bluuebunny/crossref_metadata_2025 huggingface dataset:
Romantic Relationships in Young People with Long-Term Health Conditions: A Scoping Review
Authors: Jordan Abbie , Carter Bernie , Forgeron Paula , Fournier Karine , Sanders Kate
Published: October 2020

Objective

Forming and maintaining romantic relationships is an important developmental task in adolescence and young adulthood. This scoping review seeks to explore how young people with long-term physical health conditions understand and experience romantic relationships.

Methods

Using Arksey and O’Malley’s scoping review framework, a systematic search of five databases was conducted (PsychINFO, Cinahl, MEDLINE, Embase, and Web of Science). Studies were eligible for inclusion in the review if they were published in peer-reviewed journals, used primary data collection methods, and adopted quantitative, qualitative, or mixed-methods approaches to study romantic relationships in 11–25 year olds with long-term physical health conditions. Using a data extraction form, data pertaining to demographic characteristics of young people with long-term physical health conditions and relationship engagement were extracted from eligible papers.

Results

Searches returned 4645 papers after duplicate removal, with a two-stage screening process resulting in 111 full-text papers being reviewed. Thirty-three eligible papers were included across a range of long-term physical health conditions. Findings identified that living with a long-term physical health condition impacted young people’s perceptions and experiences of romantic relationships across the relationship lifespan, from envisaging future relationships, to forming relationships, and sustaining relationships. Issues around body confidence and self-esteem were identified as challenging in terms of perceptions and experiences of romantic relationships.

Conclusions

Findings demonstrate that young people wish to engage with romantic relationships, yet many report particular challenges associated with forming and sustaining relationships due to the constraints of their condition and treatment. Future research should consider nonheterosexual relationships.
Secret Codes & Oppressive Histories
Authors: Bliss Jackson
Published: October 2020

In this short story with an oscillating point of view and a secret coded message, an estranged hapa daughter and her Japanese American father are about to meet for the first time in fifteen years as they retell their stories separately of moving from town to town in Michigan as drivers and passengers, a power dynamic that doubles as generational, gender, hierarchical, and positional signifiers in their own relationship.
crisprSQL: a novel database platform for CRISPR/Cas off-target cleavage assays
Authors: Störtz Florian , Minary Peter
Published: October 2020

With ongoing development of the CRISPR/Cas programmable nuclease system, applications in the area of in vivo therapeutic gene editing are increasingly within reach. However, non-negligible off-target effects remain a major concern for clinical applications. Even though a multitude of off-target cleavage datasets have been published, a comprehensive, transparent overview tool has not yet been established. Here, we present crisprSQL (http://www.crisprsql.com), an interactive and bioinformatically enhanced collection of CRISPR/Cas9 off-target cleavage studies aimed at enriching the fields of cleavage profiling, gene editing safety analysis and transcriptomics. The current version of crisprSQL contains cleavage data from 144 guide RNAs on 25,632 guide-target pairs from human and rodent cell lines, with interaction-specific references to epigenetic markers and gene names. The first curated database of this standard, it promises to enhance safety quantification research, inform experiment design and fuel development of computational off-target prediction algorithms.
Critical couplings in topological-insulator waveguide-resonator systems observed in elastic waves
Authors: Yu Si-Yuan , He Cheng , Sun Xiao-Chen , Wang Hong-Fei , Wang Ji-Qian , Zhang Zi-Dong , Xie Bi-Ye , Tian Yuan , Lu Ming-Hui , Chen Yan-Feng
Published: October 2020

Waveguides and resonators are core components in the large-scale integration of electronics, photonics and phononics, both in existing and future scenarios. In certain situations, there is critical coupling of the two components; i.e. no energy passes through the waveguide after the incoming wave couples into the resonator. The transmission spectral characteristics resulting from this phenomenon are highly advantageous for signal filtering, switching, multiplexing and sensing. In the present study, adopting an elastic-wave platform, we introduce topological insulator (TI), a remarkable achievement in condensed matter physics over the past decade, into a classical waveguide-ring-resonator configuration. Along with basic similarities with classical systems, a TI system has important differences and advantages, mostly owing to the spin-momentum locked transmission states at the TI boundaries. As an example, a two-port TI waveguide resonator can fundamentally eliminate upstream reflections while completely retaining useful transmission spectral characteristics, and maximize the energy in the resonator, with possible applications being novel signal processing, gyro/sensing, lasering, energy harvesting and intense wave–matter interactions, using phonons, photons or even electrons. The present work further enhances confidence in using topological protection for practical device performance and functionalities, especially considering the crucial advantage of introducing (pseudo)spins to existing conventional configurations. More in-depth research on advancing phononics/photonics, especially on-chip, is foreseen.
Evolution of Drug Interactions With Antiretroviral Medication in People With HIV
Authors: El Moussaoui Majdouline , Lambert Iseult , Maes Nathalie , Sauvage Anne-Sophie , Frippiat Frédéric , Meuris Christelle , Uurlings Françoise , Lecomte Marianne , Léonard Philippe , Fombellida Karine , Vaira Dolores , Vercheval Christelle , Moutschen Michel , Darcis Gilles
Published: October 2020

Background

Polypharmacy and drug interactions are important issues for HIV-infected individuals. The number and nature of those interactions are continuously evolving with the use of new antiretroviral drugs and the aging of HIV-infected individuals. We aimed to analyze this evolution over time.

Methods

This retrospective cohort study was conducted in the University Hospital of Liège (Belgium). Treatments of HIV-infected outpatients attending Liège University Hospital were collected and analyzed in 2012 and 2016. The University of Liverpool HIV drug interactions database was used to determine drug interactions.

Results

We included 1038 patients in 2016, of whom 78% had 1 comedication. Polypharmacy was seen in 20% of the cohort. Four percent of the patients presented red flag interactions, and 38% had orange flag interactions. Nonantiretroviral (non-ARV) therapeutic classes involved in drug interactions were mostly cardiovascular and central nervous system drugs. They were followed by hormone drugs and dietary supplements for orange flag interactions. Two factors significantly contributed to both red and orange flag interactions: the number of non-ARV comedications and protease inhibitor–based ARV regimens. The proportion of patients with red or orange flag interactions remained stable from 2012 to 2016.

Conclusions

This study highlights the persistence of an alarming number of contraindicated drug interactions and a high prevalence of potential drug interactions over time. Identification, prevention, and management of drug interactions remain a key priority in HIV care.
Global Seasonality of Human Coronaviruses: A Systematic Review
Authors: Park Sangshin , Lee Yeonjin , Michelow Ian C , Choe Young June
Published: October 2020

In the context of the coronavirus disease 2019 pandemic, we aimed to systematically address the global seasonal patterns of human coronavirus (HCoV) infections. We identified relevant articles from MEDLINE, EMBASE, and CINAHL Plus as of May 11, 2020. The main outcomes were the peak months of HCoV infections each year and the months during which more than 5% of positive respiratory specimen tests were attributable to HCoV. Of 707 articles reviewed, 22 met the inclusion criteria. The annual percentage of HCoV infections reached a peak in February globally. We found a higher HCoV positivity rate among studies that tested only children (median: 5.9%, range: 0.9%–18.4%), compared with other studies of adults alone (median: 5.2%, range: 3.3%–7.1%) or the entire population (median: 1.9%, range: 0.2%–8.1%). We found the largest global peak of HCoV during the winter season, with the highest rate of positivity among children.
Cerebrospinal Analysis in Patients With COVID-19
Authors: Miller Emily Happy , Namale Vivian S , Kim Carla , Dugue Rachelle , Waldrop Greer , Ciryam Prajwal , Chong Alexander M , Zucker Jason , Miller Eliza C , Bain Jennifer M , Willey Joshua Z , Doyle Kevin , Boehme Amelia , Claassen Jan , Uhlemann Anne-Catrin , Thakur Kiran T
Published: October 2020

Background

Assessment of the impact of cerebrospinal fluid (CSF) analysis including investigation for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential for the optimization of patient care.

Methods

In this case series, we review patients diagnosed with SARS-CoV-2 undergoing lumbar puncture (LP) admitted to Columbia University Irving Medical Center (New York, NY, USA) from March 1 to May 26, 2020. In a subset of patients, CSF SARS-CoV-2 quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) testing is performed.

Results

The average age of 27 patients who underwent LP with definitive SARS-CoV-2 (SD) was 37.5 (28.7) years. CSF profiles showed elevated white blood cell counts and protein in 44% and 52% of patients, respectively. LP results impacted treatment decisions in 10 (37%) patients, either by change of antibiotics, influence in disposition decision, or by providing an alternative diagnosis. CSF SARS-CoV-2 qRT-PCR was performed on 8 (30%) patients, with negative results in all samples.

Conclusions

Among patients diagnosed with SARS-CoV-2, CSF results changed treatment decisions or disposition in over one-third of our patient cohort. CSF was frequently abnormal, though CSF SARS-CoV-2 qRT-PCR was negative in all samples. Further studies are required to define whether CSF SARS-CoV-2 testing is warranted in certain clinical contexts.
Physiological Characteristic Changes and Full-Length Transcriptome of Rose (Rosa chinensis) Roots and Leaves in Response to Drought Stress
Authors: Li Wei , Fu Lufeng , Geng Ziwen , Zhao Xiaojuan , Liu Qinghua , Jiang Xinqiang
Published: October 2020

Rose (Rosa chinensis) is the most important ornamental crops worldwide. However, the physiological and molecular mechanism of rose under drought stress remains elusive. In this study, we analyzed the changes of photosynthetic and phytohormone levels in the leaves and roots of rose seedlings grown under control (no drought), mild drought (MD) and severe drought stress. The total chlorophyll content and water use efficiency were significantly enhanced under MD in rose leaves. In addition, the concentration of ABA was higher in the leaves compared to the roots, whereas the roots accumulated more IAA, methylindole-3-acetic acid and indole-3-propionic acid. We also constructed the first full-length transcriptome for rose, and identified 96,201,862 full-length reads of average length 1,149 bp that included 65,789 novel transcripts. A total of 3,657 and 4,341 differentially expressed genes (DEGs) were identified in rose leaves and roots respectively. KEGG pathway analysis showed enrichment of plant hormone, signal transduction and photosynthesis are among the DEGs. 42,544 alternatively spliced isoforms were also identified, and alternative 3′ splice site was the major alternative splicing (AS) event among the DEGs. Variations in the AS patterns of three genes between leaves and roots indicated the possibility of tissue-specific posttranscriptional regulation in response to drought stress. Furthermore, 2,410 novel long non-coding RNAs were detected that may participate in regulating the drought-induced DEGs. Our findings identified previously unknown splice sites and new genes in the rose transcriptome, and elucidated the drought stress-responsive genes as well as their intricate regulatory networks.
Thermal performance of marine diatoms under contrasting nitrate availability
Authors: Aranguren-Gassis María , Litchman Elena
Published: October 2020

Environmental factors that interact with increasing temperature under the ongoing global warming are an urgent issue determining marine phytoplankton’s performance. Previous studies showed that nutrient limitation alters phytoplankton responses to temperature and may lower their temperature optima (Topt), making them more susceptible to high temperatures. The generality of this relationship is unknown, as very few species were tested. Here we investigated how growth rate depended on temperature at two contrasting nitrogen concentrations in six marine diatoms isolated from different thermal environments, including the tropics. Low nitrate had a significant effect on thermal performance in five of the six species. The effect size was larger around the optimum temperature for growth, resulting in flattened thermal performance curves but no shift in Topt. While that trend is independent of the thermal regime from which each species was isolated, the implications for the phytoplankton response to global warming may be region dependent.
Post-Partition Citizenship Policies: Lessons from Post-Yugoslav Federal States
Authors: Džankić Jelena , Keil Soeren
Published: October 2020

Citizenship policies are important tools of inclusion and exclusion in a post-partition context. In most cases, they reflect the unitary and mono-ethnic character of newly established states. Their function in countries and territories where an ethnonational break-up resulted in further ethnically diverse societies is far more complex. Citizenship in multilevel states created through state disintegration is a counterintuitive combination of (1) the legacies of the old citizenship tradition and replications of the old federal structure, and (2) processes of ethnic engineering and designing group-centric citizenship regimes. Legacies of the old structure are framed by the modalities of break-up and initial determination of citizenry (e.g., the absence of zero solution), but strongly mirror elements of the previous multilevel construction of citizenship, including bottom-up derivation, ethno-national determination of membership, voting rights and representation. Discontinuities in citizenship policies reflect wider tensions between nation- and state-building (and destruction), and how these processes have been molded through different international influences. We undertake a case-study of two post-Yugoslav multilevel states, Bosnia and Herzegovina and the Federal Republic of Yugoslavia/the State Union of Serbia and Montenegro, with the intent of drawing broader conclusions on how citizenship policies can keep states together or break them apart.
Tuberculosis risk with biologics by screening-guided preventive strategy in rheumatoid arthritis under intermediate tuberculosis burden
Authors: Shin Anna , Lee Yun Jong , Lee Eun Bong , Song Yeong Wook , Kim Seoyoung C , Kang Eun Ha
Published: October 2020

Objectives

We aimed to compare tuberculosis (TB) risk during biologics treatment between patients with RA who did (prophylaxis) and did not (non-prophylaxis) undergo chemoprophylaxis following pre-biologic latent TB screening in Korea of an intermediate TB burden.

Methods

Using the 2002–16 Korea National Health Insurance database, we conducted a cohort study examining TB risk, defined by International Classification of Diseases Tenth Revision codes plus anti-TB drugs, among RA patients initiating a biologic drug with and without chemoprophylaxis after screening triage for latent TB. To control baseline confounding, we used propensity score-based fine stratification (PSS) and weighting. Cox proportional hazards models estimated hazard ratios and 95% CIs comparing TB risk between the prophylaxis vs non-prophylaxis groups.

Results

The PSS-weighted study cohort (mean age 57.0 years; 81.3% female) included 2249 and 7225 RA patients in the prophylaxis and non-prophylaxis groups, respectively. During 2.42 years of biologics treatment, 118 patients developed TB with the incidence rate per 100 person-years of 0.33 in the prophylaxis and 0.63 in the non-prophylaxis groups. The PSS-weighted hazard ratio (95% CI) for TB associated with the prophylaxis was 0.52 (0.32, 0.86). During the follow-up time, the incidence rate of TB remained consistently low in the prophylaxis group but it was highest in the first year, then time-dependently declined in the non-prophylaxis group.

Conclusion

This population-based cohort study warns that the current screening-based preventive strategy generates a substantially higher TB risk after biologics initiation among screening-negative patients compared with screening-positive patients receiving chemoprophylaxis, when the background TB burden is not low.
Morning brain: real-world neural evidence that high school class times matter
Authors: Dikker Suzanne , Haegens Saskia , Bevilacqua Dana , Davidesco Ido , Wan Lu , Kaggen Lisa , McClintock James , Chaloner Kim , Ding Mingzhou , West Tessa , Poeppel David
Published: October 2020

Researchers, parents and educators consistently observe a stark mismatch between biologically preferred and socially imposed sleep–wake hours in adolescents, fueling debate about high school start times. We contribute neural evidence to this debate with electroencephalogram data collected from high school students during their regular morning, mid-morning and afternoon classes. Overall, student alpha power was lower when class content was taught via videos than through lectures. Students’ resting state alpha brain activity decreased as the day progressed, consistent with adolescents being least attentive early in the morning. During the lessons, students showed consistently worse performance and higher alpha power for early morning classes than for mid-morning classes, while afternoon quiz scores and alpha levels varied. Together, our findings demonstrate that both class activity and class time are reflected in adolescents’ brain states in a real-world setting, and corroborate educational research suggesting that mid-morning may be the best time to learn.
Spatial Expression Pattern of ZNF391 Gene in the Brains of Patients With Schizophrenia, Bipolar Disorders or Major Depressive Disorder Identifies New Cross-Disorder Biotypes: A Trans-Diagnostic, Top-Down Approach
Authors: Ren Hongyan , Meng Yajing , Zhang Yamin , Wang Qiang , Deng Wei , Ma Xiaohong , Zhao Liansheng , Li Xiaojing , Wang Yingcheng , Sham Pak , Li Tao
Published: October 2020

The results generated from large psychiatric genomic consortia show us some new vantage points to understand the pathophysiology of psychiatric disorders. We explored the potential of integrating the transcription output of the core gene underlying the commonality of psychiatric disorders with a clustering algorithm to redefine psychiatric disorders. Our results showed that an extended MHC region was associated with the common factor of schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) at the level of genomic significance, with rs7746199 (P = 4.905e-08), a cis-eQTL to the gene ZNF391, pinpointed as a potential causal variant driving the signals in the region. Gene expression pattern of ZNF391 in the brain led to the emergence of 3 biotypes, independent of disorder. The 3 biotypes performed significantly differently in working memory and demonstrated different gray matter volumes in the right inferior frontal orbital gyrus (RIFOG), with a partial causal pathway arising from ZNF391 to RIFOG to working memory. Our study illustrates the potential of a trans-diagnostic, top-down approach in understanding the commonality of psychiatric disorders.
In silico design and automated learning to boost next-generation smart biomanufacturing
Authors: Carbonell Pablo , Le Feuvre Rosalind , Takano Eriko , Scrutton Nigel S
Published: October 2020

The increasing demand for bio-based compounds produced from waste or sustainable sources is driving biofoundries to deliver a new generation of prototyping biomanufacturing platforms. Integration and automation of the design, build, test and learn (DBTL) steps in centers like SYNBIOCHEM in Manchester and across the globe (Global Biofoundries Alliance) are helping to reduce the delivery time from initial strain screening and prototyping towards industrial production. Notably, a portfolio of producer strains for a suite of material monomers was recently developed, some approaching industrial titers, in a tour de force by the Manchester Centre that was achieved in less than 90 days. New in silico design tools are providing significant contributions to the front end of the DBTL pipelines. At the same time, the far-reaching initiatives of modern biofoundries are generating a large amount of high-dimensional data and knowledge that can be integrated through automated learning to expedite the DBTL cycle. In this Perspective, the new design tools and the role of the learning component as an enabling technology for the next generation of automated biofoundries are discussed. Future biofoundries will operate under completely automated DBTL cycles driven by in silico optimal experimental planning, full biomanufacturing devices connectivity, virtualization platforms and cloud-based design. The automated generation of robotic build worklists and the integration of machine-learning algorithms will collectively allow high levels of adaptability and rapid design changes toward fully automated smart biomanufacturing.
Cohabitation des intérêts des créanciers et des actionnaires de la société anonyme dans la protection du capital social: quid de la législation burundaise et de l’espace OHADA?
Authors: Nzohabonayo Anaclet
Published: October 2020

Les intérêts des actionnaires et des créanciers sont moins antagonistes qu’ils le paraissent en dépit des différences les caractérisant. Les premiers n’existent pas sans les seconds et vice versa. Dès lors, seule une protection concurrente de ces intérêts constitue le soubassement de la confiance de ces partenaires et le garant de la continuité de l’exploitation de la société. Cette réflexion est organisée autour de l’analyse des aménagements mis en place dans le code burundais des sociétés privées et à participation publique et dans l’acte uniforme de l’OHADA portant droit des sociétés commerciales et groupement d’intérêt économique pour assurer une cohabitation fructueuse des intérêts des partenaires suscités dans la protection du capital social. La forme juridique qui sert de cadre d’analyse est la société anonyme.

En explicitant les mécanismes de protection des intérêts des actionnaires et des créanciers, cette analyse met en lumière les principes de protection du capital social et des intérêts de ceux qui participent à sa formation. L’étude se veut un ingrédient indispensable pour maintenir la performance financière de la société. Étant par essence comparative, cette réflexion expose les textes commentés et est par conséquent susceptible de susciter les commentaires pouvant provoquer leur relecture par les décideurs.

De l’ensemble de l’analyse, il s’avère que les principes qui protègent les intérêts des actionnaires préservent aussi par ricochet les intérêts des créanciers et vice versa. Il y a donc une interdépendance entre ces principes qui converge vers la protection du capital, centre d’intérêt des partenaires de la SA.
Additional analyses exploring the hypothesized transdifferentiation of plasmablasts to developing neutrophils in severe COVID-19
Authors: Wilk Aaron J. , Rustagi Arjun , Zhao Nancy Q. , Martin Beth A. , Rogers Angela J. , Blish Catherine A.
Published: October 2020

We thank Alquicira-Hernandez et al. for their reanalysis of our single-cell transcriptomic dataset profiling peripheral immune responses to severe COVID-19. We agree that careful analysis of single-cell sequencing data is important for generating cogent hypotheses but find several aspects of their criticism of our analysis to be problematic. Here we respond briefly to misunderstandings and inaccuracies in their commentary that may have led to misinformed interpretation of our results.
Deep-learning based fully automatic segmentation of the globus pallidus interna and externa using ultra-high 7 Tesla MRI
Authors: Solomon Oren , Palnitkar Tara , Patriat Remi , Braun Henry , Aman Joshua , Park Michael C. , Vitek Jerry , Sapiro Guillermo , Harel Noam
Published: October 2020

Deep brain stimulation (DBS) surgery has been shown to dramatically improve the quality of life for patients with various motor dysfunctions, such as those afflicted with Parkinson’s disease (PD), dystonia, and essential tremor (ET), by relieving motor symptoms associated with such pathologies. The success of DBS procedures is directly related to the proper placement of the electrodes, which requires the ability to accurately detect and identify relevant target structures within the subcortical basal ganglia region. In particular, accurate and reliable segmentation of the globus pallidus (GP) interna is of great interest for DBS surgery for PD and dystonia. In this work, we present a deep-learning based neural network, which we term GP-net, for the automatic segmentation of both the external and internal segments of the globus pallidus. High resolution 7 Tesla images from 101 subjects were used in this study; GP-net is trained on a cohort of 58 subjects, containing patients with movement disorders as well as healthy control subjects. GP-net performs 3D inference in a patient-specific manner, alleviating the need for atlas-based segmentation. GP-net was extensively validated, both quantitatively and qualitatively over 43 test subjects including patients with movement disorders and healthy control and is shown to consistently produce improved segmentation results compared with state-of-the-art atlas-based segmentations. We also demonstrate a post-operative lead location assessment with respect to a segmented globus pallidus obtained by GP-net.
Multivalency transforms SARS-CoV-2 antibodies into broad and ultrapotent neutralizers
Authors: Rujas Edurne , Kucharska Iga , Tan Yong Zi , Benlekbir Samir , Cui Hong , Zhao Tiantian , Wasney Gregory A. , Budylowski Patrick , Guvenc Furkan , Newton Jocelyn C. , Sicard Taylor , Semesi Anthony , Muthuraman Krithika , Nouanesengsy Amy , Prieto Katherine , Bueler Stephanie A. , Youssef Sawsan , Liao-Chan Sindy , Glanville Jacob , Christie-Holmes Natasha , Mubareka Samira , Gray-Owen Scott D. , Rubinstein John L. , Treanor Bebhinn , Julien Jean-Philippe
Published: October 2020

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes Coronavirus Disease 2019 (COVID-19), has caused a global pandemic. Antibodies are powerful biotherapeutics to fight viral infections; however, discovery of the most potent and broadly acting clones can be lengthy. Here, we used the human apoferritin protomer as a modular subunit to drive oligomerization of antibody fragments and transform antibodies targeting SARS-CoV-2 into exceptionally potent neutralizers. Using this platform, half-maximal inhibitory concentration (IC50) values as low as 9 × 10−14M were achieved as a result of up to 10,000-fold potency enhancements. Combination of three different antibody specificities and the fragment crystallizable (Fc) domain on a single multivalent molecule conferred the ability to overcome viral sequence variability together with outstanding potency and Ig-likein vivobioavailability. This MULTi-specific, multi-Affinity antiBODY (Multabody; or MB) platform contributes a new class of medical countermeasures against COVID-19 and an efficient approach to rapidly deploy potent and broadly-acting therapeutics against infectious diseases of global health importance.

One Sentence Summary

multimerization platform transforms antibodies emerging from discovery screens into potent neutralizers that can overcome SARS-CoV-2 sequence diversity.
Predicting COVID-19 Severity with a Specific Nucleocapsid Antibody plus Disease Risk Factor Score
Authors: Sen S. , Sanders E.C. , Gabriel K.N. , Miller B.M. , Isoda H.M. , Salcedo G.S. , Garrido J.E. , Dyer R.P. , Nakajima R. , Jain A. , Caldaruse A.-M. , Santos A.M. , Bhuvan K. , Tifrea D.F. , Ricks-Oddie J.L. , Felgner P.L. , Edwards R.A. , Majumdar S. , Weiss G.A.
Published: October 2020

Effective methods for predicting COVID-19 disease trajectories are urgently needed. Here, ELISA and coronavirus antigen microarray (COVAM) analysis mapped antibody epitopes in the plasma of COVID-19 patients (n = 86) experiencing a wide-range of disease states. The experiments identified antibodies to a 21-residue epitope from nucleocapsid (termed Ep9) associated with severe disease, including admission to the ICU, requirement for ventilators, or death. Importantly, anti-Ep9 antibodies can be detected within six days post-symptom onset and sometimes within one day. Furthermore, anti-Ep9 antibodies correlate with various comorbidities and hallmarks of immune hyperactivity. We introduce a simple-to-calculate, disease risk factor score to quantitate each patient’s comorbidities and age. For patients with anti-Ep9 antibodies, scores above 3.0 predict more severe disease outcomes with a 13.42 Likelihood Ratio (96.7% specificity). The results lay the groundwork for a new type of COVID-19 prognostic to allow early identification and triage of high-risk patients. Such information could guide more effective therapeutic intervention.

Significance statement

The COVID-19 pandemic has resulted in over two million deaths worldwide. Despite efforts to fight the virus, the disease continues to overwhelm hospitals with severely ill patients. Diagnosis of COVID-19 is readily accomplished through a multitude of reliable testing platforms; however, prognostic prediction remains elusive. To this end, we identified a short epitope from the SARS-CoV-2 nucleocapsid protein and also a disease risk factor score based upon comorbidities and age. The presence of antibodies specifically binding to this epitope plus a score cutoff can predict severe COVID-19 outcomes with 96.7% specificity.
Functional spreading of hyperexcitability induced by human and synthetic intracellular Aβ oligomers
Authors: Fernandez-Perez Eduardo J. , Muñoz Braulio , Bascuñan Denisse A. , Peters Christian , Riffo-Lepe Nicolas O. , Espinoza Maria P. , Morgan Peter J. , Filippi Caroline , Bourboulou Romain , Sengupta Urmi , Kayed Rakez , Epsztein Jérôme , Aguayo Luis G.
Published: October 2020

Background

Intracellular amyloid-beta oligomers (iAβo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer’s disease (AD). However, to date, no mechanism linking them has been reported.

Methods

Here, the effects of human AD brain-derived (h-iAβo) and synthetic (iAβo) peptides on synaptic currents and action potential (AP) firing were investigated in hippocampal neuronsin vitro, ex vivoandin vivo.

Results

Starting from 500 pM, iAβo rapidly increased the frequency of synaptic currents and higher concentrations potentiated the AMPA receptor-mediated current. Both effects were PKC-dependent. Parallel recordings of synaptic currents and nitric oxide (NO)-related fluorescence changes indicated that the increased frequency, related to pre-synaptic release, was dependent on a NO-mediated retrograde signaling. Moreover, increased synchronization in NO production was also observed in neurons neighboring those dialyzed with iAβo, indicating that iAβo can increase network excitability at a distance. Current-clamp recordings suggested that iAβo increased neuronal excitability via AMPA-driven synaptic activity without altering membrane intrinsic properties.

Conclusion

These results strongly indicate that iAβo causes functional spreading of hyperexcitability through a synaptic-driven mechanism and offer an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures.
Highly efficient CRISPR-Cas9-mediated gene knockout in primary human B cells for functional genetic studies of Epstein-Barr virus infection
Authors: Akidil Ezgi , Albanese Manuel , Buschle Alexander , Ruhle Adrian , Keppler Oliver T. , Hammerschmidt Wolfgang
Published: October 2020

Gene editing is now routine in all prokaryotic and metazoan cells but has not received much attention in immune cells when the CRISPR-Cas9 technology was introduced in the field of mammalian cell biology less than ten years ago. This versatile technology has been successfully adapted for gene modifications in human myeloid cells and T cells, among others, but applications to human primary B cells have been scarce and limited to activated B cells. This limitation has precluded conclusive studies into cell activation, differentiation or cell cycle control in this cell type. We report on highly efficient, simple and rapid genome engineering in primary resting human B cells using nucleofection of Cas9 ribonucleoprotein complexes. We provide proof-of-principle of gene editing in quiescent human B cells using two model genes:CD46andCDKN2A. The latter encodes the cell cycle regulator p16INK4awhich is an important target of Epstein-Barr virus (EBV). Infection of B cells carrying a knockout ofCDKN2Awith wildtype and EBNA3 oncoprotein mutant strains of EBV allowed us to conclude that EBNA3C controlsCDKN2A, the only barrier to B cell proliferation in EBV infected cells. Together, this approach enables efficient targeting of specific gene loci in quiescent human B cells supporting basic research as well as immunotherapeutic strategies.

Author summary

Human hematopoietic stem cells and their derivatives of the myeloid and lymphoid lineages are important targets for gene correction or modifications using the CRISPR-Cas9 technology. Among others, this approach can support site-specific insertion of chimeric antigen receptors (CARs) or T cell receptors (TCRs) into primary T cells. Their subsequent adoptive transfer to patient donors is a promising immunotherapeutic concept that may control chronic infection or certain types of cancer. Human B cells have a similar potential but, in contrast to T cells, they are very sensitive, difficult to handle, and short-livedex vivoprecluding their genetic modification. Here, we provide means to manipulate primary human B cells genetically usingin vitroassembled Cas9 ribonucleoprotein complexes and electroporation for their delivery. Our study demonstrates near-to-complete loss of a model target gene and provides examples to evaluate a cellular gene with a critical role during infection with Epstein-Barr virus (EBV).
Neural inflammation alters synaptic plasticity probed by 10 Hz repetitive magnetic stimulation
Authors: Lenz Maximilian , Eichler Amelie , Kruse Pia , Strehl Andreas , Rodriguez-Rozada Silvia , Goren Itamar , Yogev Nir , Frank Stefan , Waisman Ari , Deller Thomas , Jung Steffen , Maggio Nicola , Vlachos Andreas
Published: October 2020

Systemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [C57BL6-Tg(TNFa-eGFP)] confirms thatex vivoLPS administration triggers microglial tumor necrosis factor alpha (TNFα) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNFα, IL6, IL1β, and IFNγ and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation.
A new approach of dissecting genetic effects for complex traits
Authors: Luo Meng , Gu Shiliang
Published: October 2020

During the past decades, genome-wide association studies (GWAS) have been used to successfully identify tens of thousands of genetic variants associated with complex traits included in humans, animals, and plants. All common genome-wide association (GWA) methods rely on population structure correction to avoid false genotype and phenotype associations. However, population structure correction is a stringent penalization, which also impedes the identification of real associations. Here, we used recent statistical advances and proposed iterative screen regression (ISR), which enables simultaneous multiple marker associations and shown to appropriately correction population stratification and cryptic relatedness in GWAS. Results from analyses of simulated suggest that the proposed ISR method performed well in terms of power (sensitivity) versus FDR (False Discovery Rate) and specificity, also less bias (higher accuracy) in effect (PVE) estimation than the existing multi-loci (mixed) model and the single-locus (mixed) model. We also show the practicality of our approach by applying it to rice, outbred mice, and A.thaliana datasets. It identified several new causal loci that other methods did not detect. Our ISR provides an alternative for multi-loci GWAS, and the implementation was computationally efficient, analyzing large datasets practicable (n>100,000).
A paired liver biopsy and plasma proteomics study reveals circulating biomarkers for alcohol-related liver disease
Authors: Niu Lili , Thiele Maja , Geyer Philipp E. , Rasmussen Ditlev Nytoft , Webel Henry Emanuel , Santos Alberto , Gupta Rajat , Meier Florian , Strauss Maximilian , Kjaergaard Maria , Lindvig Katrine , Jacobsen Suganya , Rasmussen Simon , Hansen Torben , Krag Aleksander , Mann Matthias
Published: October 2020

Existing tests for detecting liver fibrosis, inflammation and steatosis, three stages of liver disease that are still reversible are severely hampered by limited accuracy or invasive nature. Here, we present a paired liver-plasma proteomics approach to infer molecular pathophysiology and to identify biomarkers in a cross-sectional alcohol-related liver disease cohort of nearly 600 individuals. Metabolic functions were downregulated whereas fibrosis-associated signaling and novel immune responses were upregulated, but only half of tissue proteome changes were transmitted to the circulation. Machine learning models based on our biomarker panels outperformed existing tests, laying the foundation for a generic proteomic liver health assessment.
Phosphorylation-dependent sub-functionalization of the calcium-dependent protein kinase CPK28
Authors: Bredow Melissa , Bender Kyle W. , Dingee Alexandra Johnson , Holmes Danalyn R. , Thomson Alysha , Ciren Danielle , Tanney Cailun A. S. , Dunning Katherine E. , Trujillo Marco , Huber Steven C. , Monaghan Jacqueline
Published: October 2020

Calcium (Ca2+)-dependent protein kinases (CDPKs or CPKs) are a unique family of Ca2+-sensor/kinase-effector proteins with diverse functions in plants. InArabidopsis thaliana, CPK28 contributes to immune homeostasis by promoting degradation of the key immune signaling receptor-like cytoplasmic kinase BOTRYTIS-INDUCED KINASE 1 (BIK1), and additionally functions in vegetative-to-reproductive stage transition. How CPK28 controls these seemingly disparate pathways is unknown. Here, we identify a single phosphorylation site in the kinase domain of CPK28 (Ser318) that is differentially required for its function in immune homeostasis and stem elongation. We show that CPK28 undergoes intra- and inter-molecular auto-phosphorylation on Ser318 and can additionally be trans-phosphorylated on this residue by BIK1. Analysis of several other phosphorylation sites demonstrates that Ser318 phosphorylation is uniquely required to prime CPK28 for Ca2+activation at physiological concentrations of Ca2+, possibly through stabilization of the Ca2+-bound active state as indicated by intrinsic fluorescence experiments. Together, our data indicate that phosphorylation of Ser318 is required for the activation of CPK28 at low intracellular [Ca2+] to prevent initiation of an immune response in the absence of infection. By comparison, phosphorylation of Ser318 is not required for stem-elongation, indicating pathway specific requirements for phosphorylation-based Ca2+-sensitivity priming. We additionally provide evidence for a conserved function for Ser318 phosphorylation in related group IV CDPKs which holds promise for biotechnological applications by generating CDPK alleles that enhance resistance to microbial pathogens without consequences to yield.
Malleability of the cortical hand map following a finger nerve block
Authors: Wesselink Daan B. , Sanders Zeena-Britt , Edmondson Laura R. , Dempsey-Jones Harriet , Kieliba Paulina , Kikkert Sanne , Themistocleous Andreas C. , Emir Uzay , Diedrichsen Jörn , Saal Hannes P. , Makin Tamar R.
Published: October 2020

Individual fingers in the primary somatosensory cortex (S1) are known to be represented separately and adjacently, forming a cortical hand map. Electrophysiological studies in monkeys show that finger amputation triggers increased selectivity to the neighbouring fingers within the deprived S1, causing local reorganisation. Neuroimaging research in humans, however, shows persistent S1 finger representation of the missing hand, even decades after amputation. We aimed to resolve these apparently contrasting evidence by examining finger representation in humans following pharmacological ‘amputation’ using single-finger nerve block and 7T neuroimaging. We hypothesised that beneath the apparent selectivity of individual fingers in the hand map, peripheral and central processing is distributed across fingers. If each finger contributes to the cortical representation of the others, then localised input loss will weaken finger representation across the hand map. For the same reason, the non-blocked fingers will stabilise the blocked finger’s representation, resulting in persistent representation of the blocked finger. Using univariate selectivity profiling, we replicated the electrophysiological findings of local S1 reorganisation. However, more comprehensive analyses confirmed that local blocking reduced representation of all fingers across the entire hand area. Importantly, multivariate analysis demonstrated that despite input loss, representation of the blocked finger remained persistent and distinct from the unblocked fingers. Computational modelling suggested that the observed findings are driven by distributed processing underlying the topographic map, combined with homeostatic mechanisms. Our findings suggest that the long-standing depiction of the somatosensory hand map is misleading. As such, accounts for map reorganisation, e.g. following amputation, need to be reconsidered.
Translation-dependent and independent mRNA decay occur through mutually exclusive pathways that are defined by ribosome density during T Cell activation
Authors: Mercier Blandine C. , Labaronne Emmanuel , Cluet David , Bicknell Alicia , Corbin Antoine , Guiguettaz Laura , Aube Fabien , Modolo Laurent , Auboeuf Didier , Moore Melissa J. , Ricci Emiliano P.
Published: October 2020

mRNA translation and degradation are strongly interconnected processes that participate in the fine tuning of gene expression. Particularly, targeting mRNAs to translation-dependent degradation (TDD) could attenuate protein expression by making any increase in mRNA translation self-limiting. However, the extent to which TDD is a general mechanism for limiting protein expression is currently unknown. Here we describe a comprehensive analysis of basal and signal-induced TDD in mouse primary CD4 T cells. Our data indicate that most cellular transcripts are decayed to some extent in a translation-dependent manner, both in resting and activated cells. Our analysis further identifies the length of untranslated regions, the density of ribosomes and the GC content of the coding region as major determinants of TDD magnitude. Consistent with this, all transcripts that undergo changes in ribosome density upon T cell activation display a corresponding change in their TDD level. Surprisingly, the amplitude of translation-independent mRNA decay (TID) appears as a mirror image of TDD. Moreover, TID also responds to changes in ribosome density upon T cell activation but in the opposite direction from the one observed for TDD. Our data demonstrate a strong interconnection between mRNA translation and decay in mammalian cells. Furthermore, they indicate that ribosome density is a major determinant of the pathway by which transcripts are degraded within cells.
Histone modifications form a cell-type-specific chromosomal bar code that modulates and maintains patterns of gene expression through the cell cycle
Authors: Halsall John A. , Andrews Simon , Krueger Felix , Rutledge Charlotte E. , Ficz Gabriella , Reik Wolf , Turner Bryan M.
Published: October 2020

Background

Chromatin configuration influences gene expression in eukaryotes at multiple levels, from individual nucleosomes to chromatin domains several Mb long. Post-translational modifications (PTM) of core histones seem to be involved in chromatin structural transitions, but how remains unclear.

To explore this, we used ChIP-seq and two cell types, HeLa and lymphoblastoid (LCL) to define how changes in chromatin packaging through the cell cycle influence the distributions of three transcription-associated histone modifications, H3K9ac, H3K4me3 and H3K27me3.

Results

Chromosome regions (bands) of 10-50Mb, detectable by immunofluorescence microscopy of metaphase (M) chromosomes, are also present in G1and G2. We show that they comprise 1-5Mb sub-bands that differ between HeLa and LCL but remain consistent through the cell cycle. The same sub-bands are defined by H3K9ac and H3K4me3, while H3K27me3 spreads more widely.

We found little change between cell cycle phases, whether compared by 5Kb rolling windows or when analysis was restricted to functional elements such as transcription start sites and topologically associating domains.

Only a small number of genes showed cell-cycle related changes: at genes encoding proteins involved in mitosis, H3K9 became highly acetylated in G2M, possibly because of ongoing transcription.

Conclusions

Modified histone isoforms H3K9ac, H3K4me3 and H3K27me3 exhibit a characteristic genomic distribution at resolutions of 1Mb and below that differs between HeLa and lymphoblastoid cells but remains remarkably consistent through the cell cycle. We suggest that this cell-type-specific chromosomal bar-code is part of a homeostatic mechanism by which cells retain their characteristic gene expression patterns, and hence their identity, through multiple mitoses.