bluuebunny/crossref_metadata_2025 huggingface dataset:
Rare case of torsion of giant ovarian mass post-colonoscopy
Authors: Ng Irene A T , Wong Jolene S M , Wong Jermaine , Chia Claramae S , Ong Chin-Ann J
Published: March 2021

We present an unprecedented case of torsion of a large ovarian cyst following colonoscopy. A 43-year-old female was found to have a 20 × 13 × 19 cm pelviabdominal mass possibly arising from the right ovary. Endoscopic evaluation was performed prior to planned resection of the ovarian mass. The patient experienced progressive lower abdominal pain after the procedure with a computed topography finding of torsion. She underwent exploratory laparotomy, right salpingo-oophorectomy with intra-operative frozen section and omentectomy. Final histology revealed features of benign serous cystadenoma with extensive haemorrhagic infarction in keeping with torsion. To our knowledge, this is the first reported case of torsion of a large ovarian cyst after colonoscopy. We propose a postulated mechanism of this patient’s ovarian torsion and urge clinicians to be cognizant of acute ovarian torsion as a cause of severe abdominal pain following endoscopy.
Creativity complicates tweets: a quantitative lens on syntactic characteristics of twitter
Authors: Wang Yaqin , Liu Haitao
Published: March 2021

Twitter is a newly emerged computer-mediated discourse (CMD) genre in recent years for exchanging short textual messages with the 140-character constraint. Little explicitly quantitative attention has been given to the syntactic structure of twitter, though. Under the framework of dependency grammar, the present study intends to investigate the syntactic characteristics of twitter based on quantitative methods by a comparison with traditional written genres and CMD genres. Results show that (1) most tweets are syntactically easy to understand, shaped by the principle of least effort. With the shortest sentence length, twitter has more syntactically difficult sentences than do traditional fictions, which somehow contradicts the common belief. (2) The word order of twitter demonstrates a different distribution from that of the other genres. (3) Twitter’s distribution of dependency types in relation to all the other genres shows a dynamic property. Some of the frequencies of syntactic relations of twitter are similar to those of traditional fiction and others close to those of traditional news. To summarize, creative linguistic features of twitter interestingly complicate syntactic characteristics, through which we may obtain new insights regarding twitter syntax as well as possible contextual factors behind that.
U.S. Neurosurgical Response to COVID-19: Forging a Path Toward Disaster Preparedness
Authors: Ravindra Vijay M , Dunn Gavin P , Belverud Shawn , Carroll Christopher P , Zuckerman Scott L , Menger Richard , Malone David , Cooke Jonathon , Porenksy Paul , Klugh III Arnett , Gilhooly Jonathan , Tomlin Jeffrey , Bell Randy , Ikeda Daniel S
Published: March 2021

Introduction

The worldwide COVID-19 pandemic poses challenges to healthcare capacity and infrastructure. The authors discuss the structure and efficacy of the U.S. Navy’s response to COVID-19 and evaluate the utility of this endeavor, with the objective of providing future recommendations for managing worldwide healthcare and medical operational demands from the perspective of Navy Neurosurgery.

Materials and Methods

The authors present an extensive review of topics and objectively highlight the efforts of U.S. Navy Neurosurgery as it pertains to the humanitarian mission during the COVID-19 pandemic.

Results

During the humanitarian mission (March 27, 2020–April 14, 2020), the response of active duty and reserve neurosurgeons in the U.S. Navy was robust. Neurosurgical coverage was present on board the U.S. Navy Ships Mercy and Comfort, with additional neurosurgical deployment to New York City for intensive care unit management and coverage.

Conclusions

The U.S. Navy neurosurgical response to the COVID-19 pandemic was swift and altruistic. Although neurosurgical pathologies were limited among the presenting patients, readiness and manpower continue to be strong influences within the Armed Forces. The COVID-19 response demonstrates that neurosurgical assets can be rapidly mobilized and deployed in support of wartime, domestic, and global humanitarian crises to augment both trauma and critical care capabilities.
The tidal evolution of dark matter substructure – II. The impact of artificial disruption on subhalo mass functions and radial profiles
Authors: Green Sheridan B , van den Bosch Frank C , Jiang Fangzhou
Published: March 2021

Several recent studies have indicated that artificial subhalo disruption (the spontaneous, non-physical disintegration of a subhalo) remains prevalent in state-of-the-art dark matter (DM)-only cosmological simulations. In order to quantify the impact of disruption on the inferred subhalo demographics, we augment the semi-analytical SatGen dynamical subhalo evolution model with an improved treatment of tidal stripping that is calibrated using the Dynamical Aspects of SubHaloes database of idealized high-resolution simulations of subhalo evolution, which are free from artificial disruption. We also develop a model of artificial disruption that reproduces the statistical properties of disruption in the Bolshoi simulation. Using this framework, we predict subhalo mass functions (SHMFs), number density profiles, and substructure mass fractions and study how these quantities are impacted by artificial disruption and mass resolution limits. We find that artificial disruption affects these quantities at the $10{-}20{{\ \rm per\ cent}}$ level, ameliorating previous concerns that it may suppress the SHMF by as much as a factor of 2. We demonstrate that semi-analytical substructure modelling must include orbit integration in order to properly account for splashback haloes, which make up roughly half of the subhalo population. We show that the resolution limit of N-body simulations, rather than artificial disruption, is the primary cause of the radial bias in subhalo number density found in DM-only simulations. Hence, we conclude that the mass resolution remains the primary limitation of using such simulations to study subhaloes. Our model provides a fast, flexible, and accurate alternative to studying substructure statistics in the absence of both numerical resolution limits and artificial disruption.
DETERMINATION OF NATURAL RADIOACTIVITY AND RADIOLOGICAL HAZARD ASSOCIATED WITH SEDIMENTS SOURCED FROM OGUNPA RIVER CHANNELS, IBADAN, NIGERIA
Authors: Jibiri N N , Egwu S O , Adesiji N E
Published: March 2021

The natural radionuclides content and radiological assessment of sediments of the Ogunpa waste-water channel were evaluated to ascertain the radiological safety of the sediments as a building material. The mean activity concentrations of 40K, 226Ra and 232Th in Bq kg−1 were found to be 171 ± 69, 11 ± 5 and 10 ± 4, respectively. The overall mean radium equivalent 29 ± 13 Bq kg−1 was <370 Bq kg−1 that can give the maximum recommended dose of 1 mSv to the general public. The activity concentrations of the radionuclides were all less than world average for soils and sediments. Thus, the use of the sediments from the Ogunpa water channel as building material is safe and would not pose any significant radiological health hazards.
Reproductive activation in honeybee (
Apis mellifera
) workers protects against abiotic and biotic stress
Authors: Kennedy Anissa , Herman Jacob , Rueppell Olav
Published: March 2021

Social insect reproductives exhibit exceptional longevity instead of the classic trade-off between somatic maintenance and reproduction. Even normally sterile workers experience a significant increase in life expectancy when they assume a reproductive role. The mechanisms that enable the positive relation between the antagonistic demands of reproduction and somatic maintenance are unclear. To isolate the effect of reproductive activation, honeybee workers were induced to activate their ovaries. These reproductively activated workers were compared to controls for survival and gene expression patterns after exposure to Israeli Acute Paralysis Virus or the oxidative stressor paraquat. Reproductive activation increased survival, indicating better immunity and oxidative stress resistance. After qPCR analysis confirmed our experimental treatments at the physiological level, whole transcriptome analysis revealed that paraquat treatment significantly changed the expression of 1277 genes in the control workers but only two genes in reproductively activated workers, indicating that reproductive activation preemptively protects against oxidative stress. Significant overlap between genes that were upregulated by reproductive activation and in response to paraquat included prominent members of signalling pathways and anti-oxidants known to affect ageing. Thus, while our results confirm a central role of vitellogenin, they also point to other mechanisms to explain the molecular basis of the lack of a cost of reproduction and the exceptional longevity of social insect reproductives. Thus, socially induced reproductive activation preemptively protects honeybee workers against stressors, explaining their longevity.

This article is part of the theme issue ‘Ageing and sociality: why, when and how does sociality change ageing patterns?'
Why and how do termite kings and queens live so long?
Authors: Tasaki Eisuke , Takata Mamoru , Matsuura Kenji
Published: March 2021

Lifespan varies greatly across the tree of life. Of the various explanations for this phenomenon, those that involve trade-offs between reproduction and longevity have gained considerable support. There is an important exception: social insect reproductives (queens and in termites, also kings) exhibit both high reproductive outputs and extraordinarily long lives. As both the ultimate and proximate mechanisms underlying the absence of the fecundity/longevity trade-off could shed light on the unexpected dynamics and molecular mechanisms of extended longevity, reproductives of social insects have attracted much attention in the field of ageing research. Here, we highlight current ecological and physiological studies on ageing and discuss the various possible evolutionary and molecular explanations of the extended lifespans of termite reproductives. We integrate these findings into a coherent framework revealing the evolution of longevity in these reproductives. Studies on termites may explain why and how ageing is shaped by natural selection.

This article is part of the theme issue ‘Ageing and sociality: why, when and how does sociality change ageing patterns?’
Development and Implementation of a scalable and versatile test for COVID-19 diagnostics in rural communities
Authors: Ceci A. , Muñoz-Ballester C. , Tegge A. , Brown K.L. , Umans R.A. , Michel F.M. , Patel D. , Tewari B. , Martin J. , Alcoreza O. , Maynard T. , Martinez-Martinez D. , Bordwine P. , Bissell N. , Friedlander M. , Sontheimer H. , Finkielstein C.V.
Published: March 2021

Rapid and widespread testing of severe acute respiratory coronavirus 2 (SARS-CoV-2) is essential for an effective public health response aimed at containing and mitigating the coronavirus disease 2019 (COVID-19) pandemic. Successful health policy implementation relies on early identification of infected individuals and extensive contact tracing.However, rural communities, where resources for testing are sparse or simply absent, face distinctive challenges to achieving this success. Accordingly, we report the development of an academic, public land grant University laboratory-based detection assay for the identification of SARS-CoV-2 in samples from various clinical specimens that can be readily deployed in areas where access to testing is limited. The test, which is a quantitative reverse transcription polymerase chain reaction (RT-qPCR)-based procedure, was validated on samples provided by the state laboratory and submitted for FDA Emergency Use Authorization. Our test exhibits comparable sensitivity and exceeds specificity and inclusivity values compared to other molecular assays. Additionally, this test can be re-configured to meet supply chain shortages, modified for scale up demands, and is amenable to several clinical specimens. Test development also involved 3D engineering critical supplies and formulating a stable collection media that allowed samples to be transported for hours over a dispersed rural region without the need for a cold-chain. These two elements that were critical when shortages impacted testing and when personnel needed to reach areas that were geographically isolated from the testing center. Overall, using a robust, easy-to-adapt methodology, we show that an academic laboratory can supplement COVID-19 testing needs and help local health departments assess and manage outbreaks. This additional testing capacity is particularly germane for smaller cities and rural regions that would otherwise be unable to meet the testing demand.
“We also deserve help during the pandemic”: The effect of the COVID-19 pandemic on foreign domestic workers in Hong Kong
Authors: Lui Ingrid D. , Vandan Nimisha , Davies Sara E. , Harman Sophie , Morgan Rosemary , Smith Julia , Wenham Clare , Grépin Karen Ann
Published: March 2021

The coronavirus disease 2019 (COVID-19) pandemic poses particular challenges for migrant workers around the world. This study explores the unique experiences of foreign domestic workers (FDWs) in Hong Kong, and how COVID-19 impacted their health and economic wellbeing. Interviews with FDWs (n= 15) and key informants (n= 3) were conducted between May and August 2020. FDWs reported a dual-country experience of the pandemic, where they expressed concerns about local transmission risks as well as worries about their family members in their home country. Changes to their current work situation included how their employers treated them, as well as their employment status. FDWs also cited blind spots in the Hong Kong policy response that also affected their experience of the pandemic, including a lack of support from the Hong Kong government. Additional support is needed to mitigate the particularly negative effects of the pandemic on FDWs.
Evaluation of Junior Doctors’ Knowledge of Corneal Donation and the New Opt-Out System in England
Authors: Gopal Bhavesh , Titi-Lartey Owuraku Asiedu , Fernandes Princeton , Noubani Nur-Emel , Blatherwick Elizabeth , Said Dalia G. , Dua Harminder S. , Ting Darren Shu Jeng
Published: March 2021

Objectives

To evaluate the knowledge of corneal donation and the new opt-out system among junior doctors in the East Midlands, UK.

Methods

This was a cross-sectional study performed during June-September 2020. A 26-item questionnaire-based survey was disseminated to all 340 junior doctors working in the East Midlands, UK. Relevant data, including participants background, knowledge of corneal donation and the new opt-out system introduced in England, were analysed.

Results

A total of 143 responses were received (response rate=42.1%). Nineteen (13.3%) junior doctors had previously discussed about corneal donation. The majority (100, 69.9%) of them perceived the importance of obtaining consent for corneal donation as junior doctors, but only 24 (16.8%) felt comfortable in discussing corneal donation. The knowledge of corneal donation was low, with a mean correct response rate of 33.3+/-20.8%. Only 28 (19.6%) doctors were aware of the 24-hour death-to-enucleation time limit. The majority (116, 81.1%) of doctors would consider certifying a death on the ward quicker if they knew it could potentially compromise the quality of corneas. Most (103, 72%) doctors were aware of the new opt-out system but only 56 (39.2%) doctors correctly stated that donation can only proceed with family consent.

Conclusion

Junior doctors working at the frontline services serve as valuable members in contributing to the process of obtaining consent for organ/tissue donation. Our study highlights the lack of knowledge of corneal donation and the opt-out system amongst junior doctors in the UK. Targeted postgraduate training during the induction process may potentially enhance the donation rate.
Covid-19 in the California State Prison System: An Observational Study of Decarceration, Ongoing Risks, and Risk Factors
Authors: Chin Elizabeth T. , Ryckman Theresa , Prince Lea , Leidner David , Alarid-Escudero Fernando , Andrews Jason R. , Salomon Joshua A. , Studdert David M. , Goldhaber-Fiebert Jeremy D.
Published: March 2021

Background

Correctional institutions nationwide are seeking to mitigate Covid-19-related risks.

Objective

To quantify changes to California’s prison population since the pandemic began and identify risk factors for Covid-19 infection.

Design

We described residents’ demographic characteristics, health status, Covid-19 risk scores, room occupancy, and labor participation. We used Cox proportional hazard models to estimate the association between rates of Covid-19 infection and room occupancy and out-of-room labor, respectively.

Setting

California state prisons (March 1-October 10, 2020).

Participants

Residents of California state prisons.

Measurements

Changes in the incarcerated population’s size, composition, housing, and activities. For the risk factor analysis, the exposure variables were room type (cells vs dormitories) and labor participation (any room occupant participating in the prior 2 weeks) and the outcome variable was incident Covid-19 case rates.

Results

The incarcerated population decreased 19.1% (119,401 to 96,623) during the study period.On October 10, 2020, 11.5% of residents were aged ≥60, 18.3% had high Covid-19 risk scores, 31.0% participated in out-of-room labor, and 14.8% lived in rooms with ≥10 occupants. Nearly 40% of residents with high Covid-19 risk scores lived in dormitories. In 9 prisons with major outbreaks (6,928 rooms; 21,750 residents), dormitory residents had higher infection rates than cell residents (adjusted hazard ratio [AHR], 2.51 95%CI, 2.25-2.80) and residents of rooms with labor participation had higher rates than residents of other rooms (AHR, 1.56; 95%CI, 1.39-1.74).

Limitations

Inability to measure density of residents’ living conditions or contact networks among residents and staff.

Conclusion

Despite reductions in room occupancy and mixing, California prisons still house many medically vulnerable residents in risky settings. Reducing risks further requires a combination of strategies, including rehousing, decarceration, and vaccination.

Funding Sources

Horowitz Family Foundation; National Institute on Drug Abuse; National Science Foundation Graduate Research Fellowship; Open Society Foundations.
The COVIDome Explorer Researcher Portal
Authors: Sullivan Kelly D. , Galbraith Matthew D. , Kinning Kohl T. , Bartsch Kyle , Levinsky Nik , Araya Paula , Smith Keith P. , Granrath Ross E. , Shaw Jessica R. , Baxter Ryan , Jordan Kimberly R. , Russell Seth , Dzieciatkowska Monika , Reisz Julie A. , Gamboni Fabia , Cendali Francesca , Ghosh Tusharkanti , Monte Andrew A. , Bennett Tellen D. , Miller Michael G. , Hsieh Elena W.Y. , D’Alessandro Angelo , Hansen Kirk C. , Espinosa Joaquin M.
Published: March 2021

COVID-19 pathology involves dysregulation of diverse molecular, cellular, and physiological processes. In order to expedite integrated and collaborative COVID-19 research, we completed multi-omics analysis of hospitalized COVID-19 patients including matched analysis of the whole blood transcriptome, plasma proteomics with two complementary platforms, cytokine profiling, plasma and red blood cell metabolomics, deep immune cell phenotyping by mass cytometry, and clinical data annotation. We refer to this multidimensional dataset as the COVIDome. We then created the COVIDome Explorer, an online researcher portal where the data can be analyzed and visualized in real time. We illustrate here the use of the COVIDome dataset through a multi-omics analysis of biosignatures associated with C-reactive protein (CRP), an established marker of poor prognosis in COVID-19, revealing associations between CRP levels and damage-associated molecular patterns, depletion of protective serpins, and mitochondrial metabolism dysregulation. We expect that the COVIDome Explorer will rapidly accelerate data sharing, hypothesis testing, and discoveries worldwide.
Sensitivity to missing not at random dropout in clinical trials: use and interpretation of the Trimmed Means Estimator
Authors: Hazewinkel Audinga-Dea , Bowden Jack , Wade Kaitlin H. , Palmer Tom , Wiles Nicola , Tilling Kate
Published: March 2021

Outcome values in randomized controlled trials (RCTs) may be missing not at random (MNAR), if patients with extreme outcome values are more likely to drop out (e.g., due to perceived ineffectiveness of treatment, or adverse effects). In such scenarios, estimates from complete case analysis (CCA) and multiple imputation (MI) will be biased. The trimmed means (TM) estimator operates by setting missing values to the most extreme value, and then “trimming” away equal fractions of both treatment groups, estimating the treatment effect using the remaining data. The TM estimator relies on two assumptions, which we term the “strong MNAR” and “location shift” assumptions. In this article, we derive formulae for the bias resulting from the violation of these assumptions for normally distributed outcomes. We propose an adjusted estimator, which relaxes the location shift assumption and detail how our bias formulae can be used to establish the direction of bias of CCA, MI and TM estimates under a range of plausible data scenarios, to inform sensitivity analyses. The TM approach is illustrated with simulations and in a sensitivity analysis of the CoBalT RCT of cognitive behavioural therapy (CBT) in 469 individuals with 46 months follow-up. Results were consistent with a beneficial CBT treatment effect. The MI estimates are closer to the null than the CCA estimate, whereas the TM estimate was further from the null. We propose using the TM estimator as a sensitivity analysis for data where it is suspected that extreme outcome values are missing.
Torque teno virus load predicts allograft rejection but not viral infection after kidney transplantation
Authors: van Rijn Aline L , Wunderink Herman F , Sidorov Igor A , de Brouwer Caroline S , Kroes Aloysius CM , Putter Hein , de Vries Aiko PJ , Rotmans Joris I , Feltkamp Mariet CW
Published: March 2021

The main challenge of immunosuppressive therapy after solid organ transplantation is to create a new immunological balance that prevents organ rejection and does not promote opportunistic infection. Torque teno virus (TTV) a ubiquitous and non-pathogenic single-stranded DNA virus has been proposed as a marker of functional immunity in immunocompromised patients. Here investigate whether TTV loads predict the risk of common viral infection and allograft rejection in kidney transplantation recipients.

In a retrospective cohort of 389 kidney transplantation recipients, individual TTV loads in were measured by qPCR in consecutive plasma samples during one year follow-up. The endpoints were allograft rejection, BK polyomavirus (BKPyV) viremia and cytomegalovirus (CMV) viremia. Repeated TTV measurements and rejection and infection survival data were analysed in a joint model.

During follow-up, TTV DNA detection in the transplant recipients increased from 85 to 100%. The median viral load increased to 107genome copies/ml within three months after transplantation. Rejection, BKPyV viremia and CMV viremia occurred in 23%, 27% and 17% of the patients, respectively. With every 10-fold TTV load-increase, the risk of rejection decreased considerably (HR: 0.74, CI 95%: 0.71-0.76), while the risk of BKPyV and CMV viremia remained the same (HR: 1.03, CI 95%: 1.03-1.04 and HR: 1.01, CI 95%: 1.01-1.01).

In conclusion, TTV load kinetics predict allograft rejection in kidney transplantation recipients, but not the BKPyV and CMV infection. The potential use of TTV load levels as a guide for optimal immunosuppressive drug dosage to prevent allograft rejection deserves further validation.
Comparing a new device to measure lung volumes with three traditional methods in individuals with different lung conditions
Authors: Zac Jacob , Zac Salomon , Pérez-Padilla Rogelio , Remigio-Luna Arantxa , Guzmán-Boulloud Nicolas , Gochicoa-Rangel Laura , Guzmán-Valderrábano Carlos , Thirión-Romero Ireri
Published: March 2021

Background

Lung volumes can be measured by body plethysmography (BP), by inert gas dilution during a single-breath or multiple breaths and by radiographic methods based on chest roentgenogram or CT scanning. Our objective was to analyze the concordance between several methods including a new instrument in a variety of pulmonary conditions.

Methods

We recruited four groups of adult volunteers at the COPD and Tobacco Clinic of a respiratory referral hospital: patients with lung bullae, with obstructive lung diseases, with restrictive lung diseases and healthy controls; all subjects underwent lung volume measurements according to ATS/ERS standards in random order with each method and then CT scanning. Differences among groups were estimated by Kruskal-Wallis tests. Concordance correlation coefficients (CCC) and Bland-Altman plots were performed.

Results

Sixty-two patients were studied including 15 with lung bullae, 14 with obstructive lung diseases, 12 with restrictive lung disease and 21 healthy subjects. Highest concordance was obtained between BP and CT scanning (CCC 0.95, mean difference −0.35 L) and the lowest, with TLC-DLCOsb (CCC 0.65, difference - 1.05 L). TLC measured by BP had a moderate concordance with Minibox (CCC=0.91, mean difference −0.19 L). Minibox, on the other hand had the lowest intratest repeatibility (2.7%) of all tested methods.

Conclusions

Lung volumes measured by BP and CT had a substantial concordance in the scenario of varied pulmonary conditions including lung bullae, restrictive and obstructive diseases. The new minibox device, had low intratest variability, and was easy to perform, with a reasonable concordance with BP.
Genetic heterogeneity and subtypes of major depression
Authors: Nguyen Thuy-Dung , Harder Arvid , Xiong Ying , Kowalec Kaarina , Hägg Sara , Cai Na , Kuja-Halkola Ralf , Dalman Christina , Sullivan Patrick F , Lu Yi
Published: March 2021

Major depression (MD) is a heterogeneous disorder; however, the extent to which genetic factors distinguish MD patient subgroups (genetic heterogeneity) remains uncertain. This study sought evidence for genetic heterogeneity in MD. Using UK Biobank cohort, the authors defined 16 MD subtypes within eight comparison groups (vegetative symptoms, symptom severity, comorbid anxiety disorder, age at onset, recurrence, suicidality, impairment and postpartum depression; N∼3 000-47 000). To compare genetic component of these subtypes, subtype-specific genome-wide association studies were performed to estimate SNP-heritability, and genetic correlations within subtype comparison and with other related disorders or traits. The findings indicated that MD subtypes were divergent in their SNP-heritability, and genetic correlations both within subtype comparisons and with other related disorders/traits. Three subtype comparisons (vegetative symptoms, age at onset, and impairment) showed significant differences in SNP-heritability; while genetic correlations within subtype comparisons ranged from 0.55 to 0.86, suggesting genetic profiles are only partially shared among MD subtypes. Furthermore, subtypes that are more clinically challenging, e.g., early-onset, recurrent, suicidal, more severely impaired, had stronger genetic correlations with other psychiatric disorders. MD with atypical-like features showed a positive genetic correlation (+0.40) with BMI while a negative correlation (−0.09) was found in those without atypical-like features. Novel genomic loci with subtype-specific effects were identified. These results provide the most comprehensive evidence to date for genetic heterogeneity within MD, and suggest that the phenotypic complexity of MD can be effectively reduced by studying the subtypes which share partially distinct etiologies.
North Carolina macular dystrophy: phenotypic variability and computational analysis of disease-implicated non-coding variants
Authors: Green David J. , Lenassi Eva , Manning Cerys S. , McGaughey David , Sharma Vinod , Black Graeme C. , Ellingford Jamie M. , Sergouniotis Panagiotis I.
Published: March 2021

Purpose

North Carolina macular dystrophy (NCMD) is an autosomal dominant, congenital disorder affecting the central retina. Here, we report clinical and genetic findings in three families segregating NCMD and use epigenomic datasets from human tissues to gain insights into the effect of NCMD-implicated variants.

Methods

Clinical assessment and genetic testing were performed. Publicly-available transcriptomic and epigenomic datasets were analyzed and the ‘Activity-by-Contact’ (ABC) method for scoring enhancer elements and linking them to target genes was used.

Results

A previously-described, heterozygous, non-coding variant upstream of thePRDM13gene was detected in all six affected study participants (chr6:100,040,987G>C [GRCh37/hg19]). Inter- and intra-familial variability were observed; the visual acuity ranged from 0.0 to 1.6 LogMAR and fundoscopic findings ranged from visually insignificant, confluent, drusen-like macular deposits to coloboma-like macular lesions. Variable degrees of peripheral retinal spots (which were easily detected on widefield retinal imaging) were observed in all study subjects. Notably, a 6-year-old patient developed choroidal neovascularization and required treatment with intravitreal bevacizumab injections. Computational analysis of the five single nucleotide variants that have been implicated in NCMD revealed that these non-coding changes lie within two putative enhancer elements; these elements are predicted to interact withPRDM13in the developing human retina.PRDM13was found to be expressed in the fetal retina, with highest expression in the amacrine precursor cell population.

Conclusions

We provide further evidence supporting the role ofPRDM13dysregulation in the pathogenesis of NCMD and highlight the utility of widefield retinal imaging in individuals suspected to have this condition.
A Novel Computer-Assisted Drug-Induced Liver Injury Causality Assessment Tool (DILI-CAT)
Authors: Tillmann Hans L. , Suzuki Ayako , Merz Michael , Hermann Richard , Rockey Don C.
Published: March 2021

Objective

We hypothesized that a drug-characteristic DILI-phenotype could be defined and be used to develop a computer-assisted DILI causality assessment-tool (DILI-CAT).

Design

A drug-specific DILI-phenotype was developed for amoxicillin-clavulanate (AMX/CLA), cefazolin, cyproterone, and polygonum multiflorum using data from published case series, and subsequently a DILI-CAT Score (DILI-CAT-S) was created for each drug. The phenotype was made up of the following three parameters: (1) latency, R-value, and (3) AST/ALT ratio (also de Ritis ratio). A point allocation system was developed with points allocated depending on the degree of deviation from the core of published data for the three phenotypic parameters.

Results

The four drugs had a significantly different phenotype based on the three parameters utilized. For example, the median cyproterone latency was 150 days versus less than 43 days for the other three drugs (median: 26 for AMX/CLA, 20 for cefazolin, and 20 days for polygonum multiflorum; p<0·001). The R-value for the four drugs was also significantly different (median: cyproterone [12.4] and polygonum multiflorum [10.9]) from AMX/CLA (1.44) and cefazolin (1.57; p<0.001). The resulting DILI-CAT-S effectively separated cyproterone and polygonum multiflorum from AMX/CLA and cefazolin, respectively (p<0·001). Notably, because of overlap in phenotype AMX/CLA and cefazolin could not be differentiated by DILI-CAT-S.

Conclusion

DILI-CAT is a data-driven, diagnostic tool built to define drug-specific phenotypes. Data presented here provide proof of principle that a drug-specific, data-driven causality assessment tool can be developed for different drugs and raise the possibility that such a process could improve and standardize causality assessment methods.

Funding

DCR was supported by the NIH, grant P30 DK 123704
Inflammatory, but not respiratory symptoms, associated with ongoing upper airway viral replication in outpatients with uncomplicated COVID-19
Authors: Jacobson Karen B. , Purington Natasha , Parsonnet Julie , Andrews Jason , Balasubramanian Vidhya , Bonilla Hector , Edwards Karlie , Desai Manisha , Singh Upinder , Hedlin Haley , Jagannathan Prasanna
Published: March 2021

Background

The vast majority of SARS-CoV-2 infections are uncomplicated and do not require hospitalization, but contribute to ongoing transmission. Our understanding of the clinical course of uncomplicated COVID-19 remains limited.

Methods

We detailed the natural history of uncomplicated COVID-19 among 120 outpatients enrolled in a randomized clinical trial of Peginterferon Lambda. We characterized symptom trajectory and clusters using exploratory factor analysis, assessed predictors of symptom resolution and cessation of oropharyngeal viral shedding using Cox proportional hazard models, and evaluated associations between symptoms and viral shedding using mixed effects linear models.

Results

Headache, myalgias and chills peaked at day 4 after symptom onset; cough peaked on day 9. Two distinct symptom cluster trajectories were identified; one with mild, upper respiratory symptoms, and the other with more severe and prolonged inflammatory symptoms. The median time to symptom resolution from earliest symptom onset was 17 days (95% CI 14-18). Neither enrollment SARS-CoV-2 IgG levels (Hazard ratio [HR] 1.88, 95% CI 0.84-4.20) nor oropharyngeal viral load at enrollment (HR 1.01, 95% CI 0.98-1.05) were significantly associated with the time to symptom resolution. The median time to cessation of viral shedding was 10 days (95% CI 8-12), with higher SARS-CoV-2 IgG levels at enrollment associated with hastened resolution of viral shedding (HR 3.12, 95% CI 1.4-6.9, p=0.005). Myalgia, joint pains, and chills were associated with a significantly greater odds of oropharyngeal SARS-CoV-2 RNA detection.

Conclusions

In this outpatient cohort, inflammatory symptoms peaked early and were associated with ongoing SARS-CoV-2 replication. SARS-CoV-2 antibody levels were associated with more rapid viral shedding cessation, but not with time to symptom resolution. These findings have important implications for COVID-19 screening approaches and clinical trial design.
A Simple Fluorescence Assay for Cystine Uptake via the xCT in Cells using Selenocystine and a Fluorescent Probe
Authors: Shimomura Takashi , Hirakawa Norio , Ohuchi Yuya , Ishiyama Munetaka , Shiga Masanobu , Ueno Yuichiro
Published: March 2021

The cystine/glutamate antiporter (xCT) is a crucial transporter that maintains cellular redox balance by regulating intracellular glutathione synthesis via cystine uptake. However, no robust and simple method to determine the cystine uptake activity of xCT is currently available. We have developed a method to measure the xCT activity via the reaction of selenocysteine and fluoresceinO,O′-diacrylate (FOdA). Selenocystine, a cystine analog, is transported into cells through xCT on the cell membrane. The amount of the transported selenocystine was then determined by a reaction using tris(2-carboxyethyl)phosphine (TCEP) and FOdA in a weak acidic buffer at pH 6. Using this method, the cystine uptake activity of xCT in various cells, and the inhibitory efficiency of xCT inhibitors, were evaluated.
Disentangling effects of climate and land use on biodiversity and ecosystem services – a multi-scale experimental design
Authors: Redlich Sarah , Zhang Jie , Benjamin Caryl , Dhillon Maninder Singh , Englmeier Jana , Ewald Jörg , Fricke Ute , Ganuza Cristina , Haensel Maria , Hovestadt Thomas , Kollmann Johannes , Koellner Thomas , Kübert-Flock Carina , Kunstmann Harald , Menzel Annette , Moning Christoph , Peters Wibke , Riebl Rebekka , Rummler Thomas , Botero Sandra Rojas , Tobisch Cynthia , Uhler Johannes , Uphus Lars , Müller Jörg , Steffan-Dewenter Ingolf
Published: March 2021

Climate and land-use change are key drivers of environmental degradation in the Anthropocene, but too little is known about their interactive effects on biodiversity and ecosystem services. Long-term data on biodiversity trends are currently lacking. Furthermore, previous ecological studies have rarely considered climate and land use in a joint design, did not achieve variable independence or lost statistical power by not covering the full range of environmental gradients.

Here, we introduce a multi-scale space-for-time study design to disentangle effects of climate and land use on biodiversity and ecosystem services. The site selection approach coupled extensive GIS-based exploration and correlation heatmaps with a crossed and nested design covering regional, landscape and local scales. Its implementation in Bavaria (Germany) resulted in a set of study plots that maximizes the potential range and independence of environmental variables at different spatial scales.

Stratifying the state of Bavaria into five climate zones and three prevailing land-use types, i.e. near-natural, agriculture and urban, resulted in 60 study regions covering a mean annual temperature gradient of 5.6–9.8 °C and a spatial extent of 380×360 km. Within these regions, we nested 180 study plots located in contrasting local land-use types, i.e. forests, grasslands, arable land or settlement (local climate gradient 4.5–10 °C). This approach achieved low correlations between climate and land-use (proportional cover) at the regional and landscape scale with |r≤0.33| and |r≤0.29|, respectively. Furthermore, using correlation heatmaps for local plot selection reduced potentially confounding relationships between landscape composition and configuration for plots located in forests, arable land and settlements.

The suggested design expands upon previous research in covering a significant range of environmental gradients and including a diversity of dominant land-use types at different scales within different climatic contexts. It allows independent assessment of the relative contribution of multi-scale climate and land use on biodiversity and ecosystem services. Understanding potential interdependencies among global change drivers is essential to develop effective restoration and mitigation strategies against biodiversity decline, especially in expectation of future climatic changes. Importantly, this study also provides a baseline for long-term ecological monitoring programs.
Scarcity of hosts for gregarious parasitoids indicates an increase of individual offspring fertility by reducing their own fertility
Authors: Samková Alena , Raška Jan , Hadrava Jiří , Skuhrovec Jiří
Published: March 2021

The gregarious parasitoid strategy allows multiple larvae to complete development in a single host due to their tolerance and/or lower mobility and thus flexibly adjust their reproductive potential amidst changing environmental conditions. Reproductive success is generally measured as the number of each mother’s offspring. We propose that with scarcity of host, for gregarious parasitoids is important the view on the fertility not only of a mother but also of her offspring (F1 generation). Due to the body size-fitness correlation, each female deliberately adjusts the clutch size, determining the offspring body size and their reproductive potential. In our study, usingAnaphes flavipesas a model species, we showed that under a limited number of hosts, the females reduced their fertility. We propose that the lower fertility of mothers can cause higher fertility in the F2 generation using a larger offspring body while halving fertility. The females increase their individual offspring’s fertility by reducing their own fertility. Moreover, we showed that with a scarcity of hosts, the mothers increased the number of their female offspring, and thus, they obtained more offspring in the F2 generation. Additionally, other costs and benefits of the gregarious strategy in relation to superparasitism were tested and discussed.
Network diffusion for scalable embedding of massive single-cell ATAC-seq data
Authors: Dong Kangning , Zhang Shihua
Published: March 2021

With the rapid development of single-cell ATAC-seq technology, it has become possible to profile the chromatin accessibility of massive individual cells. However, it remains challenging to characterize their regulatory heterogeneity due to the high-dimensional, sparse and near-binary nature of data. Most existing data representation methods were designed based on correlation, which may be ill-defined for sparse data. Moreover, these methods do not well address the issue of excessive zeros. Thus, a simple, fast and scalable approach is needed to analyze single-cell ATAC-seq data with massive cells, address the “missingness” and accurately categorize cell types. To this end, we developed a network diffusion method for scalable embedding of massive single-cell ATAC-seq data (named as scAND). Specifically, we considered the near-binary single-cell ATAC-seq data as a bipartite network that reflects the accessible relationship between cells and accessible regions, and further adopted a simple and scalable network diffusion method to embed it. scAND can take information from similar cells to alleviate the sparsity and improve cell type identification. Extensive tests and comparison with existing methods using synthetic and real data as benchmarks demonstrated its distinct superiorities in terms of clustering accuracy, robustness, scalability and data integration.

Availability

The Python-based scAND tool is freely available athttp://page.amss.ac.cn/shihua.zhang/software.html.
Coordination of movement via complementary interactions of leaders and followers in termite mating pairs
Authors: Mizumoto Nobuaki , Lee Sang-Bin , Valentini Gabriele , Chouvenc Thomas , Pratt Stephen C.
Published: March 2021

Leadership of animal group movements depends on social feedback, hence leader’s signals and follower’s responses should be attuned to each other. However, leader and follower roles are difficult to disentangle in species with high levels of coordination. To overcome this challenge, we investigated a simple case of movement coordination: termite pairs in which a female leads a male as they search for a nest site. To tease apart leader and follower roles, we created conspecific and heterospecific pairs ofCoptotermes gestroiandC. formosanus, which share a pairing pheromone so that males follow females of either species. Conspecific pairs were stable for both species, even thoughC. gestroifemales produce less pheromone thanC. formosanus. Heterospecific pairs withC. gestroimales were also stable, but not those withC. formosanusmales. We attributed this difference to theC. gestroimale’s unique capacity to follow females that release small amounts of pheromone;C. formosanusmales cannot follow or rejectC. gestroifemales as unsuitable. This conclusion was supported by an information-theoretic analysis that detected information flow fromC. formosanusfemales toC. gestroimales as in conspecific pairs, but not fromC. gestroifemales toC. formosanusmales. Despite their following ability,C. gestroimales lost toC. formosanusmales in competitions to followC. formosanusfemales. Thus, partner selection has shaped the species-specific association of mating pairs. Our results demonstrate that a similar level of coordination can emerge from distinct sets of complementary sender-receiver interactions.
Conserved, divergent and heterochronic gene expression duringBrachypodiumandArabidopsisembryo development
Authors: Hao Zhaodong , Zhang Zhongjuan , Xiang Daoquan , Venglat Prakash , Chen Jinhui , Gao Peng , Datla Raju , Weijers Dolf
Published: March 2021

Embryogenesis, transforming the zygote into the mature embryo, represents a fundamental process for all flowering plants. Current knowledge of cell specification and differentiation during plant embryogenesis is largely based on studies of the dicot model plantArabidopsis thaliana. However, the major crops are monocots and the transcriptional programs associated with the differentiation processes during embryogenesis in this clade were largely unknown. Here, we combined analysis of cell division patterns with development of a temporal transcriptomic resource during embryogenesis of the monocot model plantBrachypodium distachyon. We found that early divisions of theBrachypodiumembryo were highly regular, while later stages were marked by less stereotypic patterns. Comparative transcriptomic analysis betweenBrachypodiumandArabidopsisrevealed that the early and late embryogenesis shared a common transcriptional program, whereas mid-embryogenesis was divergent between species. Analysis of orthology groups revealed widespread heterochronic expression of potential developmental regulators between the species. Interestingly,Brachypodiumgenes tend to be expressed at earlier stages thanArabidopsiscounterparts, which suggests that embryo patterning may occur early duringBrachypodiumembryogenesis. Detailed investigation of auxin-related genes shows that the capacity to synthesize, transport, and respond to auxin is established early in the embryo. However, while early PIN1 polarity could be confirmed, it is unclear if an active response is mounted. This study presents a resource for studyingBrachypodiumand grass embryogenesis, and shows that divergent angiosperms share a conserved genetic program that is marked by heterochronic gene expression.

Key message

Developmental and transcriptomic analysis ofBrachypodiumembryogenesis, and comparison withArabidopsis, identifies conserved and divergent phases of embryogenesis, and reveals widespread heterochrony of developmental gene expression.
Neurodegeneration in human brain organoids infected with herpes simplex virus type 1
Authors: Rybak-Wolf Agnieszka , Wyler Emanuel , Legnini Ivano , Loewa Anna , Glažar Petar , Kim Seung Joon , Pentimalli Tancredi Massimo , Martinez Anna Oliveras , Beyersdorf Benjamin , Woehler Andrew , Landthaler Markus , Rajewsky Nikolaus
Published: March 2021

Herpes simplex virus type 1 (HSV-1) infection of the nervous system may lead to brain damage, including neurodegeneration. However, lack of suitable experimental models hinders understanding molecular mechanisms and cell-type-specific responses triggered by HSV-1. Here, we infected human brain organoids with HSV-1. Known features of HSV-1 infection such as alteration of neuronal electrophysiology and induction of antisense transcription were confirmed. Full-length mRNA-sequencing revealed aberrant 3’ end formation and poly(A)-tail lengthening. Single-cell RNA-seq and spatial transcriptomics uncovered changes in the cellular composition of the infected organoids caused by viral replication and dysregulation of molecular pathways in cell-type specific manner. Furthermore, hallmarks of early neurodegeneration were observed, namely extracellular matrix disruption, STMN2 and TARDBP/TDP43 downregulation, and upregulation of the AD-related non-coding RNA BC200/BCYRN1. These hallmarks were weaker/absent when infecting with a mutant HSV-1 control. Together, our data indicate that brain organoids serve as a powerful model to study mechanisms of HSV-1-driven neurodegeneration.