bluuebunny/crossref_metadata_2025 huggingface dataset:
Opportunities and Challenges in Translational Research: The Development of Photodynamic Therapy and Anti-Vascular Endothelial Growth Factor Drugs
Authors: Marko Christina Kaiser , Miller Joan W.
Published: April 2021

The development of photodynamic therapy and anti-vascular endothelial growth factor agents have revolutionized the treatment of retinal diseases, transforming the retina subspecialty by ushering in an age of pharmacological treatments for a wide range of diseases, including age-related macular degeneration (AMD).
Controls on range shifts of coastal Californian bivalves during the peak of the last interglacial and baseline predictions for today
Authors: Orzechowski Emily A. , Finnegan Seth
Published: April 2021

As the most recent time in Earth history when global temperatures were warmer than at present, the peak of the last interglacial (Marine Isotope Substage [MIS] 5e; ~120,000 years ago) can serve as a pre-anthropogenic baseline for a warmer near-future world. Here we use a new compilation of 22 fossil localities in California that have been reliably dated to MIS 5e to establish baseline expectations for contemporary bivalve species movements by identifying and analyzing bivalve species with “extralimital” ranges, that is, species that occupied the California region during MIS 5e but are now restricted to adjacent regions. We find that 15% of species (n= 142) found in MIS 5e localities have extralimital ranges and currently occupy warmer waters to the south of the California region. The majority of extralimital occurrences occur in paleo-embayments, suggesting that these sheltered habitats were more suitable habitats for warm-water species than exposed coasts during the MIS 5e. We further find that extralimital species now tend to occur in cooler, more seasonally productive coastal waters and to occupy more offshore islands when compared with the broader species pool immediately south of California. These findings suggest that high dispersal potential and preexisting tolerances to environmental conditions similar to California's comparatively cool and seasonally productive environments may have enabled extralimital bivalves to colonize the California region during MIS 5e.
AFTER 1860: DEBATING RELIGION, REFORM, AND NATIONALISM IN THE OTTOMAN EMPIRE
Authors: Makdisi Ussama
Published: April 2021

The events of 1860 constitute a turning point in the modern history of Lebanon. In the space of a few weeks between the end of May and the middle of June, Maronite and Druze communities clashed in Mount Lebanon in a struggle to see which community would control, and define, a stretch of mountainous territory at the center of complicated Eastern Question politics.1 The Druzes carried the day. Every major Maronite town within reach of the Druzes was pillaged, its population either massacred or forced to flee. In July, Damascene Muslims rioted to protest deteriorating economic conditions, targeting and massacring several hundred of the city's Christian population. Although the reasons for the fighting in Mount Lebanon and the riot in Damascus were quite different, the Ottoman, local, and European reactions inevitably conflated both events.2 Following the restoration of order, the conflict of 1860 was the subject, effectively, of an Ottoman government mandate of silence—a desire to forget the events and proceed with administering the newly constituted Mutasarrifiyya of Mount Lebanon. At the same time, however, the sectarian violence prompted an outpouring of local memories that the Ottoman government could neither control nor suppress.
A method for simulating risk profiles of wheat yield in data-sparse conditions
Authors: Bracho-Mujica G. , Hayman P.T. , Sadras V.O. , Ostendorf B.
Published: April 2021

Process-based crop models are a robust approach to assess climate impacts on crop productivity and long-term viability of cropping systems. However, these models require high-quality climate data that cannot always be met. To overcome this issue, the current research tested a simple method for scaling daily data and extrapolating long-term risk profiles of modelled crop yields. An extreme situation was tested, in which high-quality weather data was only available at one single location (reference site: Snowtown, South Australia, 33.78°S, 138.21°E), and limited weather data was available for 49 study sites within the Australian grain belt (spanning from 26.67 to 38.02°S of latitude, and 115.44 to 151.85°E of longitude). Daily weather data were perturbed with a delta factor calculated as the difference between averaged climate data from the reference site and the study sites. Risk profiles were built using a step-wise combination of adjustments from the most simple (adjusted series of precipitation only) to the most detailed (adjusted series of precipitation, temperatures and solar radiation), and a variable record length (from 10 to 100 years). The simplest adjustment and shortest record length produced bias of modelled yield grain risk profiles between −10 and 10% in 41% of the sites, which increased to 86% of the study sites with the most detailed adjustment and longest record (100 years). Results indicate that the quality of the extrapolation of risk profiles was more sensitive to the number of adjustments applied rather than the record length per se.
Impaired executive function exacerbates neural markers of posttraumatic stress disorder
Authors: Jagger-Rickels Audreyana , Stumps Anna , Rothlein David , Park Hannah , Fortenbaugh Francesca , Zuberer Agnieszka , Fonda Jennifer R. , Fortier Catherine B. , DeGutis Joseph , Milberg William , McGlinchey Regina , Esterman Michael
Published: April 2021

Background

A major obstacle in understanding and treating posttraumatic stress disorder (PTSD) is its clinical and neurobiological heterogeneity. To address this barrier, the field has become increasingly interested in identifying subtypes of PTSD based on dysfunction in neural networks alongside cognitive impairments that may underlie the development and maintenance of symptoms. The current study aimed to determine if subtypes of PTSD, based on normative-based cognitive dysfunction across multiple domains, have unique neural network signatures.

Methods

In a sample of 271 veterans (90% male) that completed both neuropsychological testing and resting-state fMRI, two complementary, whole-brain functional connectivity analyses explored the link between brain functioning, PTSD symptoms, and cognition.

Results

At the network level, PTSD symptom severity was associated with reduced negative coupling between the limbic network (LN) and frontal-parietal control network (FPCN), driven specifically by the dorsolateral prefrontal cortex and amygdala Hubs of Dysfunction. Further, this relationship was uniquely moderated by executive function (EF). Specifically, those with PTSD and impaired EF had the strongest marker of LN-FPCN dysregulation, while those with above-average EF did not exhibit PTSD-related dysregulation of these networks.

Conclusion

These results suggest that poor executive functioning, alongside LN-FPCN dysregulation, may represent a neurocognitive subtype of PTSD.
Sample size, sample size planning, and the impact of study context: systematic review and recommendations by the example of psychological depression treatment
Authors: Schuster Raphael , Kaiser Tim , Terhorst Yannik , Messner Eva Maria , Strohmeier Lucia-Maria , Laireiter Anton-Rupert
Published: April 2021

Background

Sample size planning (SSP) is vital for efficient studies that yield reliable outcomes. Hence, guidelines, emphasize the importance of SSP. The present study investigates the practice of SSP in current trials for depression.

Methods

Seventy-eight randomized controlled trials published between 2013 and 2017 were examined. Impact of study design (e.g. number of randomized conditions) and study context (e.g. funding) on sample size was analyzed using multiple regression.

Results

Overall, sample size during pre-registration, during SSP, and in published articles was highly correlated (r's ≥ 0.887). Simultaneously, only 7–18% of explained variance related to study design (p = 0.055–0.155). This proportion increased to 30–42% by adding study context (p = 0.002–0.005). The median sample size was N = 106, with higher numbers for internet interventions (N = 181; p = 0.021) compared to face-to-face therapy. In total, 59% of studies included SSP, with 28% providing basic determinants and 8–10% providing information for comprehensible SSP. Expected effect sizes exhibited a sharp peak at d = 0.5. Depending on the definition, 10.2–20.4% implemented intense assessment to improve statistical power.

Conclusions

Findings suggest that investigators achieve their determined sample size and pre-registration rates are increasing. During study planning, however, study context appears more important than study design. Study context, therefore, needs to be emphasized in the present discussion, as it can help understand the relatively stable trial numbers of the past decades. Acknowledging this situation, indications exist that digital psychiatry (e.g. Internet interventions or intense assessment) can help to mitigate the challenge of underpowered studies. The article includes a short guide for efficient study planning.
Enacting citizenship through participation in a technological society: a longitudinal three-year study among people with dementia in Sweden
Authors: Gaber Sophie Nadia , Nygård Louise , Malinowsky Camilla , Brorsson Anna , Kottorp Anders , Hedman Annicka
Published: April 2021

The role of Everyday Technology (ET) use is presented as subsidiary or neutral in policy for age- and dementia-friendly communities; and yet, research suggests that older people, especially those with dementia, experience increased challenges using ET in their everyday lives. Through the lens of micro-citizenship, the study aims to deepen the knowledge about how use of ET outside the home, including portable ETs, relates to participation in places visited within public space among people with dementia over time. Using a longitudinal study design, 35 people with dementia were recruited at baseline and followed over three years. Data were collected through semi-structured interviews using standardised questionnaires: the Participation in ACTivities and Places OUTside Home Questionnaire (ACT-OUT) and the Everyday Technology Use Questionnaire (ETUQ). Random intercept modelling and descriptive statistics were used to analyse the data. Throughout the three-year study, decreasing use of ET outside the home, including portable ETs, was associated with decreasing participation in places visited within public space, in a statistically significant way when controlling for age (F= 7.59,p= 0.01). The findings indicate that facilitating access and use of ET outside the home, among people with dementia, should be integral to promoting and maintaining participation in age- and dementia-friendly communities.
Naturalizing affection, securing property: Family, slavery, and the courts in Antebellum South Carolina, 1830–1860
Authors: Alphonso Gwendoline M.
Published: April 2021

The scholarship on race and political development demonstrates that race has long been embedded in public policy and political institutions. Less noticed in this literature is how family, as a deliberate political institution, is used to further racial goals and policy purposes. This article seeks to fill this gap by tracing the foundations of the political welding of family and race to the slave South in the antebellum period from 1830 to 1860. Utilizing rich testimonial evidence in court cases, I demonstrate how antebellum courts in South Carolina constructed a standard of “domestic affection” from the everyday lives of southerners, which established affection as a natural norm practiced by white male slaveowners in their roles as fathers, husbands, and masters. By constructing and regulating domestic affection to uphold slavery amid the waves of multiple modernizing forces (democratization, advancing market economy, and household egalitarianism), Southern courts in the antebellum period presaged their postbellum role of reconstructing white supremacy in the wake of slavery's demise. In both cases the courts played a formative role in naturalizing family relations in racially specific ways, constructing affection and sexuality, respectively, to anchor the white family as the bulwark of white social and political hegemony.
Making meaning withbe able to: modality and actualisation
Authors: LECLERCQ BENOÎT , DEPRAETERE ILSE
Published: April 2021

This article sheds new light on the usage constraints ofbe able to, by combining empirical evidence from theBritish National Corpus(BNC, Davies 2004–) with theoretical insights on the semantics–pragmatics interface. First, we show thatbe able todoes not, contrary to the general assumption, express only ‘ability’ but it shares most of the root meanings usually associated with the possibility modalscanandcould(Coates 1983: 124). The data analysis shows that what is called ‘opportunity’ in Depraetere & Reed's (2011) taxonomy is the most frequent meaning ofbe able to. We then turn to the notion of actualisation, which is often claimed to be the main distinguishing feature betweenbe able toandcan/could. The qualitative analysis of the BNC dataset provides the empirical evidence, lacking in previous research, for the claim that actualisation is indeed a defining property of the modal periphrastic form. Starting from a reassessment of the semantics–pragmatics interface in terms of a fourfold distinction, we argue that actualisation is a generalised conversational implicature and constitutes conventional pragmatic meaning (that is, conventional non-truth-conditional meaning).
Cross-linguistic interactions across modalities: Effects of the oral language on sign production
Authors: Gimeno-Martínez Marc , Mädebach Andreas , Baus Cristina
Published: April 2021

To investigate cross-linguistic interactions in bimodal bilingual production, behavioural and electrophysiological measures (ERPs) were recorded from 24 deaf bimodal bilinguals while naming pictures in Catalan Sign Language (LSC). Two tasks were employed, a picture-word interference and a picture-picture interference task. Cross-linguistic effects were explored via distractors that were either semantically related to the target picture, to the phonology/orthography of the Spanish name of the target picture, or were unrelated. No semantic effects were observed in sign latencies, but ERPs differed between semantically related and unrelated distractors. For the form-related manipulation, a facilitation effect was observed both behaviourally and at the ERP level. Importantly, these effects were not influenced by the type of distractor (word/picture) presented providing the first piece of evidence that deaf bimodal bilinguals are sensitive to oral language in sign production. Implications for models of cross-linguistic interactions in bimodal bilinguals are discussed.
China – Tariff Rate Quotas for Certain Agricultural Products. Against the Grain: Can the WTO Open Chinese Markets? A Contaminated Experiment
Authors: Glauber Joseph , Lester Simon
Published: April 2021

The US complaint about Chinese tariff-rate quotas (TRQs) on certain grain products helps illustrate several key issues in US–China trade relations and the effectiveness of WTO disputes. First, do international obligations based on transparency and fairness work in relation to an authoritarian country not known for the rule of law domestically? Second, can there be a disconnect between the legal aspects of a dispute and the underlying economic interests, with a DSB ruling sometimes not leading to improved trade flows? And third, given the bilateral trade war and ‘phase one’ trade deal between the United States and China, has the WTO been superseded in this trade relationship? This paper summarizes the facts and law of the China–TRQs dispute, and examines each of these questions in that context.
Association mapping of genomic loci linked with Fusarium wilt resistance (Foc2) in chickpea
Authors: Jha Uday Chand , Jha Rintu , Bohra Abhishek , Manjunatha Lakshmaiah , Saabale Parasappa Rajappa , Parida Swarup K. , Chaturvedi Sushil Kumar , Thakro Virevol , Singh Narendra Pratap
Published: April 2021

Improving plant resistance against Fusarium wilt (FW) is key to sustaining chickpea production worldwide. Given this, the current study tested a set of 75 FW-responsive chickpea breeding lines including checks in a wilt-sick plot for two consecutive years (2016 and 2017). Genetic diversity analysis using 75 simple sequence repeats (SSRs) revealed a total of 267 alleles with an average of 3.56 alleles per marker. The entire set was divided into two major classes based on clustering method and factorial analysis. Similarly, STRUCTURE analysis placed the 75 genotypes into three distinct sub-groups (K = 3). Marker-trait association (MTA) analysis using the generalized linear model approach revealed nine and eight significant MTAs for FW resistance in the years 2016 and 2017, respectively. Three significant MTAs were obtained for FW resistance following the mixed linear model approach for both years. The SSR markers CESSR433, NCPGR21 and ICCM0284 could be potentially employed for targeted and accelerated improvement of FW resistance in chickpea. To the best of our knowledge, this is the first report on association mapping of the genomic loci controlling FW (Foc2) resistance in chickpea.
The business model as a generative replicator
Authors: Brette Olivier , Chassagnon Virgile
Published: April 2021

This paper proposes a new conceptualization of business model (BM) that rigorously exploits the important insights this notion offers and links them to related views developed in economics and business studies. We develop the foundations of a BM concept consistent with the principles of generalized Darwinism (GD) and with contributions already developed within this framework. Thus, we demonstrate the relevance of GD as a unifying framework for developing the evolutionary theory of firm and industry. We suggest analysing BM as a generative replicator hosted by the firm, which structures interactions between the members of this organization and the social entities of its industrial environment. We argue that GD allows us to clarify the nature and boundaries of the BM concept and to specify its relationships to other key evolutionary concepts, such as organizational routines.
The Devil That You Know: Christian Nationalism and Intent to Change One's Voting Behavior For or Against Trump in 2020
Authors: Perry Samuel L. , Whitehead Andrew L. , Grubbs Joshua B.
Published: April 2021

Christian nationalist ideology was among the strongest predictors of Americans voting for Trump in 2016 and remained a strong predictor of intent to vote for him prior to the 2020 election. This study uses national data to examine whether Christian nationalism could potentially convert the previously-unconverted to supporting Trump or, conversely, prevent apostatizing from Trump. Among Americans whodid notvote for Trump in 2016, Christian nationalism increased the likelihood that they intended to vote for Trump in 2020, but only those who earlier did not vote at all or voted third party. Conversely, among Americans whodidvote for Trump in 2016, Christian nationalism reduced the likelihood that they planned on voting for a Democratic or third party candidate. Christian nationalism thus potentially inclined Americans who previously did not vote for Trump in 2016 to vote his way in 2020 and inoculated previous Trump-voters from considering other candidates in 2020.
Modelling national transformations to achieve the SDGs within planetary boundaries in small island developing states
Authors: Allen Cameron , Metternicht Graciela , Wiedmann Thomas , Pedercini Matteo
Published: April 2021

Non-technical summary

The Sustainable Development Goals (SDGs) provide an integrated and ambitious roadmap for sustainable development by 2030. National implementation will be crucial and there is an urgent need to understand the scale and pace of transformations to achieve the goals. There is also concern that achieving socio-economic objectives will undermine longer-term environmental sustainability. This study uses modelling to explore how different policy and investment settings can enable the necessary transformations, adopting Fiji as a use-case. Modest investment over the coming decade can deliver improved performance. However, far more ambitious actions are needed to accelerate progress while managing long-term trade-offs with environmental objectives.

Technical summary

This paper presents the results from a national scenario modelling study for Fiji with broader relevance for other countries seeking to achieve the SDGs. We develop and simulate a business-as-usual and six alternative future scenarios using the integrated (iSDG-Fiji) system dynamics model and evaluate their performance on the SDGs in 2030 and global planetary boundaries (PBs) and the ‘safe and just space’ (SJS) framework in 2050. Modest investment over the coming decade through a ‘sustainability transition’ scenario accelerates SDG progress from 40% to 70% by 2030 but fails to meet all SJS thresholds. Greatly scaling up investment and ambition through an SDG transformation scenario highlights possibilities for Fiji to accelerate progress to 83% by 2030 while improving SJS performance. The scale of investment is highly ambitious and could not be delivered without scaled-up international support, but despite this investment progress still falls short. The analysis highlights where key trade-offs remain as well as options to address these, however closing the gap to 100% achievement will prove very challenging. The approach and findings are relevant to other countries with similar characteristics to increase the understanding of the transformations needed to achieve the SDGs within PBs in different country contexts.

Social media summary

How can countries accelerate progress on the SDGs by 2030 while ensuring longer-term coherence with climate and sustainability thresholds?
Analysis of Outdoor Thermal Discomfort Over the Kingdom of Saudi Arabia
Authors: Dasari Hari Prasad , Desamsetti Srinivas , Langodan Sabique , Viswanadhapalli Yesubabu , Hoteit Ibrahim
Published: April 2021

In this study, the variability and trends of the outdoor thermal discomfort index (DI) in the Kingdom of Saudi Arabia (KSA) were analyzed over the 39‐year period of 1980–2018. The hourly DI was estimated based on air temperature and relative humidity data obtained from the next‐generation global reanalysis from the European Center for Medium‐Range Weather Forecasts and in‐house high‐resolution regional reanalysis generated using an assimilative Weather Research Forecast (WRF) model. The DI exceeds 28°C, that is, the threshold for human discomfort, in all summer months (June to September) over most parts of the KSA due to a combination of consistently high temperatures and relative humidity. The DI is greater than 28°C for 8–16 h over the western parts of KSA and north of the central Red Sea. A DI of >28°C persistes for 7–9 h over the Red Sea and western KSA for 90% of summer days. The spatial extent and number of days with DI > 30°C, that is, the threshold for severe human discomfort, are significantly lower than those with DI > 28°C. Long‐term trends in the number of days with DI > 28°C indicate a reduced rate of increase or even a decrease over some parts of the southwestern KSA in recent decades (1999–2018). Areas with DI > 30°C, in particular the northwestern regions of the Arabian Gulf and its adjoining regions, also showed improved comfort levels during recent decades. Significant increases in population and urbanization have been reported throughout the KSA during the study period. Analysis of five‐years clinical data suggests a positive correlation between higher temperatures and humidity with heat‐related deaths during the Hajj pilgrimage. The information provided herein is expected to aid national authorities and policymakers in developing necessary strategies to mitigate the exposure of humans to high levels of thermal discomfort in the KSA.
The Role of Hyporheic Connectivity in Determining Nitrogen Availability: Insights From an Intermittent Antarctic Stream
Authors: Singley J. G. , Gooseff M. N. , McKnight D. M. , Hinckley E. S.
Published: April 2021

Due to widespread manipulation of nitrogen (N), much research has focused on processes controlling the fate of anthropogenic N in streams. Yet, in a variety of oligotrophic systems, N fixed by periphyton is a significant driver of ecosystem metabolism. Due to difficulties partitioning allochthonous and autochthonous sources, there is limited information regarding how the latter is processed. Autochthonous N may be particularly important in alpine, arid, or polar environments. We test the hypothesis that the availability of remineralized autochthonous N is controlled by connectivity between the hyporheic zone and main channel due to the contrasting biogeochemical functions of benthic autotrophs (including N‐fixing Nostoc) and hyporheic heterotrophs in an intermittent Antarctic stream. There, we collected surface water and hyporheic water concurrently at 4–6 h intervals over a 32.5 h period during one flow season and opportunistically throughout a second. Hyporheic water had 7 to 30 times greater nitrate‐N concentrations relative to surface water across all flow conditions. In contrast, ammonium concentrations were generally lower, although similar among locations. Additionally, nitrate in hyporheic water was positively correlated with silica, an indicator of hyporheic residence time. A laboratory assay confirmed prior inferences that hyporheic microbial communities possess the functional potential to perform nitrification. Together, these findings suggest that remineralized autochthonous N accumulates in the hyporheic zone even as streamflow varies and likely subsidizes stream N availability, which supports prior inferences from N stable isotope data at this site. These results highlight the importance of hyporheic connectivity in controlling autochthonous N cycling and availability in streams.
Compressively sampling the optical transmission matrix of a multimode fibre
Authors: Li Shuhui , Saunders Charles , Lum Daniel J. , Murray-Bruce John , Goyal Vivek K , Čižmár Tomáš , Phillips David B.
Published: April 2021

The measurement of the optical transmission matrix (TM) of an opaque material is an advanced form of space-variant aberration correction. Beyond imaging, TM-based methods are emerging in a range of fields, including optical communications, micro-manipulation, and computing. In many cases, the TM is very sensitive to perturbations in the configuration of the scattering medium it represents. Therefore, applications often require an up-to-the-minute characterisation of the fragile TM, typically entailing hundreds to thousands of probe measurements. Here, we explore how these measurement requirements can be relaxed using the framework of compressive sensing, in which the incorporation of prior information enables accurate estimation from fewer measurements than the dimensionality of the TM we aim to reconstruct. Examples of such priors include knowledge of a memory effect linking the input and output fields, an approximate model of the optical system, or a recent but degraded TM measurement. We demonstrate this concept by reconstructing the full-size TM of a multimode fibre supporting 754 modes at compression ratios down to ∼5% with good fidelity. We show that in this case, imaging is still possible using TMs reconstructed at compression ratios down to ∼1% (eight probe measurements). This compressive TM sampling strategy is quite general and may be applied to a variety of other scattering samples, including diffusers, thin layers of tissue, fibre optics of any refractive profile, and reflections from opaque walls. These approaches offer a route towards the measurement of high-dimensional TMs either quickly or with access to limited numbers of measurements.
Correction to: Prospective randomized pharmacogenetic study of topiramate for treating alcohol use disorder
Authors: Kranzler Henry R. , Morris Paige E. , Pond Timothy , Crist Richard C. , Kampman Kyle M. , Hartwell Emily E. , Lynch Kevin G.
Published: April 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41386-021-01013-6
Rapid heat discharge during deep-sea eruptions generates megaplumes and disperses tephra
Authors: Pegler Samuel S. , Ferguson David J.
Published: April 2021

Deep-marine volcanism drives Earth’s most energetic transfers of heat and mass between the crust and the oceans. While magmatic activity on the seafloor has been correlated with the occurrence of colossal enigmatic plumes of hydrothermal fluid known as megaplumes, little is known of the primary source and intensity of the energy release associated with seafloor volcanism. As a result, the specific origin of megaplumes remains ambiguous. By developing a mathematical model for the dispersal of submarine tephras, we show that the transport of pyroclasts requires an energy discharge that is sufficiently powerful (~1-2 TW) to form a hydrothermal plume with characteristics matching those of observed megaplumes in a matter of hours. Our results thereby directly link megaplume creation, active magma extrusion, and tephra dispersal. The energy flux at the plume source required to drive the dispersal is difficult to attain by purely volcanogenic means, and likely requires an additional input of heat, potentially from rapid evacuations of hot hydrothermal fluids triggered by dyke intrusion. In view of the ubiquity of submarine tephra deposits, our results demonstrate that intervals of rapid hydrothermal discharge are likely commonplace during deep-ocean volcanism.
A comprehensive characterization of the cell-free transcriptome reveals tissue- and subtype-specific biomarkers for cancer detection
Authors: Larson Matthew H. , Pan Wenying , Kim Hyunsung John , Mauntz Ruth E. , Stuart Sarah M. , Pimentel Monica , Zhou Yiqi , Knudsgaard Per , Demas Vasiliki , Aravanis Alexander M. , Jamshidi Arash
Published: April 2021

Cell-free RNA (cfRNA) is a promising analyte for cancer detection. However, a comprehensive assessment of cfRNA in individuals with and without cancer has not been conducted. We perform the first transcriptome-wide characterization of cfRNA in cancer (stage III breast [n = 46], lung [n = 30]) and non-cancer (n = 89) participants from the Circulating Cell-free Genome Atlas (NCT02889978). Of 57,820 annotated genes, 39,564 (68%) are not detected in cfRNA from non-cancer individuals. Within these low-noise regions, we identify tissue- and cancer-specific genes, defined as “dark channel biomarker” (DCB) genes, that are recurrently detected in individuals with cancer. DCB levels in plasma correlate with tumor shedding rate and RNA expression in matched tissue, suggesting that DCBs with high expression in tumor tissue could enhance cancer detection in patients with low levels of circulating tumor DNA. Overall, cfRNA provides a unique opportunity to detect cancer, predict the tumor tissue of origin, and determine the cancer subtype.
AAV2/9-mediated silencing of PMP22 prevents the development of pathological features in a rat model of Charcot-Marie-Tooth disease 1 A
Authors: Gautier Benoit , Hajjar Helene , Soares Sylvia , Berthelot Jade , Deck Marie , Abbou Scarlette , Campbell Graham , Ceprian Maria , Gonzalez Sergio , Fovet Claire-Maëlle , Schütza Vlad , Jouvenel Antoine , Rivat Cyril , Zerah Michel , François Virginie , Le Guiner Caroline , Aubourg Patrick , Fledrich Robert , Tricaud Nicolas
Published: April 2021

Charcot-Marie-Tooth disease 1 A (CMT1A) results from a duplication of the PMP22 gene in Schwann cells and a deficit of myelination in peripheral nerves. Patients with CMT1A have reduced nerve conduction velocity, muscle wasting, hand and foot deformations and foot drop walking. Here, we evaluate the safety and efficacy of recombinant adeno-associated viral vector serotype 9 (AAV2/9) expressing GFP and shRNAs targeting Pmp22 mRNA in animal models of Charcot-Marie-Tooth disease 1 A. Intra-nerve delivery of AAV2/9 in the sciatic nerve allowed widespread transgene expression in resident myelinating Schwann cells in mice, rats and non-human primates. A bilateral treatment restore expression levels of PMP22 comparable to wild-type conditions, resulting in increased myelination and prevention of motor and sensory impairments over a twelve-months period in a rat model of CMT1A. We observed limited off-target transduction and immune response using the intra-nerve delivery route. A combination of previously characterized human skin biomarkers is able to discriminate between treated and untreated animals, indicating their potential use as part of outcome measures.
Force-FAK signaling coupling at individual focal adhesions coordinates mechanosensing and microtissue repair
Authors: Zhou Dennis W. , Fernández-Yagüe Marc A. , Holland Elijah N. , García Andrés F. , Castro Nicolas S. , O’Neill Eric B. , Eyckmans Jeroen , Chen Christopher S. , Fu Jianping , Schlaepfer David D. , García Andrés J.
Published: April 2021

How adhesive forces are transduced and integrated into biochemical signals at focal adhesions (FAs) is poorly understood. Using cells adhering to deformable micropillar arrays, we demonstrate that traction force and FAK localization as well as traction force and Y397-FAK phosphorylation are linearly coupled at individual FAs on stiff, but not soft, substrates. Similarly, FAK phosphorylation increases linearly with external forces applied to FAs using magnetic beads. This mechanosignaling coupling requires actomyosin contractility, talin-FAK binding, and full-length vinculin that binds talin and actin. Using an in vitro 3D biomimetic wound healing model, we show that force-FAK signaling coupling coordinates cell migration and tissue-scale forces to promote microtissue repair. A simple kinetic binding model of talin-FAK interactions under force can recapitulate the experimental observations. This study provides insights on how talin and vinculin convert forces into FAK signaling events regulating cell migration and tissue repair.
Strategy for COVID-19 vaccination in India: the country with the
second highest population and number of cases
Authors: Kumar Velayudhan Mohan , Pandi-Perumal Seithikurippu R. , Trakht Ilya , Thyagarajan Sadras Panchatcharam
Published: April 2021

Free vaccination against COVID-19 commenced in India on January 16,
2021, and the government is urging all of its citizens to be immunized, in what is
expected to be the largest vaccination program in the world. Out of the eight
COVID-19 vaccines that are currently under various stages of clinical trials in
India, four were developed in the country. India’s drug regulator has
approved restricted emergency use of Covishield (the name employed in India for the
Oxford-AstraZeneca vaccine) and Covaxin, the home-grown vaccine produced by Bharat
Biotech. Indian manufacturers have stated that they have the capacity to meet the
country’s future needs for COVID-19 vaccines. The manpower and cold-chain
infrastructure established before the pandemic are sufficient for the initial
vaccination of 30 million healthcare workers. The Indian government has taken urgent
measures to expand the country’s vaccine manufacturing capacity and has also
developed an efficient digital system to address and monitor all the aspects of
vaccine administration.
Assessment of patient specific information in the wild on fundus photography and optical coherence tomography
Authors: Munk Marion R. , Kurmann Thomas , Márquez-Neila Pablo , Zinkernagel Martin S. , Wolf Sebastian , Sznitman Raphael
Published: April 2021

In this paper we analyse the performance of machine learning methods in predicting patient information such as age or sex solely from retinal imaging modalities in a heterogeneous clinical population. Our dataset consists of N = 135,667 fundus images and N = 85,536 volumetric OCT scans. Deep learning models were trained to predict the patient’s age and sex from fundus images, OCT cross sections and OCT volumes. For sex prediction, a ROC AUC of 0.80 was achieved for fundus images, 0.84 for OCT cross sections and 0.90 for OCT volumes. Age prediction mean absolute errors of 6.328 years for fundus, 5.625 years for OCT cross sections and 4.541 for OCT volumes were observed. We assess the performance of OCT scans containing different biomarkers and note a peak performance of AUC = 0.88 for OCT cross sections and 0.95 for volumes when there is no pathology on scans. Performance drops in case of drusen, fibrovascular pigment epitheliuum detachment and geographic atrophy present. We conclude that deep learning based methods are capable of classifying the patient’s sex and age from color fundus photography and OCT for a broad spectrum of patients irrespective of underlying disease or image quality. Non-random sex prediction using fundus images seems only possible if the eye fovea and optic disc are visible.
Assessing the effectiveness of two intervention methods for stony coral tissue loss disease on Montastraea cavernosa
Authors: Shilling Erin N. , Combs Ian R. , Voss Joshua D.
Published: April 2021

Stony coral tissue loss disease (SCTLD) was first observed in Florida in 2014 and has since spread to multiple coral reefs across the wider Caribbean. The northern section of Florida’s Coral Reef has been heavily impacted by this outbreak, with some reefs experiencing as much as a 60% loss of living coral tissue area. We experimentally assessed the effectiveness of two intervention treatments on SCTLD-affectedMontastraea cavernosacolonies in situ. Colonies were tagged and divided into three treatment groups: (1) chlorinated epoxy, (2) amoxicillin combined with CoreRx/Ocean Alchemists Base 2B, and (3) untreated controls. The experimental colonies were monitored periodically over 11 months to assess treatment effectiveness by tracking lesion development and overall disease status. The Base 2B plus amoxicillin treatment had a 95% success rate at healing individual disease lesions but did not necessarily prevent treated colonies from developing new lesions over time. Chlorinated epoxy treatments were not significantly different from untreated control colonies, suggesting that chlorinated epoxy treatments are an ineffective intervention technique for SCTLD. The results of this experiment expand management options during coral disease outbreaks and contribute to overall knowledge regarding coral health and disease.
Occipital cortex is modulated by transsaccadic changes in spatial frequency: an fMRI study
Authors: Baltaretu Bianca R. , Dunkley Benjamin T. , Stevens W. Dale , Crawford J. Douglas
Published: April 2021

Previous neuroimaging studies have shown that inferior parietal and ventral occipital cortex are involved in the transsaccadic processing of visual object orientation. Here, we investigated whether the same areas are also involved in transsaccadic processing of a different feature, namely, spatial frequency. We employed a functional magnetic resonance imaging paradigm where participants briefly viewed a grating stimulus with a specific spatial frequency that later reappeared with the same or different frequency, after a saccade or continuous fixation. First, using a whole-brain Saccade > Fixation contrast, we localized two frontal (left precentral sulcus and right medial superior frontal gyrus), four parietal (bilateral superior parietal lobule and precuneus), and four occipital (bilateral cuneus and lingual gyri) regions. Whereas the frontoparietal sites showed task specificity, the occipital sites were also modulated in a saccade control task. Only occipital cortex showed transsaccadic feature modulations, with significant repetition enhancement in right cuneus. These observations (parietal task specificity, occipital enhancement, right lateralization) are consistent with previous transsaccadic studies. However, the specific regions differed (ventrolateral for orientation, dorsomedial for spatial frequency). Overall, this study supports a general role for occipital and parietal cortex in transsaccadic vision, with a specific role for cuneus in spatial frequency processing.
Optimized preoperative determination of nerve of origin in patients with vestibular schwannoma
Authors: Rahne Torsten , Plontke Stefan K. , Fröhlich Laura , Strauss Christian
Published: April 2021

In vestibular schwannoma (VS) patients hearing outcome and surgery related risks can vary and depend on the nerve of origin. Preoperative origin differentiation between inferior or superior vestibular nerve may influence the decision on treatment, and the selection of optimal treatment and counselling modalities. A novel scoring system based on functional tests was designed to predict the nerve of origin for VS and was applied to a large number of consecutive patients. A prospective, double blind, cohort study including 93 patients with suspected unilateral VS was conducted at a tertiary referral centre. Preoperatively before tumor resection a functional test battery [video head-impulse test (vHIT) of all semicircular canals (SCC)], air-conducted cervical/ocular vestibular evoked myogenic potential tests (cVEMP, oVEMP), pure-tone audiometry, and speech discrimination was applied. Sensitivity and specificity of prediction of intraoperative finding by a preoperative score based on vHIT gain, cVEMP and oVEMP amplitudes and asymmetry ratios was calculated. For the prediction of inferior vestibular nerve origin, sensitivity was 73% and specificity was 80%. For the prediction of superior vestibular nerve origin, sensitivity was 60% and specificity was 90%. Based on the trade-off between sensitivity and specificity, optimized cut-off values of − 0.32 for cVEMP and − 0.11 for oVEMP asymmetry ratios and vHIT gain thresholds of 0.77 (anterior SCC), 0.84 (lateral SCC) and 0.80 (posterior SCC) were identified by receiver operator characteristic curves. The scoring system based on preoperative functional tests improves prediction of nerve of origin and can be applied in clinical routine.
Identification, Shiga toxin subtypes and prevalence of minor serogroups of Shiga toxin-producing Escherichia coli in feedlot cattle feces
Authors: Capps Kaylen M. , Ludwig Justin B. , Shridhar Pragathi B. , Shi Xiaorong , Roberts Elisabeth , DebRoy Chitrita , Cernicchiaro Natalia , Phebus Randall K. , Bai Jianfa , Nagaraja T. G.
Published: April 2021

Shiga toxin-producing Escherichia coli (STEC) are foodborne pathogens that cause illnesses in humans ranging from mild to hemorrhagic enteritis with complications of hemolytic uremic syndrome and even death. Cattle are a major reservoir of STEC, which reside in the hindgut and are shed in the feces, a major source of food and water contaminations. Seven serogroups, O26, O45, O103, O111, O121, O145 and O157, called ‘top-7’, are responsible for the majority of human STEC infections in North America. Additionally, 151 serogroups of E. coli are known to carry Shiga toxin genes (stx). Not much is known about fecal shedding and prevalence and virulence potential of STEC other than the top-7. Our primary objectives were to identify serogroups of STEC strains, other than the top-7, isolated from cattle feces and subtype stx genes to assess their virulence potential. Additional objective was to develop and validate a novel multiplex PCR assay to detect and determine prevalence of six serogroups, O2, O74, O109, O131, O168, and O171, in cattle feces. A total of 351 strains, positive for stx gene and negative for the top-7 serogroups, isolated from feedlot cattle feces were used in the study. Of the 351 strains, 291 belonged to 16 serogroups and 60 could not be serogrouped. Among the 351 strains, 63 (17.9%) carried stx1 gene and 300 (82.1%) carried stx2, including 12 strains positive for both. The majority of the stx1 and stx2 were of stx1a (47/63; 74.6%) and stx2a subtypes (234/300; 78%), respectively, which are often associated with human infections. A novel multiplex PCR assay developed and validated to detect six serogroups, O2, O74, O109, O131, O168, and O171, which accounted for 86.9% of the STEC strains identified, was utilized to determine their prevalence in fecal samples (n = 576) collected from a commercial feedlot. Four serogroups, O2, O109, O168, and O171 were identified as the dominant serogroups prevalent in cattle feces. In conclusion, cattle shed in the feces a number of STEC serogroups, other than the top-7, and the majority of the strains isolated possessed stx2, particularly of the subtype 2a, suggesting their potential risk to cause human infections.
Introducing two types of psychological resilience with partly unique genetic and environmental sources
Authors: Hofgaard Live Skow , Nes Ragnhild Bang , Røysamb Espen
Published: April 2021

Psychological resilience is indicated when individuals demonstrate good mental health despite exposure to significant stress or adversity. Good mental health may involve low levels of illbeing and/or high levels of wellbeing. There is still very limited knowledge about the potential differences between these outcomes in relation to stressors. We propose a distinction between type 1 and type 2 resilience, examine their underlying genetic and environmental architecture, and identify modifiable resilience factors. The data come from a population-based twin sample (N = 1987, mean age = 63) in the Norwegian Twin Registry. Type 1 and type 2 resilience are operationalised as the residual of anxiety/depression symptoms and life satisfaction, respectively, after lifetime cumulative adversity has been regressed out. We used biometric modelling and cotwin-control linear mixed models to estimate underlying factors and identify predictors while controlling for genetic confounding. The results support the notion of two separate, but partly overlapping types of resilience. We find heritabilities of 0.30 (type 1) and 0.24 (type 2) and a genetic correlation of 0.43. Potentially causal resilience factors include, but are not limited to, meaning in life, physical activity, positive affect and relationship satisfaction. Whereas some factors are associated with both resilience types, other factors are unique to each type.
Circulating short and medium chain fatty acids are associated with normoalbuminuria in type 1 diabetes of long duration
Authors: Moon Salina , Tsay John J. , Lampert Heather , Md Dom Zaipul I. , Kostic Aleksandar D. , Smiles Adam , Niewczas Monika A.
Published: April 2021

A substantial number of subjects with Type 1 Diabetes (T1D) of long duration never develop albuminuria or renal function impairment, yet the underlying protective mechanisms remain unknown. Therefore, our study included 308 Joslin Kidney Study subjects who had T1D of long duration (median: 24 years), maintained normal renal function and had either normoalbuminuria or a broad range of albuminuria within the 2 years preceding the metabolomic determinations. Serum samples were subjected to global metabolomic profiling. 352 metabolites were detected in at least 80% of the study population. In the logistic analyses adjusted for multiple testing (Bonferroni corrected α = 0.000028), we identified 38 metabolites associated with persistent normoalbuminuria independently from clinical covariates. Protective metabolites were enriched in Medium Chain Fatty Acids (MCFAs) and in Short Chain Fatty Acids (SCFAs) and particularly involved odd-numbered and dicarboxylate Fatty Acids. One quartile change of nonanoate, the top protective MCFA, was associated with high odds of having persistent normoalbuminuria (OR (95% CI) 0.14 (0.09, 0.23); p < 10–12). Multivariable Random Forest analysis concordantly indicated to MCFAs as effective classifiers. Associations of the relevant Fatty Acids with albuminuria seemed to parallel associations with tubular biomarkers. Our findings suggest that MCFAs and SCFAs contribute to the metabolic processes underlying protection against albuminuria development in T1D that are independent from mechanisms associated with changes in renal function.