bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of Microbiome Biomarkers for IgA: a Joint Modeling Approach
Authors: Sengupta Rudradev , Owokotomo Olajumoke Evangelina , Shkedy Ziv
Published: April 2021

Our aim in this study is to develop predictive microbiome biomarkers for intestinal IgA levels. In this article, a operational taxonomic units(OTU)-specific (family-specific) and time-specific joint model is presented as a tool to model the association between OTU (or family) and biological response (measured by IgA level) taking into account the treatment group (Control or PAT) of the subjects. The model allows detecting OTUs (families) that are associated with the IgA; for some OTUs (families), the association is driven by the treatment while for others the association reflects the correlation between the OTUs (families) and IgA.The results of the analysis reveal that: (1) the observed diversity of S24-7 family can be used as a biomarker to classify samples according to treatment group for days 6 and 12; (2) the treatment effect induces the corrlelation between the S24-7 diversity and the IgA level at day 20; (3) The OTUs that are identified to be significantly differentially abundant (FDR level of 0.05) between the two treatment groups for days 12 and 20 are all part of the S24-7 family, although most of the differentially abundant ones at day 1 are from the Lactobacillaceae family; (4) only the Lachnospiraceae family diversity at day 6, and 20 can be used as predictive biomarker for the IgA level at day 20; (5) New.ReferenceOTU513, correlated with the IgA level at day 20, since day 12, belongs to the Lachnospiraceae family and all other OTUs among the top 10 significantly associated OTUs at day 20 are from the S24-7 family; (6) the observed alpha diversity at day 6 is significantly differentially abundant and can be used as predictive biomarker for IgA level at day 20.
Mitochondrial genomes of two parasiticCuscutaspecies lack clear evidence of horizontal gene transfer and retain unusually fragmentedccmFCgenes
Authors: Anderson Benjamin M , Krause Kirsten , Petersen Gitte
Published: April 2021

Background

The intimate association between parasitic plants and their hosts favours the exchange of genetic material, potentially leading to horizontal gene transfer (HGT) between plants. With the recent publication of several parasitic plant nuclear genomes, there has been considerable focus on such non-sexual exchange of genes. To enhance the picture on HGT events in a widely distributed parasitic genus,Cuscuta(dodders), we assembled and analyzed the organellar genomes of two recently sequenced species,C. australisandC. campestris, making this the first account of complete mitochondrial genomes (mitogenomes) for this genus.

Results

The mitogenomes are 265,696 and 275,898 bp in length and contain a typical set of mitochondrial genes, with ten missing or pseudogenized genes often lost from angiosperm mitogenomes. Each mitogenome also possesses a structurally unusualccmFCgene, which exhibits splitting of one exon and a shift to trans-splicing of its intron. Based on phylogenetic analysis of mitochondrial genes from across angiosperms and similarity-based searches, there is little to no indication of HGT into theCuscutamitogenomes. A few candidate regions for plastome-to-mitogenome transfer were identified, with one suggestive of possible HGT.

Conclusions

The lack of HGT is surprising given examples from the nuclear genomes, and may be due in part to the relatively small size of theCuscutamitogenomes, limiting the capacity to integrate foreign sequences.
Machine learning sequence prioritization for cell type-specific enhancer design
Authors: Lawler Alyssa J , Ramamurthy Easwaran , Brown Ashley R , Shin Naomi , Kim Yeonju , Toong Noelle , Kaplow Irene M , Wirthlin Morgan , Zhang Xiaoyu , Fox Grant , Pfenning Andreas R
Published: April 2021

Recent discoveries of extreme cellular diversity in the brain warrant rapid development of technologies to access specific cell populations, enabling characterization of their roles in behavior and in disease states. Available approaches for engineering targeted technologies for new neuron subtypes are low-yield, involving intensive transgenic strain or virus screening. Here, we introduce SNAIL (Specific Nuclear-Anchored Independent Labeling), a new virus-based strategy for cell labeling and nuclear isolation from heterogeneous tissue. SNAIL works by leveraging machine learning and other computational approaches to identify DNA sequence features that confer cell type-specific gene activation and using them to make a probe that drives an affinity purification-compatible reporter gene. As a proof of concept, we designed and validated two novel SNAIL probes that target parvalbumin-expressing (PV) neurons. Furthermore, we show that nuclear isolation using SNAIL in wild type mice is sufficient to capture characteristic open chromatin features of PV neurons in the cortex, striatum, and external globus pallidus. Expansion of this technology has broad applications in cell type-specific observation, manipulation, and therapeutics across species and disease models.
Single-cell antigen-specific activation landscape of CAR T infusion product identifies determinants of CD19 positive relapse in patients with ALL
Authors: Bai Zhiliang , Woodhouse Steven , Kim Dongjoo , Lundh Stefan , Sun Hongxing , Deng Yanxiang , Xiao Yang , Barrett David M. , Myers Regina M. , Grupp Stephan A. , June Carl H. , Melenhorst J. Joseph , Camara Pablo G. , Fan Rong
Published: April 2021

Chimeric antigen receptor-modified (CAR) T cells targeting CD19 have mediated dramatic responses in relapsed/refractory acute lymphoblastic leukemia (ALL), yet a notable number of patients have CD19-positive relapse within one year of treatment. It remains unclear if the long-term response is associated with the characteristics of CAR T cells in infusion products, hindering the identification of biomarkers to predict therapeutic outcomes prior to treatment. Herein we present 101,326 single cell transcriptomes and surface protein landscape from the CAR T infusion products of 12 pediatric ALL patients upon CAR antigen-specific stimulation in comparison with TCR-mediated activation and controls. We observed substantial heterogeneity in the antigen-specific activation states, among which a deficiency of Th2 function was associated with CD19-positive relapsed patients (median remission 9.6 months) compared with very durable responders (remission>54 months). Proteomic profiles also revealed that the frequency of early memory T cell subsets, rather than activation or co-inhibitory signatures could distinguish CD19-positive relapse. Additionally, a deficit of type 1 helper and cytotoxic effector function and an enrichment for terminally differentiated CD8+ T cells exhibiting low cytokine polyfunctionality was associated with initial non-responders. By contrast, the single-cell transcriptomic data of unstimulated or TCR-activated CAR T cells failed to predict clinical responses. In aggregate, our results dissect the landscape of CAR-specific activation states in infusion products that can identify patients who do not develop a durable response to the therapy, and unveil the molecular mechanisms that may inform strategies to boost specific T cell function to maintain long term remission.
Comparison of Genomic Selection Models for Exploring Predictive Ability of Complex Traits in Breeding Programs
Authors: Merrick Lance F. , Carter Arron H.
Published: April 2021

Traits with a complex unknown genetic architecture are common in breeding programs. However, they pose a challenge for selection due to a combination of complex environmental and pleiotropic effects that impede the ability to create mapping populations to characterize the trait’s genetic basis. One such trait, seedling emergence of wheat (Triticum aestivumL.) from deep planting, presents a unique opportunity to explore the best method to use and implement GS models to predict a complex trait. 17 GS models were compared using two training populations, consisting of 473 genotypes from a diverse association mapping panel (DP) phenotyped from 2015-2019 and the other training population consisting of 643 breeding lines phenotyped in 2015 and 2020 in Lind, WA with 40,368 markers. There were only a few significant differences between GS models, with support vector machines reaching the highest accuracy of 0.56 in a single breeding line trial using cross-validations. However, the consistent moderate accuracy of cBLUP and other parametric models indicates no need to implement computationally demanding non-parametric models for complex traits. There was an increase in accuracy using cross-validations from 0.40 to 0.41 and independent validations from 0.10 to 0.17 using diversity panels lines to breeding lines. The environmental effects of complex traits can be overcome by combining years of the same populations. Overall, our study showed that breeders can accurately predict and implement GS for a complex trait by using parametric models within their own breeding programs with increased accuracy as they combine training populations over the years.
Rapid global phaseout of animal agriculture has the potential to stabilize greenhouse gas levels for 30 years and offset 68 percent of CO2emissions this century
Authors: Eisen Michael B. , Brown Patrick O.
Published: April 2021

Animal agriculture contributes significantly to global warming through ongoing emissions of the potent greenhouse gases methane and nitrous oxide, and displacement of biomass carbon on the land used to support livestock. However, because estimates of the magnitude of the effect of ending animal agriculture often focus on only one factor, the full potential benefit of a more radical change remains underappreciated. Here we quantify the full “climate opportunity cost” of current global livestock production, by modeling the combined, long-term effects of emission reductions and biomass recovery that would be unlocked by a phaseout of animal agriculture. We show that, even in the absence of any other emission reductions, persistent drops in atmospheric methane and nitrous oxide levels, and slower carbon dioxide accumulation, following a phaseout of livestock production would, through the end of the century, have the same cumulative effect on the warming potential of the atmosphere as a 25 gigaton per year reduction in anthropogenic CO2emissions, providing half of the net emission reductions necessary to limit warming to 2°C. The magnitude and rapidity of these potential effects should place the reduction or elimination of animal agriculture at the forefront of strategies for averting disastrous climate change.

Significance Statement

The use of animals to produce food has a negative impact on the climate, but the benefits of a global switch to a plant based diet are underappreciated. We show that the global warming impact, through the rest of this century, of eliminating greenhouse gas emissions from livestock and allowing native ecosystems to regrow on the land currently used to house and feed livestock, would be equivalent to a 68% reduction in carbon dioxide emissions. We hope putting clearer numbers on the “climate opportunity cost” of our continued use of animals as food technology will help policymakers and the public properly prioritize dietary change as a climate defense strategy.

Declaration of Conflict of Interest

Patrick Brown is the founder and CEO of Impossible Foods, a company developing alternatives to animals in food-production. Michael Eisen is an advisor to Impossible Foods. Both are shareholders in the company and thus stand to benefit financially from reduction of animal agriculture.
The dominant axes of lifetime behavioral variation in honey bees
Authors: Smith Michael L , Davidson Jacob D , Wild Benjamin , Dormagen David M , Landgraf Tim , Couzin Iain D
Published: April 2021

Insect colonies are decentralized systems that employ task allocation, whereby individuals undertake different roles to fulfil colony needs, such as honey bee “nurses”, “nest workers”, and “foragers”. However, the extent to which individuals can be well-classified by discrete “roles”, how they change behavior from day-to-day, over entire lifetimes, and with environmental conditions, is poorly understood. Using long-term automated tracking of over 4,200 individually-identified beesApis mellifera, we use behavioral metrics to quantify and compare behavior. We show that individuals exhibit behavioral variation along two dominant axes that represent nest substrate use and movement within the nest. Across lifetimes, we find that individuals differ in foraging onset, and that certain bees exhibit lifelong consistencies in their movement patterns. Furthermore, we examine a period of sudden nectar availability where the honey stores tripled over 6 days, and see that the colony exhibits a distributed shift in activity that did not require a large-scale colony reorganization. Our quantitative approach shows how collective units differ over days and lifetimes, and how sources of variation and variability contribute to the colony’s robust yet flexible response.
Scalable, methanol-free manufacturing of the SARS-CoV-2 receptor binding domain in engineeredKomagataella phaffii
Authors: Dalvie Neil C. , Biedermann Andrew M. , Rodriguez-Aponte Sergio A. , Naranjo Christopher A. , Rao Harish D. , Rajurkar Meghraj P. , Lothe Rakesh R. , Shaligram Umesh S. , Johnston Ryan S. , Crowell Laura E. , Castelino Seraphin , Tracey Mary Kate , Whittaker Charles A. , Love J. Christopher
Published: April 2021

Prevention of COVID-19 on a global scale will require the continued development of high-volume, low-cost platforms for the manufacturing of vaccines to supply on-going demand. Vaccine candidates based on recombinant protein subunits remain important because they can be manufactured at low costs in existing large-scale production facilities that use microbial hosts likeKomagataella phaffii(Pichia pastoris). Here, we report an improved and scalable manufacturing approach for the SARS-CoV-2 spike protein receptor binding domain (RBD); this protein is a key antigen for several reported vaccine candidates. We genetically engineered a manufacturing strain ofK. phaffiito obviate the requirement for methanol-induction of the recombinant gene. Methanol-free production improved the secreted titer of the RBD protein by >5x by alleviating protein folding stress. Removal of methanol from the production process enabled scale up to a 1,200 L pre-existing production facility. This engineered strain is now used to produce an RBD-based vaccine antigen that is currently in clinical trials and could be used to produce other variants of RBD as needed for future vaccines.
Switch-like and persistent memory formation in individualDrosophilalarvae
Authors: Lesar Amanda , Tahir Javan , Wolk Jason , Gershow Marc
Published: April 2021

Associative learning allows animals to use past experience to predict future events. The circuits underlying memory formation support immediate and sustained changes in function, often in response to a single example. LarvalDrosophilais a genetic model for memory formation that can be accessed at molecular, synaptic, cellular, and circuit levels, often simultaneously, but existing behavioral assays for larval learning and memory do not address individual animals, and it has been difficult to form long lasting memories, especially those requiring synaptic re-organization. We demonstrate a new assay for learning and memory capable of tracking the changing preferences of individual larvae. We use this assay to explore how activation of a pair of reward neurons changes the response to the innately aversive gas Carbon Dioxide (CO2). We confirm that when coupled to odor presentation in appropriate temporal sequence, optogenetic reward reduces avoidance of CO2. We find that learning is switch-like: all-or-none and quantized in two states. Memories can be extinguished by repeated unrewarded exposure to CO2but are stabilized against extinction by repeated training or overnight consolidation. Finally, we demonstrate long-lasting protein synthesis dependent and independent memory formation.
Folding of VemP into translation-arresting secondary structure is driven by the ribosome exit tunnel
Authors: Kolář Michal H. , Nagy Gabor , Kunkel John , Vaiana Sara M. , Bock Lars V. , Grubmüller Helmut
Published: April 2021

The ribosome is a fundamental biomolecular complex responsible for protein production in cells. Nascent proteins emerge from the ribosome through a tunnel, where they may interact with the tunnel walls or small molecules such as antibiotics. These interactions can cause translational arrest with notable physiologic consequences. Here, we studied the arrest caused by the regulatory peptide VemP, which is known to form anα-helix in the ribosome tunnel near the peptidyl transferase center under specific conditions. We used all-atom molecular dynamics simulations of the entire ribosome and circular dichroism spectroscopy to study the driving forces of helix formation and how VemP causes the translational arrest. To that aim, we compared VemP dynamics in the ribosome tunnel with its dynamics in solution. We show that the VemP sequence has a low helical propensity in water and that the propensity is higher in more hydrophobic solvents. We propose that helix formation within the ribosome is driven by the tunnel environment and that a portion of VemP acts as an anchor. This anchor might slow down VemP progression through the tunnel enabling theα-helix formation, which causes the elongation arrest.
Alterations in chromosome spatial compartmentalization classify prostate cancer progression
Authors: Martin Rebeca San , Das Priyojit , Marques Renata Dos Reis , Xu Yang , McCord Rachel Patton
Published: April 2021

Prostate cancer aggressiveness and metastatic potential are influenced by gene expression, genomic aberrations, and cellular morphology. These processes are in turn dependent in part on the 3D structure of chromosomes, packaged inside the nucleus. Using chromosome conformation capture (Hi-C), we conducted a systematic genome architecture comparison on a cohort of cell lines that model prostate cancer progression, ranging from normal epithelium to bone metastasis. Here, we describe how chromatin compartmentalization identity (A-open vs. B-closed) changes with progression: specifically, we find that 48 gene clusters switch from the B to the A compartment, including androgen receptor, WNT5A, and CDK14. These switches could prelude transcription activation and are accompanied by changes in the structure, size, and boundaries of the topologically associating domains (TADs). Further, compartmentalization changes in chromosome 21 are exacerbated with progression and may explain, in part, the genesis of the TMPRSS2-ERG translocation: one of the main drivers of prostate cancer. These results suggest that discrete, 3D genome structure changes play a deleterious role in prostate cancer progression.

Through a systematic analysis of chromosome conformation capture in a cohort of cells that model cancer progression, San Martin et.al. find that rearrangement of the 3D genome structure in prostate cancer is a potential mechanism for disease exacerbation and that genome-wide compartment identity can classify cancer according to progression.
Linking Population Dynamics to Microbial Kinetics for Hybrid Modeling of Engineered Bioprocesses
Authors: Cheng Zhang , Yao Shiyun , Yuan Heyang
Published: April 2021

Mechanistic and data-driven models have been developed to provide predictive insights into the design and optimization of engineered bioprocesses. These two modeling strategies can be combined to form hybrid models to address the issues of parameter identifiability and prediction interpretability. Herein, we developed a novel and robust hybrid modeling strategy by incorporating microbial population dynamics into model construction. The hybrid model was constructed using bioelectrochemical systems (BES) as a platform system. We collected 77 samples from 13 publications, in which the BES were operated under diverse conditions, and performed holistic processing of the 16S rRNA amplicon sequencing data. Community analysis revealed core populations composed of putative electroactive taxaGeobacter, Desulfovibrio, Pseudomonas, andAcinetobacter. Primary Bayesian networks were trained with the core populations and environmental parameters, and directed Bayesian networks were trained by defining the operating parameters to improve the prediction interpretability. Both networks were validated with Bray-Curtis similarly, relative root-mean-square error (RMSE), and a null model. The hybrid model was developed by first building a three-population mechanistic component and subsequently feeding the estimated microbial kinetic parameters into network training. The hybrid model generated a simulated community that shared a Bray-Curtis similarity of 72% with the actual microbial community and an average relative RMSE of 7% for individual taxa. When examined with additional samples that were not included in network training, the hybrid model achieved accurate prediction of current production with a relative error-based RMSE of 0.8 and outperformed the data-driven models. The genomics-enabled hybrid modeling strategy represents a significant step toward robust simulation of a variety of engineered bioprocesses.
Genome-Wide Association Studies and Genomic Selection for Grain Protein Content Stability in a Nested Association Mapping Population of Spring Wheat
Authors: Sandhu Karansher S. , Mihalyov Paul D. , Lewien Megan J. , Pumphrey Michael O. , Carter Arron H.
Published: April 2021

Grain protein content (GPC) is controlled by complex genetic systems and their interactions, and is an important quality determinant for hard spring wheat as it has a positive effect on bread and pasta quality. GPC is variable among genotypes and strongly influenced by environment. Thus, understanding the genetic control of wheat GPC and identifying genotypes with improved stability is an important breeding goal. The objectives of this research were to identify genetic backgrounds with less variation for GPC across environments and identify quantitative trait loci (QTLs) controlling the stability of GPC. A spring wheat nested association mapping (NAM) population of 650 recombinant inbred lines (RIL) derived from 26 diverse founder parents crossed to one common parent, ‘Berkut’, was phenotyped over three years of field trials (2014-2016). Genomic selection models were developed and compared based on prediction of GPC and GPC stability. After observing variable genetic control of GPC within the NAM population, seven RIL families displaying reduced marker-by-environment interaction were selected based on a stability index derived from Finlay-Wilkinson regression. A genome-wide association study identified seven significant QTLs for GPC stability with a Bonferroni-adjustedPvalue <0.05. This study also demonstrated that genome-wide prediction of GPC with ridge regression best linear unbiased estimates reached up tor= 0.69. Genomic selection can be used to apply selection pressure for GPC and improve genetic gain for GPC.
A soil-binding polysaccharide complex released from root hairs functions in rhizosheath formation
Authors: Galloway Andrew F. , Akhtar Jumana , Burak Emma , Marcus Susan E. , Field Katie J. , Dodd Ian C. , Knox Paul
Published: April 2021

To elucidate factors involved in rhizosheath formation, wild type (WT) barley (Hordeum vulgareL. cv. Pallas) and a root hairless mutant,bald root barley(brb), were investigated with a combination of physiological, biochemical and immunochemical assays. When grown in soil, WT barley roots bound ∼5-fold more soil thanbrbper unit root length. High molecular weight (HMW) polysaccharide exudates ofbrbroots had less soil-binding capacity than those of WT root exudates. Carbohydrate and glycan monoclonal antibody analyses of HMW polysaccharide exudates indicated differing glycan profiles. Relative to WT plants, root exudates ofbrbhad reduced signals for arabinogalactan-protein (AGP), extensin and heteroxylan epitopes thanbrb. In contrast, thebrbroot exudate contained ∼25-fold more detectable xyloglucan epitope relative to WT. Epitope detection chromatography indicated that the increased detection of xyloglucan inbrbexudates was due to enhanced abundance of a neutral polymer. Exudate preparations frombrbhad decreased amounts of an acidic form of xyloglucan associated with root-hair located glycoprotein and heteroxylan epitopes and with soil-binding properties. Therefore, in addition to physically structuring soil particles, root hairs facilitate rhizosheath formation by releasing a soil-binding polysaccharide complex.

One sentence summary

The root exudate of a root hairless mutant of barley, relative to wild type, has an altered pattern of polysaccharide epitopes and lesser amounts of an acidic soil-binding polysaccharide complex.
MiR-212-3p functions as a tumor suppressor gene in group 3 medulloblastoma via targeting Nuclear Factor I/B (NFIB)
Authors: Perumal Naveenkumar , Kanchan Ranjana K. , Doss David , Bastola Noah , Atri Pranita , Venkata Ramakanth C. , Thapa Ishwor , Vengoji Raghupathy , Maurya Shailendra K. , Klinkebiel David , Talmon Geoffrey A. , Nasser Mohd W. , Batra Surinder K. , Mahapatra Sidharth
Published: April 2021

Background

Medulloblastoma (MB), the most frequent malignant pediatric brain tumor, is subdivided into four primary subgroups, wingless-type (WNT), sonic hedgehog (SHH), group 3, and group 4. Haploinsufficiency of chromosome 17p13.3 and c-Myc amplification distinguish high-risk group 3 tumors associated with rapid metastasis, recurrence and early mortality. We sought to identify the role of miR-212-3p, which resides on chromosome 17p13.3, in the pathophysiology of group 3 MB.

Methods

We first determined miR-212-3p expression in group 3 MB using several publicly-available datasets with confirmatory studiesin vitro. We then identified epigenetic regulation by studying methylation and HDAC modifications along the promoter region. We used two systems for expression restoration, i.e. transient transfection or stable induction, to delineate miR-212-3p’s tumor suppressive and biochemical properties via assays assessing cancer proliferation, migration, invasion, colony formation, along with cell cycle and apoptosis analyses. We then compared MB and miR target databases to isolate a putative target whose biochemical and oncogenic properties were similarly elucidated using either transient silencing of target expression or stable induction of miR-212-3p.

Results

RNA expression analyses revealed dramatically reduced miR-212-3p levels in group 3 tumors and cell lines mainly through epigenetic silencing via histone modifications. Restoring miR-212-3p expression reducedin vitrocancer cell proliferation, migration, colony formation, and wound healing. Elevated miR-212-3p levels shifted c-Myc phosphorylation (from serine-62 to threonine-58), triggering destabilization and degradation; concurrently, its pro-apoptotic binding partners, i.e., Bin-1 and P19ARF, were upregulated with subsequent elevated apoptotic signals. Using a combination of transcriptomic data and dual luciferase assay, we isolated an oncogenic target of miR-212-3p, i.e. NFIB, a nuclear transcription factor implicated in metastasis and recurrence in various cancers. Increased expression of NFIB was confirmed in group 3 tumors, with poor survival shown in high-expressing patients. Transient NFIB silencingin vitroreduced cancer cell proliferation, colony formation, migration, and invasion. Concurrently, in group 3 MB cells, reduced medullosphere formation along with decreased expression of stem cell markers (Nanog, Oct4, Sox2, CD133) were noted.

Conclusion

These results substantiate the tumor-suppressive role of miR-212-3p in group 3 MB and provide a potential therapeutic oncogenic target implicated in metastasis and tumor recurrence.
A Scribble-E-cadherin complex controls daughter cell patterning by multiple mechanisms
Authors: Chann Anchi S. , Chen Ye , Kinwel Tanja , Humbert Patrick O. , Russell Sarah M.
Published: April 2021

The fate of the two daughter cells is intimately connected to their positioning, which is in turn regulated by cell junction remodelling and orientation of the mitotic spindle. How multiple cues are integrated to dictate the ultimate patterning of daughters is not clear. Here, we identify novel mechanisms of regulation of daughter positioning in single MCF10A cells. The polarity protein, Scribble, links E-cadherin to NuMA and Arp2/3 signalling for sequential roles in daughter positioning. First Scribble transmits cues from E-cadherin localised in retraction fibres to control orientation of the mitotic spindle. Second, Scribble re-locates to the junction between the two daughters to allow a new E-cadherin-based-interface to form between them, influencing the width of the nascent daughter-daughter junction, generation of filopodia and subsequent cell patterning. Thus, E-cadherin and Scribble dynamically relocate to different intracellular sites during cell division to orient the mitotic spindle and control placement of the daughter cells after cell division.
SARS-CoV-2 RNA load in the lower respiratory tract, viral RNAemia and N-antigenemia in critically ill adult COVID-19 patients: relationship with biomarkers of disease severity
Authors: Olea Beatriz , Albert Eliseo , Torres Ignacio , Gozalvo-Rovira Roberto , Carbonell Nieves , Ferreres José , Poujois Sandrine , Costa Rosa , Colomina Javier , Rodríguez Jesús , Luisa Blasco María , Navarro David
Published: April 2021

Background

Little is known about the comparative kinetics of SARS-CoV-RNA load in the lower respiratory tract and in blood compartment in patients admitted to the intensive care unit, and how these relate to biomarkers of COVID-19 severity.

Methods

Seventy-three consecutive critically ill COVID-19 patients (median age, 65 years) were recruited. Serial lower respiratory tract (n=165) and plasma (n=340) specimens were collected. RT-PCR and lateral flow immunochromatography assay were used for SARS-CoV-2 RNA quantitation and N protein detection in plasma, respectively. Serum levels of inflammatory and tissue-damage biomarkers in paired specimens were analyzed.

Results

SARS-CoV-RNA was detected in the lower respiratory tract of most patients (92%). Viral RNAemia and N-antigenemia were documented in 35.6% and 40.1% of patients, respectively. Viral RNAemia and N-antigenemia cleared at a faster rate than SARS-CoV-2 RNA in tracheal aspirates (TA). SARS-CoV-2 RNA load was higher (P<0.001) in TA than in plasma, and correlated significantly (Rho, 0.41; P<0.001). A modest correlation was found between SARS-CoV-2 RNA load in TA and plasma and levels of ferritin and lactose dehydrogenase (Rho≤0.3; P≤0.008) in paired serum specimens. Neither the dynamics of SARS-CoV-2 RNA load in TA and plasma, nor N-antigenemia detection rate differed between surviving and deceased patients. Yet, a trend towards a higher mortality was seen in patients with viral RNAemia (OR; 2.82; 95% CI, 0.94-8.47; P=0.06).

Conclusion

Neither SARS-CoV-2 replication rate in the lower respiratory tract nor its presence in the blood appeared to critically impact on survival in ICU COVID-19 patients.

SARS-CoV-2 RNA load in the lower respiratory tract and plasma and N-antigenemia followed different kinetics, correlated modestly with serum levels of inflammatory and tissue-damage biomarkers and lymphopenia and did not appear to increase overall mortality risk in critically ill adult COVID-19 patients.
Longitudinal detection of SARS-CoV-2-specific antibody responses with different serological methods
Authors: Emmerich Petra , von Possel Ronald , Hemmer Christoph Josef , Fritzsche Carlos , Geerdes-Fenge Hilte , Menge Babett , Messing Claudia , Borchardt-Lohölter Viola , Deschermeier Christina , Steinhagen Katja
Published: April 2021

Serological testing for anti-SARS-CoV-2 antibodies is used to detect ongoing or past SARS-CoV-2 infections. To study the kinetics of anti-SARS-CoV-2 antibodies and to assess the diagnostic performances of eight serological assays, we used 129 serum samples collected on known days post symptom onset (dpso) from 42 patients with PCR-confirmed COVID-19 and 54 serum samples from healthy blood donors, and children infected with seasonal coronaviruses.

The sera were analyzed for the presence of IgG, IgM and IgA antibodies using indirect immunofluorescence testing (IIFT) based on SARS-CoV-2-infected cells. They were further tested for antibodies against the S1 domain of the SARS-CoV-2 spike protein (IgG, IgA) and against the viral nucleocapsid protein (IgG, IgM) using ELISA.

The assay specificities were 94.4%-100%. The sensitivities varied largely between assays, reflecting their respective purposes. The sensitivities of IgA and IgM assays were highest between 11 and 20 dpso, whereas the sensitivities of IgG assays peaked between 20 and 60 dpso.

IIFT showed highest sensitivities due to the use of the whole SARS-CoV-2 as substrate and provided information whether or not the individual has been infected with SARS-CoV-2. ELISAs provided further information about both the prevalence and concentration of specific antibodies against selected antigens of SARS-CoV-2.
A pair of non-competing neutralizing human monoclonal antibodies protecting from disease in a SARS-CoV-2 infection model
Authors: Peter Antonia Sophia , Roth Edith , Schulz Sebastian R. , Fraedrich Kirsten , Steinmetz Tobit , Damm Dominik , Hauke Manuela , Richel Elie , Mueller-Schmucker Sandra , Habenicht Katharina , Eberlein Valentina , Issmail Leila , Uhlig Nadja , Dolles Simon , Grüner Eva , Peterhoff David , Ciesek Sandra , Hoffmann Markus , Pöhlmann Stefan , McKay Paul F. , Shattock Robin J. , Wölfel Roman , Wagner Ralf , Eichler Jutta , Schuh Wolfgang , Neipel Frank , Ensser Armin , Mielenz Dirk , Tenbusch Matthias , Winkler Thomas H. , Grunwald Thomas , Überla Klaus , Jäck Hans-Martin
Published: April 2021

TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly generate human monoclonal antibodies. After immunizing these mice against the spike protein of SARS-CoV-2, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralized SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of neutralizing antibodies binds to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2 induced weight loss. Thus, we report two clusters of potent non-competing SARS-CoV-2 neutralizing antibodies providing potential candidates for therapy and prophylaxis of COVID-19. The study further supports the use of transgenic animals with human immunoglobulin gene repertoires in pandemic preparedness initiatives.
Copy number variation underlies complex phenotypes in domestic dog breeds and other canids
Authors: Serres-Armero Aitor , Davis Brian W. , Povolotskaya Inna S. , Morcillo-Suarez Carlos , Plassais Jocelyn , Juan David , Ostrander Elaine A. , Marques-Bonet Tomas
Published: April 2021

Extreme phenotypic diversity, a history of artificial selection, and socioeconomic value make domestic dog breeds a compelling subject for genomic research. Copy number variation (CNV) is known to account for a significant part of inter-individual genomic diversity in other systems. However, a comprehensive genome-wide study of structural variation as it relates to breed-specific phenotypes is lacking. We have generated whole genome CNV maps for more than 300 canids. Our data set extends the canine structural variation landscape to more than 100 dog breeds, including novel variants that cannot be assessed using microarray technologies. We have taken advantage of this data set to perform the first CNV-based genome-wide association study (GWAS) in canids. We identify 96 loci that display copy number differences across breeds, which are statistically associated with a previously compiled set of breed-specific morphometrics and disease susceptibilities. Among these, we highlight the discovery of a long-range interaction involving a CNV near MED13L and TBX3, which could influence breed standard height. Integration of the CNVs with chromatin interactions, long noncoding RNA expression, and single nucleotide variation highlights a subset of specific loci and genes with potential functional relevance and the prospect to explain trait variation between dog breeds.
Crystal structure of tris(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl-κP)-μ-oxoethenylidene-triangulo-trigold(I) bis(trifluoromethanesulfonyl)imide
Authors: Hartgerink Colin T. , Staples Richard J. , Anderson Carolyn E.
Published: April 2021

The title ketenylidene, [Au3(C2O)(C26H35O2P)3](C2F6NO4S2), was obtained upon exposure of [2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl]gold(I) bis(trifluoromethanesulfonyl)imide to acetic anhydride at elevated temperature. The ketenylidene bridge caps the tri-gold cluster. The title compound has provided crystals that upon analysis represent the first tri-gold ketenylidene with atomic distances indicative of bonding interaction between the gold atoms.
The Impact of Means‐Tested Premium Rebates and Tax Penalties on the Demand for Private Hospital Cover in Australia*
Authors: Bilgrami Anam , Cutler Henry , Sinha Kompal , Cheng Zhiming
Published: April 2021

Many governments intervene in private health insurance markets to incentivise demand, balance efficiency and equity, and counter adverse selection. In the context of rising health‐care costs, this is a complex task, and understanding the relative effectiveness of interventions can help governments design an optimal policy mix. We evaluate the impact of means‐testing a premium rebate and increasing an income tax penalty rate on private health insurance hospital coverage in Australia. We employ difference‐in‐difference (DID) analysis on a Household Income and Labour Dynamics in Australia (HILDA) survey panel of 6,179 individuals. To construct a valid control group, we employ income band restriction and match individuals below the policy income threshold to the treatment group using entropy balancing on pre‐treatment covariates and trends. Our analyses suggest that Australia’s Fairer Private Health Insurance Incentives (FPHII) reform in 2012 increased the probability of holding hospital cover by 1.5 percentage points (P < 0.1). The effect was driven by a significant increase in coverage of 2.4 percentage points (P < 0.1) for those in the highest income tier, despite this group experiencing the largest premium increase from the reform. Estimates were relatively robust to sensitivity analyses, including removing those with complicated income streams and removing potential income shifters. Our results suggest that increased tax penalty rates had a stronger impact than means‐testing premium rebates, most likely due to the low price elasticity of private health insurance demand in Australia. We discuss these findings in the context of developing an effective policy mix to attract and maintain private health insurance members and promote private health insurance market sustainability.
Europe's migration crisis: Local contact and out‐group hostility
Authors: RUDOLPH LUKAS , WAGNER MARKUS
Published: April 2021

Does a large influx of asylum seekers in the local community lead to a backlash in public opinion towards foreign populations? We assess the effects of asylum seeker presence using original survey and macro‐level municipality data from Austria, exploiting exogenous elements of the placement of asylum seekers on the municipality level. Methodologically, we draw on entropy balancing for causal identification. Our findings are threefold. First, respondents in municipalities receiving asylum seekers report substantially higher exposure on average, but largely without the stronger contact that would allow for meaningful interaction. Second, hostility towards asylum seekers on average increased in areas that housed them. Third, this backlash spilt over: general attitudes towards Muslims and immigrants are less favourable in contexts with local asylum seeker presence, while vote intention for the main anti‐immigration party is higher. Our findings go beyond existing work by examining contact directly as a mechanism, by showing a backlash effect in the medium term, and by focusing on a broad set of attitudinal and behavioural measures. Our results point to a need to design policy interventions that minimise citizen backlash against rapid migration inflows.
An Analysis of Portion Cap Rules with a Multiproduct Seller
Authors: Nuno‐Ledesma Jose G.
Published: April 2021

I study the impacts of limiting the quantity of one product in a two‐goods market with privately informed buyers. The goal is to explore effects on consumer surplus and consumption of both products. The main finding is that following moderate enough caps, a standard nonlinear pricing model predicts an increase in surplus for the buyer with low preference for the regulated good and high valuation for the unregulated product. Specific changes in allocation depend on the model's parameters. Consumption of the limited good is reduced, whereas consumption of the unregulated item often falls. Changes in screening are also interesting. Severe enough caps cause the seller to move from full separation to bunching some types. These results are applicable to food retail and other industries, where portion cap rules are a regulatory alternative and the impact on consumer surplus is an important consideration.
Prostate cancer management in the era of COVID‐19: Recommendations from the Hong Kong Urological Association and Hong Kong Society of Uro‐oncology
Authors: Poon Darren Ming‐Chun , Chan Chi‐Kwok , Chan Tim‐Wai , Cheung Foon‐Yiu , Ho Lap‐Yin , Kwong Philip Wai‐Kay , Lee Eric Ka‐Chai , Leung Angus Kwong‐Chuen , Leung Simon Yiu‐Lam , So Hing‐Shing , Tam Po Chor , Ma Wai‐Kit
Published: April 2021

Aim

In response to the fast‐developing coronavirus disease 2019 (COVID‐19) pandemic, special arrangement and coordination are urgently required in the interdisciplinary care of patients across different medical specialties. This article provides recommendations on the management of different stages of localized or metastatic prostate cancer (PC) amid this pandemic.

Methods

The Hong Kong Urological Association and Hong Kong Society of Uro‐oncology formed a joint discussion panel, which consisted of six urologists and six clinical oncologists with extensive experience in the public and private sectors. Following an evidence‐based approach, the latest relevant publications were searched and reviewed, before proceeding to a structured discussion of relevant clinical issues.

Results

The joint panel provided recommendations for PC management during the pandemic, in terms of general considerations, diagnostic procedures, different disease stages, treatment modules, patient support, and interdisciplinary collaboration. The overall goal was to minimize the risk of infection while avoiding unnecessary delays and compromises in management outcomes. Practical issues during the pandemic were addressed such as the use of invasive diagnostic procedures, robotic‐assisted laparoscopic prostatectomy, hypofractionated radiotherapy, and prolonged androgen deprivation therapy. The recommendations were explicated in the context of Hong Kong, a highly populated international city, in relation to the latest international guidelines and evidence.

Conclusion

A range of recommendations on the management of PC patients during the COVID‐19 pandemic was developed. Urologists, oncologists, and physicians treating PC patients may refer to them as practical guidance.
Validation of the factors influencing family consent for organ donation in the UK
Authors: Curtis R. M. K. , Manara A. R. , Madden S. , Brown C. , Duncalf S. , Harvey D. , Tridente A. , Gardiner D.
Published: April 2021

Between 2013 and 2019, there was an increase in the consent rate for organ donation in the UK from 61% to 67%, but this remains lower than many European countries. Data on all family approaches (16,896) for donation in UK intensive care units or emergency departments between April 2014 and March 2019 were extracted from the referral records and the national potential donor audit held by NHS Blood and Transplant. Complete data were available for 15,465 approaches. Consent for donation after brain death was significantly higher than for donation after circulatory death, 70% (4260/6060) vs. 60% (5645/9405), (OR 1.58, 95%CI 1.47–1.69). Patient ethnicity, religious beliefs, sex and socio‐economic status, and knowledge of a patient's donation decision were strongly associated with consent (p < 0.001). These factors should be addressed by medium‐ to long‐term strategies to increase community interventions, encouraging family discussions regarding donation decisions and increasing registration on the organ donor register. The most readily modifiable factor was the involvement of an organ donation specialist nurse at all stages leading up to the approach and the approach itself. If no organ donation specialist nurse was present, the consent rates were significantly lower for donation after brain death (OR 0.31, 95%CI 0.23–0.42) and donation after cardiac death (OR 0.26, 95%CI 0.22–0.31) compared with if a collaborative approach was employed. Other modifiable factors that significantly improved consent rates included less than six relatives present during the formal approach; the time from intensive care unit admission to the approach (less for donation after brain death, more for donation after cardiac death); family not witnessing neurological death tests; and the relationship of the primary consenter to the patient. These modifiable factors should be taken into consideration when planning the best bespoke approach to an individual family to discuss the option of organ donation as an end‐of‐life care choice for the patient.
Efficient detection and classification of epigenomic changes under multiple conditions
Authors: Baldoni Pedro L. , Rashid Naim U. , Ibrahim Joseph G.
Published: April 2021

Epigenomics, the study of the human genome and its interactions with proteins and other cellular elements, has become of significant interest in recent years. Such interactions have been shown to regulate essential cellular functions and are associated with multiple complex diseases. Therefore, understanding how these interactions may change across conditions is central in biomedical research. Chromatin immunoprecipitation followed by massively parallel sequencing (ChIP‐seq) is one of several techniques to detect local changes in epigenomic activity (peaks). However, existing methods for differential peak calling are not optimized for the diversity in ChIP‐seq signal profiles, are limited to the analysis of two conditions, or cannot classify specific patterns of differential change when multiple patterns exist. To address these limitations, we present a flexible and efficient method for the detection of differential epigenomic activity across multiple conditions. We utilize data from the ENCODE Consortium and show that the presented method, epigraHMM, exhibits superior performance to current tools and it is among the fastest algorithms available, while allowing the classification of combinatorial patterns of differential epigenomic activity and the characterization of chromatin regulatory states.