.
Spatial structure, phase, and the contrast of natural images
Authors: Rideaux Reuben , West Rebecca K. , Wallis Thomas S. A. , Bex Peter J. , Mattingley Jason B. , Harrison William J.
Published: June 2021

The sensitivity of the human visual system is thought to be shaped by environmental statistics. A major endeavour in vision science, therefore, is to uncover the image statistics that predict perceptual and cognitive function. When searching for targets in natural images, for example, it has recently been proposed that target detection is inversely related to the spatial similarity of the target to its local background. We tested this hypothesis by measuring observers’ sensitivity to targets that were blended with natural image backgrounds. Targets were designed to have a spatial structure that was either similar or dissimilar to the background. Contrary to masking from similarity, we found that observers were most sensitive to targets that were most similar to their backgrounds. We hypothesised that a coincidence of phase-alignment between target and background results in a local contrast signal that facilitates detection when target-background similarity is high. We confirmed this prediction in a second experiment. Indeed, we show that, by solely manipulating the phase of a target relative to its background, the target can be rendered easily visible or undetectable. Our study thus reveals that, in addition to its structural similarity, the phase of the target relative to the background must be considered when predicting detection sensitivity in natural images.
The contributions of extracellular matrix and sarcomere properties to passive muscle stiffness in cerebral palsy
Authors: Konno Ryan N. , Nigam Nilima , Wakeling James M. , Ross Stephanie A.
Published: June 2021

Cerebral palsy results from an upper motor neuron lesion and has significant effects on skeletal muscle stiffness throughout the body. The increased stiffness that occurs is partly a result of changes in the microstructural components of muscle. In particular, alterations in extracellular matrix, sarcomere length, fibre diameter, and fat content have been reported; however, experimental studies have shown wide variability in the degree to which each component is altered. Many studies have reported alterations in the extracellular matrix, while others have reported no changes. A consistent finding throughout the literature is increased sarcomere length in cerebral palsy muscle. Often more than one component is altered, making it difficult to determine the individual effects on stiffness. The purpose of this study is to use a modeling approach to isolate individual effects of microstructural alterations that typically occur during cerebral palsy on whole muscle behavior; in particular, the extracellular matrix volume fraction, stiffness, and sarcomere length. These microstructural effects can be captured using a three dimensional model of muscle. We found that the extracellular matrix volume fraction has a larger effect on stiffness compared to sarcomere length, even when coupled with decreased extracellular matrix stiffness. Additionally, the effects of sarcomere length in passive stiffness are mitigated by the increased extracellular matrix volume fraction. Using this model, we can achieve a better understanding of the possible combinations of microstructural changes that can occur during cerebral palsy. Developing these insights into diseased muscle tissue will help to direct future clinical and experimental procedures.
Non-serotype 2 isolates from healthy pigs are a potential zoonotic reservoir ofStreptococcus suisgenetic diversity and antimicrobial resistance
Authors: Kittiwan Nattinee , Calland Jessica K. , Mourkas Evangelos , Hitchings Matthew D. , Murray Susan , Tadee Pakpoom , Tadee Pacharaporn , Duangsonk Kwanjit , Méric Guillaume , Sheppard Samuel K. , Patchanee Prapas , Pascoe Ben
Published: June 2021

Streptococcus suisis a leading cause of bacterial meningitis in SE Asia, with frequent zoonotic transfer to humans associated with close contact with pigs. A small number of invasive lineages are responsible for endemic infection in the swine industry causing considerable global economic losses. A lack of surveillance and a rising trend in clinical treatment failure has raised concerns of growing antimicrobial resistance (AMR) among invasiveS. suis. The source-sink dynamics between healthy and disease isolates is poorly understood and, in this study, we sample and sequence a collection of isolates predominantly from healthy pigs in Chiang Mai province, Northern Thailand. Pangenome comparisons with a selection of invasive serotype 2 isolates identified increased genetic diversity and more frequent AMR carriage in isolates from healthy pigs. Multiple antimicrobial resistance genes were identified conferring resistance to aminoglycosides, lincosamides, tetracycline and macrolides. All isolates were non-susceptinle to three or more different antimicrobial classes, and 75% of non-serotype 2 isolates were non-susceptible to 6 or more classes (compared to 37.5% of serotype 2 isolates). Antimicrobial resistance genes were found on integrative and conjugative elements (ICE) previously observed in other species, suggesting mobile gene pool which can be accessed by invasive disease isolates.

Significance statement

The zoonotic pathogenStreptococcus suiscauses respiratory disease in pigs and is among the most common causative agents of human clinical bacterial meningitis in SE Asia. We collected isolates from farmed healthy pigs in Northern Thailand, representing a source population from which invasive isolates have recently emerged – linked to the pork production industry. Pangenome characterisation of the isolates revealed a reservoir of genetic diversity and antimicrobial resistance suggesting that One Health approaches may be beneficial in tackling the increase in antimicrobial resistance.
Tau interactome mapping reveals dynamic processes in synapses and mitochondria associated with neurodegenerative disease
Authors: Tracy Tara E. , Madero-Pérez Jesus , Swaney Danielle , Chang Timothy S. , Moritz Michelle , Konrad Csaba , Ward Michael E. , Stevenson Erica , Hüttenhain Ruth , Kauwe Grant , Mercedes Maria , Sweetland-Martin Lauren , Chen Xu , Mok Sue-Ann , Telpoukhovskaia Maria , Min Sang-Won , Wang Chao , Sohn Peter Dongmin , Martin Jordie , Zhou Yungui , Manfredi Giovanni , Coppola Giovanni , Krogan Nevan J. , Geschwind Daniel H. , Gan Li
Published: June 2021

Tau (MAPT) drives neuronal dysfunction in Alzheimer’s disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established activity-dependent interactions of Tau with presynaptic vesicle proteins during Tau secretion and mapped the exact APEX-tau-induced biotinylated tyrosines to the cytosolic domains of the interacting vesicular proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Tau’s interaction with mitochondria proteins, which were downregulated in AD brains of multiple cohorts and correlated with disease severity. These multi-modal and dynamic Tau interactomes with unprecedented spatiotemporal resolution shed novel insights into Tau’s role in neuronal function and disease-related processes with potential therapeutic targets to block Tau-mediated pathogenesis.
No evidence for changes in GABA concentration, functional connectivity, or working memory following continuous theta burst stimulation over dorsolateral prefrontal cortex
Authors: Thapa Tribikram , Hendrikse Joshua , Thompson Sarah , Suo Chao , Biabani Mana , Morrow James , Hoy Kate E , Fitzgerald Paul B , Fornito Alex , Rogasch Nigel C
Published: June 2021

Continuous theta burst stimulation (cTBS) is thought to reduce cortical excitability and modulate functional connectivity, possibly by altering cortical inhibition at the site of stimulation. However, most evidence comes from the motor cortex and it remains unclear whether similar effects occur following stimulation over other brain regions. We assessed whether cTBS over left dorsolateral prefrontal cortex altered gamma aminobutyric acid (GABA) concentration, functional connectivity and brain dynamics at rest, and brain activation and memory performance during a working memory task. Seventeen healthy individuals participated in a randomised, sham-controlled, cross-over experiment. Before and after either real or sham cTBS, magnetic resonance spectroscopy was obtained at rest to measure GABA concentrations. Functional magnetic resonance imaging (fMRI) was also recorded at rest and during an n-back working memory task to measure functional connectivity, regional brain activity (low-frequency fluctuations), and task-related patterns of brain activity. We could not find evidence for changes in GABA concentration (P=0.66, Bayes factor [BF10]=0.07), resting-state functional connectivity (P(FWE)>0.05), resting-state low-frequency fluctuations (P=0.88, BF10=0.04), blood-oxygen level dependent activity during the n-back task (P(FWE) >0.05), or working memory performance (P=0.13, BF10=0.05) following real or sham cTBS. Our findings add to a growing body of literature suggesting the effects of cTBS are highly variable between individuals and question the notion that cTBS is a universal ‘inhibitory’ paradigm.
CUB domain containing protein 1 (CDPC1) is a target for radioligand therapy in castration resistant prostate cancer
Authors: Zhao Ning , Trepka Kai , Wang Yung-hua , Chopra Shalini , Hooshdaran Nima , Kim Hyunjung , Zhuo Jie , Lim Shion A. , Yang Jianing , Leung Kevin K. , Egusa Emily , Zhang Li , Foye Adam , Chou Jonathon , Feng Felix Y. , Small Eric J. , Wells James A. , Aggarwal Rahul , Evans Michael J.
Published: June 2021

Purpose

Radioligand therapy (RLT) is relatively unexplored in metastatic castration resistant prostate cancer (mCRPC), with much of the focus having been on bone seeking radionuclides and PSMA-directed RLT. Herein, we evaluated if CUB domain containing protein 1 (CDCP1) can be exploited to treat mCRPC with RLT, particularly for subsets like small cell neuroendocrine prostate cancer (SCNC) that would not be expected to respond to current options.

Experimental Design

CDCP1 mRNA levels were evaluated in the RNA-seq data from 119 recent mCRPC biopsies. Protein expression was assessed in twelve SCNC and adenocarcinoma patient derived xenografts. Saturation binding assays were performed with 4A06, a recombinant human antibody that targets the CDCP1 ectodomain. The feasibility of imaging and treating mCRPC in vivo was tested with 89Zr-4A06 and 177Lu-4A06.

Results

CDCP1 mRNA expression was observed in over 90% of mCRPC biopsies, including SCNC and in adenocarcinoma with low FOLH1 (PSMA) levels. A modest anticorrelation was observed between CDCP1 and PTEN. Overall survival was not significantly different based on CDCP1 mRNA levels, regardless of PTEN status. Full length and/or cleaved CDCP1 was expressed in ten of twelve PDX samples. Bmax values of ~22,000 and ~6,200 fmol/mg were calculated for two human prostate cancer cell lines. Five prostate cancer models were readily detected in vivo with 89Zr-4A06. 177Lu-4A06 significantly suppressed the growth of DU145 tumors compared to control.

Conclusions

The antitumor data and the overexpression of CDCP1 reported herein provide the first evidence promoting CDCP1 directed RLT as a treatment strategy for mCRPC.

Statement of Translational Relevance

New targets for RLT are needed to address the subset of mCRPC that cannot be treated with bone seeking radionuclides or PSMA directed RLT. We report herein the first data credentialing CDCP1 as a target for mCRPC, in both adenocarcinoma and neuroendocrine subtypes. Combined with low expression in normal human tissues, these data provide a compelling scientific rationale for testing CDCP1 directed RLT clinically in mCRPC patients alone or in combination with other systemic therapies.
mRNA- and factor-driven dynamic variability controls eIF4F-cap recognition for translation initiation
Authors: Çetin Burak , O’Leary Seán E.
Published: June 2021

mRNA 5ʹ cap recognition by eIF4F is a key step in eukaryotic translational control. While different mRNAs respond differently to eIF4F-directed regulation, the molecular basis for this variability remains unclear. We developed single-molecule fluorescence assays to directly observe eIF4F– mRNA interactions. We uncovered a complex interplay of mRNA features with factor activities that differentiates cap recognition between mRNAs. eIF4E–cap association rates are anticorrelated with mRNA length. eIF4A leverages ATP binding to differentially accelerate eIF4E– mRNA association; the extent of this acceleration correlates with translation efficiencyin vivo. eIF4G lengthens eIF4E–cap binding to persist on the initiation timescale. The full eIF4F complex discriminates between mRNAs in an ATP-dependent manner. After eIF4F–mRNA binding, eIF4E is ejected from the cap by eIF4A ATP hydrolysis. Our results suggest features throughout mRNA coordinate in controlling cap recognition at the 5ʹ end, and suggest a model for how eIF4F–mRNA dynamics establish mRNA sensitivity to translational control processes.
Image quantification technique reveals novel lung cancer cytoskeletal phenotype with partial EMT signature
Authors: Basu Arkaprabha , Paul Manash K. , Alioscha-Perez Mitchel , Grosberg Anna , Sahli Hichem , Dubinett Steven M. , Weiss Shimon
Published: June 2021

Epithelial-mesenchymal Transition (EMT) is a multi-step process that involves cytoskeletal rearrangement. Here, using novel image quantification tools, we have identified an intermediate EMT state with a specific cytoskeletal signature. We have been able to partition EMT into two steps: (1) initial formation of transverse arcs and dorsal stress fibers and (2) their subsequent conversion to ventral stress fibers with a concurrent alignment of fibers. Using the Orientational Order Parameter (OOP) as a figure of merit, we have been able to track EMT progression in live cells as well as characterize and quantify drug responses. Our technique has improved throughput and is non-destructive, making it a viable candidate for studying a broad range of biological processes. Further, owing to the increased stiffness (and hence invasiveness) of the intermediate phenotype compared to mesenchymal cells, our work can be instrumental in aiding the search for new treatment strategies that combat metastasis by specifically targeting the fiber alignment process.
Nanopore callers for epigenetics from limited supervised data
Authors: Yao Brian , Hsu Chloe , Goldner Gal , Michaeli Yael , Ebenstein Yuval , Listgarten Jennifer
Published: June 2021

Nanopore sequencing platforms combined with supervised machine learning (ML) have been effective at detecting base modifications in DNA such as 5mC and 6mA. These ML-based nanopore callers have typically been trained on data that span all modifications on all possible DNA k-mer backgrounds—a complete training dataset. However, as nanopore technology is pushed to more and more epigenetic modifications, such complete training data will not be feasible to obtain. Nanopore calling has historically been performed with Hidden Markov Models (HMMs) that cannot make successful calls for k-mer contexts not seen during training because of their independent emission distributions. However, deep neural networks (DNNs), which share parameters across contexts, are increasingly being used as callers, often outperforming their HMM cousins. It stands to reason that a DNN approach should be able to better generalize to unseen k-mer contexts. Indeed, herein we demonstrate that a common DNN approach (DeepSignal) outperforms a common HMM approach (Nanopolish) in the incomplete data setting. Furthermore, we propose a novel hybrid HMM-DNN approach, Amortized-HMM, that outperforms both the pure HMM and DNN approaches on 5mC calling when the training data are incomplete. Such an approach is expected to be useful for calling 5hmC and combinations of cytosine modifications, where complete training data are not likely to be available.