bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID symptoms, testing, shielding impact on patient reported outcomes and early vaccine responses in individuals with multiple myeloma
Authors: Ramasamy Karthik , Sadler Ross , Jeans Sally , Varghese Sherin , Turner Alison , Larham Jemma , Gray Nathanael , Barrett Joe , Bowcock Stella , Cook Gordon , Kyriakou Chara , Smith Dean , Drayson Mark , Basu Supratik , Moore Sally , McDonald Sarah , Gooding Sarah , Javaid Muhammad K
Published: May 2021

Objective

Multiple myeloma (MM)-related morbidity has a profound effect on quality of life (QoL), and immune function, but few studies have prospectively examined the impact of COVID-19 pandemic and attendant vaccination on both immunity and QoL of patients with MM. We aimed to characterise these effects in a prospective cohort study.

Design

We initiated a prospective national cohort study of patients with MM from start of the second wave of SARS CoV-2 infections in December 2020 and resultant COVID lockdown in the United Kingdom. We assessed current myeloma status, history of COVID19 symptoms, testing and vaccination including response using the rudystudy.org platform. In addition, healthcare resource use, mental and social well being and loneliness (Lubben scale) from the start of the COVID-19 pandemic were assessed.

Participants

We report data from the first one hundred and nine adults with MM who completed the questionnaires and the first round of blood testing in the cohort.

Results

Five patients (4.5%) had COVID-19 infection confirmed by history and/or testing (Nucleocapsid antibody). Up to 98% of patients shielded completely or partially during both waves of the pandemic, with 18% of patients consequently changing antimyeloma therapy in the shielding period. Using the Lubben scale, 21/99 (21.2 %) reported social isolation. Using HADS scale 23.1% of patients reported symptoms of mild to moderate anxiety or mild to moderate depression during this period. Humoral immune response (spike ab) tested 3 weeks after first vaccination was detected in 17/28 (60%) patients.

Conclusion

Myeloma patients shielded during waves of the pandemic with significant change to therapy, low level natural COVID-19 infection (4%) and social isolation. Humoral response following the first dose of COVID-19 vaccine is lower than that reported in non-myeloma cohorts.

What is already known on this topic

Limited published data exist on the effect of the COVID-19 pandemic on myeloma patients. Post first vaccine response in myeloma patients has been reported in a small number of patients from two studies ranging from 25 % to 56%.

What this study adds

This study reports myeloma patients shielded during waves of the pandemic and demonstrates consequent significant social isolation and changes to therapy. Low level natural COVID-19 infection (4%) was noted in the study and humoral response following first dose of COVID-19 vaccine was lower than that reported in non-myeloma cohorts.
Modified Preparation Method of Ideal Platelet-Rich Fibrin Matrix (PRFM) from Whole Blood
Authors: Reksodiputro Mirta Hediyati , Harahap Alida Roswita , Setiawan Lyana , Yosia Mikhael
Published: May 2021

One bioproduct that is widely used in the wound healing process is Platelet Rich Plasma (PRP). PRP is a liquid solution with high autologous platelet concentration, making it a good source of growth factors to accelerate wound healing. Recent development in PRP had created a new product called Platelet Rich Fibrin Matrix (PRFM), which has a denser and more flexible structure. PRFM is the newest generation of platelet concentrate with a fibrin matrix that holds platelet in it. The key concept in creating PRFM from PRP is the addition of CaCl2 followed by centrifugation, which converts fibrinogen to fibrin, and the fibrin cross-links to form a matrix that contains viable platelets. There are many commercially available kits to create PRFM, but they are often expensive and uneconomical. This research will test a modified method of making ideal PRFM from PRP without any commercial kits. The modified method will include determining the minimum level of CaCl2 used, the type of centrifuge, and the speed and duration of centrifugation. By performing a modified preparation method on five samples of whole blood, it was found that the ideal PRFM could be made by mixing PRP with 25 mM CaCl2 1M and centrifuging it at a speed of 2264 G for 25 minutes at room temperature. The PRP and PRFM platelet counts of this method tend to be lower than the platelet counts found in other studies. Although visually comparable, further study is needed to compare the performance of PRFMs made with this method and PRFMs made with commercial kits.
Sex differences in the association of mild behavioral impairment with cognitive aging
Authors: Wolfova Katrin , Creese Byron , Aarsland Dag , Ismail Zahinoor , Corbett Anne , Ballard Clive , Hampshire Adam , Cermakova Pavla
Published: May 2021

INTRODUCTION

We aimed to explore sex differences in the association of mild behavioral impairment (MBI) with the level of cognitive performance and its rate of decline in a cohort of people without dementia with the longest term follow up of cognition.

METHODS

We studied 8,181 older adults enrolled in the online PROTECT UK Study. MBI was assessed using the MBI Checklist and cognition was measured by digit span, paired associate learning, spatial working memory and verbal reasoning. Statistical analysis was conducted using linear regression models and linear mixed-effects models.

RESULTS

Males exhibited more often symptoms of decreased motivation, impulse dyscontrol and social inappropriateness, while less often symptoms of emotional dysregulation. The associations of MBI domains with some measures of cognitive performance and decline was stronger in males than females, with the exception of emotional dysregulation.

DISCUSSION

MBI may influence cognition to a greater extent in males than in females.
Late Combination shows that MEG adds to MRI in classifying MCI versus Controls
Authors: Vaghari Delshad , Kabir Ehsanollah , Henson Richard N.
Published: May 2021

Early detection of Alzheimer’s Disease (AD) is essential for developing effective treatments. Neuroimaging techniques like Magnetic Resonance Imaging (MRI) have the potential to detect brain changes before symptoms emerge. Structural MRI can detect atrophy related to AD, but it is possible that functional changes are observed even earlier. We therefore examined the potential of Magnetoencephalography (MEG) to detect differences in functional brain activity in people with Mild Cognitive Impairment (MCI) – a state at risk of early AD. We introduce a framework for multimodal combination to ask whether MEG data from a resting-state provides complementary information beyond structural MRI data in the classification of MCI versus controls. More specifically, we used multi-kernel learning of support vector machines to classify 163 MCI cases versus 144 healthy elderly controls from the BioFIND dataset. When using the covariance of planar gradiometer data in the low Gamma range (30-48Hz), we found that adding a MEG kernel improved classification accuracy above kernels that captured several potential confounds (e.g., age, education, time-of-day, head motion). However accuracy using MEG alone (67%) was worse than MRI alone (72%). When simply concatenating (normalized) features from MEG and MRI into one kernel (early combination), there was no advantage of combining MEG with MRI versus MRI alone. When combining kernels of modality-specific features (intermediate combination), there was an improvement in multimodal classification to 75%. The biggest multimodal improvement however occurred when we combined kernels from the predictions of modality-specific classifiers (late combination), which achieved 78% accuracy (a reliable improvement in terms of permutation testing). We also explored other MEG features, such as the variance versus covariance of magnetometer versus planar gradiometer data within each of 6 frequency bands (delta, theta, alpha, beta, low gamma or high gamma), and found that they generally provided complementary information for classification above MRI, provided the frequency band was beta or higher. We conclude that high frequency information in MEG can improve on MRI-based classification of mild cognitive impairment.
Genetic Inhibition of Serum Glucocorticoid Kinase 1 Prevents Obesity-related Atrial Fibrillation
Authors: Bapat Aneesh , Li Guoping , Xiao Ling , Hulsmans Maarten , Schloss Maximillian J , Iwamoto Yoshiko , Tedeschi Justin , Yang Xinyu , Nahrendorf Matthias , Rosenzweig Anthony , Ellinor Patrick , Das Saumya , Milan David
Published: May 2021

Rationale

Given its rising prevalence in both the adult and pediatric populations, obesity has become an increasingly important risk factor in the development of atrial fibrillation. However, a better mechanistic understanding of obesity-related atrial fibrillation is required. Serum glucocorticoid kinase 1 (SGK1) is a kinase positioned downstream of multiple obesity-related pathways, and prior work has shown a pathologic role for SGK1 signaling in ventricular remodeling and arrhythmias.

Objective

To determine the mechanistic basis of obesity associated atrial fibrillation and explore the therapeutic potential of targeting SGK1 in this context.

Methods and Results

We utilized a mouse model of diet induced obesity to determine the atrial electrophysiologic effects of obesity using electrophysiologic studies, optical mapping, and biochemical analyses. In C57BL/6J mice fed a high fat diet, there was upregulation of SGK1 signaling along with an increase in AF inducibility determined at electrophysiology (EP) study. These changes were associated with an increase in fibrotic and inflammatory signaling. Transgenic mice expressing a cardiac specific dominant negative SGK1 (SGK1 DN) were protected from obesity-related AF as well as the fibrotic and inflammatory consequences of AF. Finally, optical mapping demonstrated a shorter action potential duration and patch clamp revealed effects onINa, with a decreased peak current as well as a depolarizing shift in activation/inactivation properties in atrial myocytes.

Conclusions

Diet induced obesity leads to increased cardiac SGK1 signaling as well as an increase in AF inducibility in obese mice. Genetic SGK1 inhibition reduced AF inducibility, and this effect may be mediated by effects on inflammation, fibrosis, and cellular electrophysiology.
Circulating proteins reveal prior use of menopausal hormonal therapy and increased risk of breast cancer
Authors: Thomas Cecilia E. , Dahl Leo , Byström Sanna , Chen Yan , Uhlén Mathias , Mälarstig Anders , Czene Kamila , Hall Per , Schwenk Jochen M. , Gabrielson Marike
Published: May 2021

Background

Risk prediction is crucial for early detection and prognosis of breast cancer. Circulating plasma proteins could provide a valuable source to increase the validity of risk prediction models, however, no such markers have yet been identified for clinical use.

Methods

EDTA plasma samples from 183 breast cancer cases and 366 age-matched controls were collected prior to diagnosis from the Swedish breast cancer cohort KARMA. The samples were profiled on 700 circulating proteins using an exploratory affinity proteomics approach. Linear association analyses were performed on case-control status and a data-driven analysis strategy was applied to cluster the women on their plasma proteome profiles in an unsupervised manner. The resulting clusters were subsequently annotated for the differences in phenotypic characteristics, clinical parameters, and genetic risk.

Results

Using the data-driven approach we identified five clusters with distinct proteomic plasma profiles. Women in a particular sub-group (cluster 1) were significantly more likely to have used menopausal hormonal therapy (MHT), more likely to get a breast cancer diagnosis, and were older compared to the remaining clusters. The levels of circulating proteins in cluster 1 were decreased for proteins related to DNA repair and cell replication and increased for proteins related to mammographic density and female tissues. In contrast, classical dichotomous case-control analyses did not reveal any proteins significantly associated with future breast cancer.

Conclusion

Using a data-driven approach, we identified a subset of women with circulating proteins associated with previous use of MHT and risk of breast cancer. Our findings point to the potential long-lasting effects of MHT on the circulating proteome even after ending the treatment, and hence provide valuable insights concerning risk predication of breast cancer.

Highlights

Current risk prediction models use a variety of factors to identify women at risk of developing breast cancer.

Proteins circulating in blood represent an attractive but currently still underrepresented source of candidates serving as molecular risk factors.

Plasma proteomes from women participating in a prospective breast cancer cohort study were studied for proteomic risk factors related to a future breast cancer diagnosis.

Using data-driven approaches, women with future breast cancers and previous use of menopausal hormone therapy were identified based on their circulating proteins.

Menopausal hormone therapy was found to altered the levels of the circulating proteins even years after the treatment ended.
Host stress hormones affect host, but not vector, infectiousness for West Nile virus
Authors: Martin Lynn B. , Kernbach Meredith E. , Koller Kyle , Burkett-Cadena Nathan D. , Unnasch Thomas R.
Published: May 2021

Hormones that help hosts cope with stressors also affect how hosts regulate the processes that influence their susceptibility to parasites as well as their propensity to transmit pathogens to other hosts and vectors. In birds, corticosterone (CORT), influences timing of activity, feeding behaviors, and various immune defenses that influence the number and outcomes of host interactions with vectors and parasites. No study to our knowledge, though, has investigated whether CORT in hosts affects the extrinsic incubation period (EIP) of a vector for a virus, one of the strongest drivers of vector-borne disease cycles. Our goal here was to discern whether experimental CORT alterations in zebra finches (Taeniopygia guttata) affected EIP for West Nile virus (WNV) in the mosquito, Culex quinquefasciatus, a common vector of WNV and other infections in the southern US. We experimentally manipulated CORT in birds, infected them with WNV, and then investigated whether EIP differed between vectors fed on CORT-treated or control birds. Although CORT enhanced WNV viremia in hosts, as we have observed previously, we found no effects of CORT on vector EIP or post-feeding mortality rates, another important component of epidemiological models. These results, plus our prior observations that CORT enhances host attractiveness, indicate that some but not all stages of host-vector-virus interactions are sensitive to host stress.
Kmerator Suite: design of specific k-mer signatures and automatic metadata discovery in large RNA-Seq datasets
Authors: Riquier Sébastien , Bessiere Chloé , Guibert Benoit , Bouge Anne-Laure , Boureux Anthony , Ruffle Florence , Audoux Jérôme , Gilbert Nicolas , Xue Haoliang , Gautheret Daniel , Commes Thérèse
Published: May 2021

The huge body of publicly available RNA-seq libraries is a treasure of functional information allowing to quantify the expression of known or novel transcripts in tissues. However, transcript quantification commonly relies on alignment methods requiring a lot of computational resources and processing time, which does not scale easily to large datasets. K-mer decomposition constitutes a new way to process RNA-seq data for the identification of transcriptional signatures, as k-mers can be used to quantify accurately gene expression in a less resource-consuming way. We present the Kmerator Suite, a set of three tools designed to extract specific k-mer signatures, quantify these k-mers into RNA-seq datasets and quickly visualize large datasets characteristics. The core tool, Kmerator, produces specific k-mers for 97% of human genes, enabling the measure of gene expression with high accuracy in simulated datasets. KmerExploR, a direct application of Kmerator, uses a set of predictor genes specific k-mers to infer metadata including library protocol, sample features or contaminations from RNA-seq datasets. KmerExploR results are visualised through a user-friendly interface. Moreover, we demonstrate that the Kmerator Suite can be used for advanced queries targeting known or new biomarkers such as mutations, gene fusions or long non coding-RNAs for human health applications.
Principles for Systematic Optimization of an Orthogonal Translation System with Enhanced Biological Tolerance
Authors: Mohler Kyle , Moen Jack , Rogulina Svetlana , Rinehart Jesse
Published: May 2021

Over the past twenty years, the development of orthogonal biological systems has sparked a revolution in our ability to study cellular physiology. Orthogonal translation systems (OTSs) enable site-specific incorporation of hundreds of non-standard amino acids, offering unprecedented access to the study of cellular mechanisms modulated by post-translational modifications (e.g. protein phosphorylation). Although development of phosphoserine-OTSs (pSerOTS) has been significant, little work has focused on the biology of OTS development and utilization. To better understand the impact of OTSs on host physiology, we utilize pSerOTS as a model to systematically explore the extent to which OTS components interact with Escherichia coli. Using this information, we constructed pSerOTS variants designed to enhance OTS orthogonality by minimizing interactions with host processes and decreasing stress response activation. Our expanded understanding of OTS:host interactions enables informed OTS design practices which minimize the negative impact of OTSs while improving OTS performance across a range of experimental settings.
Combined fluorescent seed selection and multiplex CRISPR/Cas9 assembly for fast generation of multiple Arabidopsis mutants
Authors: Ursache Robertas , Fujita Satoshi , Tendon Valérie Dénervaud , Geldner Niko
Published: May 2021

Multiplex CRISPR-Cas9-based genome editing is an efficient method for targeted disruption of gene function in plants. Use of CRISPR-Cas9 has increased rapidly in recent years and is becoming a routine method for generating single and higher order Arabidopsis mutants. To facilitate rapid and efficient use of CRISPR/Cas9 for Arabidopsis research, we developed a CRISPR/Cas9-based toolbox for generating large deletions at multiple genomic loci, using two-color fluorescent seed selection. In our system, up-to eight gRNAs can be routinely introduced into a binary vector carrying either FastRed, FastGreen or FastCyan fluorescent seed selection cassette. Both, FastRed and FastGreen binary vectors, can be co-transformed as a cocktail via floral dip to introduce sixteen gRNAs at the same time. The seeds can be screened either for red or green fluorescence, or for the presence of both colors at the same time. Our approach provides fast and flexible cloning, avoids very big constructs and enables screening different order mutants in the same generation. Importantly, in the second generation after transformation, Cas9 free plants are identified simply by screening the dark, non-fluorescent seeds. Our collection of binary vectors allows to choose between two widely-used promoters to drive Cas enzymes, either the egg cell-specific (pEC1.2) or ubiquitous promoter (PcUBi4-2). Available enzymes are “classical” Cas9, a recently reported, intron-optimized version or Cpf1 (Cas12a). Finally, we have taken care to introduce convenient restriction sites flanking promoter, Cas9 and fluorescent selection cassette in the final T-DNA vectors, thus allowing straightforward swapping of all three elements for further adaptation and improvement of the system.
Taxon-specific or universal? Using target capture to study the evolutionary history of rapid radiations
Authors: Yardeni Gil , Viruel Juan , Paris Margot , Hess Jaqueline , Crego Clara Groot , de La Harpe Marylaure , Rivera Norma , Barfuss Michael H. J. , Till Walter , Guzmán-Jacob Valeria , Krömer Thorsten , Lexer Christian , Paun Ovidiu , Leroy Thibault
Published: May 2021

Target capture has emerged as an important tool for phylogenetics and population genetics in non-model taxa. Whereas developing taxon-specific capture probes requires sustained efforts, available universal kits may have a lower power to reconstruct relationships at shallow phylogenetic scales and within rapidly radiating clades. We present here a newly-developed target capture set for Bromeliaceae, a large and ecologically-diverse plant family with highly variable diversification rates. The set targets 1,776 coding regions, including genes putatively involved in key innovations, with the aim to empower testing of a wide range of evolutionary hypotheses. We compare the relative power of this taxon-specific set, Bromeliad1776, to the universal Angiosperms353 kit. The taxon-specific set results in higher enrichment success across the entire family, however, the overall performance of both kits to reconstruct phylogenetic trees is relatively comparable, highlighting the vast potential of universal kits for resolving evolutionary relationships. For more detailed phylogenetic or population genetic analyses, e.g. the exploration of gene tree concordance, nucleotide diversity or population structure, the taxon-specific capture set presents clear benefits. We discuss the potential lessons that this comparative study provides for future phylogenetic and population genetic investigations, in particular for the study of evolutionary radiations.
MIRO2 regulates prostate cancer cell growth via GCN1-dependent stress signaling
Authors: Furnish Madison , Boulton Dillon P. , Genther Victoria , Ellinwood Mitchell Lee , Romero Lina , Lucia M. Scott , Cramer Scott D. , Caino M. Cecilia
Published: May 2021

There is a continued need to identify novel therapeutic targets to prevent the mortality associated with prostate cancer. In this context, we discovered a novel mitochondrial signaling pathway that controls androgen-independent and androgen-sensitive prostate cancer cell growth. Mitochondrial Rho GTPase 2 (MIRO2) mRNA was upregulated in prostate cancer compared to localized tumors, and higher MIRO2 levels were correlated with poor patient survival. Using human cell lines that represent AR-independent or androgen-sensitive prostate cancer, we show that MIRO2 depletion impaired cell growth, colony formation and tumor growth in mice. Network analysis of MIRO2’s binding partners identified metabolism, cell cycle, and cellular responses to extracellular stimuli amongst the top over-represented pathways. The top hit on our screen was General Control Non-derepressible 1 (GCN1). GCN1 was overexpressed in prostate cancer and MIRO2-GCN1 interacted in prostate cancer cell lines and in primary prostate cancer cells. Our results showed that MIRO2 is necessary for efficient GCN1-mediated GCN2 kinase activation and signaling, triggering translation of the transcription factor ATF4. Importantly, MIRO2 controlled ATF4 levels and transcriptional activity both in amino acid replete and depleted conditions. Furthermore, MIRO2’s effect on regulating prostate cancer cell growth was partially mediated by ATF4. Finally, activation of GCN2 and ATF4 expression were correlated with MIRO2 expression in prostate cancer xenografts. Overall, we propose a new mechanism driving prostate cancer growth of both AR-independent and androgen-sensitive tumors.
ASLPrep: A Generalizable Platform for Processing of Arterial Spin Labeled MRI and Quantification of Regional Brain Perfusion
Authors: Adebimpe Azeez , Bertolero Maxwell , Dolui Sudipto , Cieslak Matthew , Murtha Kristin , Baller Erica B. , Boeve Bradley , Boxer Adam , Butler Ellyn R. , Cook Phil , Colcombe Stan , Covitz Sydney , Davatzikos Christos , Davila Diego G. , Elliott Mark A. , Flounders Matthew W. , Franco Alexandre R. , Gur Raquel E. , Gur Ruben C. , Jaber Basma , McMillian Corey ,   the ALLFTD Consortium, Milham Michael , Mutsaerts Henk J.M.M. , Oathe Desmond J. , Olm Christopher A. , Phillips Jeffrey S. , Tackett Will , Roalf David R. , Rosen Howard , Tapera Tinashe M. , Tisdall M. Dylan , Esteban Oscar , Poldrack Russell A. , Detre John A. , Satterthwaite Theodore D.
Published: May 2021

Arterial spin labeled (ASL) magnetic resonance imaging (MRI) is the primary method for non-invasively measuring regional brain perfusion in humans. We introduce ASLPrep, a suite of software pipelines that ensure the reproducible and generalizable processing of ASL MRI data.
Systematic, Protein Activity-based Characterization of Single Cell State
Authors: Vlahos Lukas , Obradovic Aleksandar , Worley Jeremy , Tan Xiangtian , Howe Andrew , Laise Pasquale , Wang Alec , Drake Charles G. , Califano Andrea
Published: May 2021

While single-cell RNA sequencing provides a remarkable window on pathophysiologic tissue biology and heterogeneity, its high gene-dropout rate and low signal-to-noise ratio challenge quantitative analyses and mechanistic understanding. To address this issue, we developed PISCES, a platform for the network-based, single-cell analysis of mammalian tissue. PISCES accurately estimates the mechanistic contribution of regulatory and signaling proteins to cell state implementation and maintenance, based on the expression of their lineage-specific transcriptional targets, thus supporting discovery and visualization of Master Regulators of cell state and cell state transitions. Experimental validation assays, including by assessing concordance with antibody and CITE-Seq-based measurements, show significant improvement in the ability to identify rare subpopulations and to elucidate key lineage markers, compared to gene expression analysis. Systematic analysis of single cell profiles in the Human Protein Atlas (HPA) produced a comprehensive resource for human tissue studies, supporting fine-grain stratification of distinct cell states, molecular determinants, and surface markers.
Genetic load may increase or decrease with selfing depending upon the recombination environment
Authors: Sianta Shelley A , Peischl Stephan , Moeller David A , Brandvain Yaniv
Published: May 2021

The ability of natural selection to remove deleterious mutations from a population is a function of the effective population size. Increases in selfing rate, and concomitant increases in population-level homozygosity, can increase or decrease the efficacy of selection, depending on the dominance and selection coefficients of the deleterious mutations. Most theory has focused on how (partial) selfing affects the efficacy of selection for mutations of a given dominance and fitness effect in isolation. It remains unclear how selfing affects the purging of deleterious mutations in a genome-wide context where mutations with different selection and dominance coefficients co-segregate. Here, we use computer simulations to investigate how mutation, selection and recombination interact with selfing rate to shape genome-wide patterns of genetic load. We recover various mechanisms previously described for how (partial) selfing affects the efficacy of selection against mutations of a given dominance class. However, we find that the interaction of purifying selection against mutations of different dominance classes changes with selfing rate. In particular, as outcrossing populations transition from purifying selection to pseudo-overdominance they experience a dramatic increase in the genetic load caused by additive, mildly deleterious mutations. We describe the threshold selfing rate that prevents pseudo-overdominance and decreases genetic load.
Brain-inspired Weighted Normalization for CNN Image Classification
Authors: Pan Xu , Sánchez Giraldo Luis Gonzalo , Kartal Elif , Schwartz Odelia
Published: May 2021

Abstract

We studied a local normalization paradigm, namely weighted normalization, that better reflects the current understanding of the brain. Specifically, the normalization weight is trainable, and has a more realistic surround pool selection. Weighted normalization outperformed other normalizations in image classification tasks on Cifar10, Imagenet and a customized textured MNIST dataset. The superior performance is more prominent when the CNN is shallow. The good performance of weighted normalization may be related to its statistical effect of gaussianizing the responses.
A cellular and molecular portrait of endometriosis subtypes
Authors: Fonseca Marcos A. S. , Wright Kelly N. , Lin Xianzhi , Abbasi Forough , Haro Marcela , Sun Jennifer , Hernandez Lourdes , Orr Natasha L. , Hong Jooyoon , Choi-Kuaea Yunhee , Maluf Horacio M. , Balzer Bonnie L. , Cass Ilana , Truong Mireille , Wang Yemin , Pisarska Margareta D. , Dinh Huy , EL-Naggar Amal , Huntsman David , Anglesio Michael S. , Goodman Marc T. , Medeiros Fabiola , Siedhoff Matthew , Lawrenson Kate
Published: May 2021

Endometriosis is a common, benign condition characterized by extensive heterogeneity in lesion appearance and patient symptoms. We profiled transcriptomes of 207,949 individual cells from endometriomata (n=7), extra-ovarian endometriosis (n=19), eutopic endometrium (n=4), unaffected ovary (n=1) and endometriosis-free peritoneum (n=4) to create a cellular atlas of endometrial-type epithelial cells, endometrial-type stromal cells and microenvironmental cell populations across tissue sites. Signatures of endometrial-type epithelium and stroma differed markedly across eutopic endometrium, endometrioma, superficial extra-ovarian disease and deep infiltrating endometriosis, suggesting that extensive transcriptional reprogramming is a core component of the disease process. Endometriomas were notable for the dysregulation of pro-inflammatory pathways and upregulation of complement proteins C3 and C7. Somatic ARID1A mutation in epithelial cells was associated with upregulation of pro-angiogenic factor SOX17 and remodeling of the endothelial cell compartment. Finally, signatures of endometriosis-associated endometrial-type epithelial clusters were enriched in ovarian cancers, reinforcing the epidemiologic associations between these two diseases.
Deamidation drives molecular aging of the SARS-CoV-2 spike receptor-binding motif
Authors: Lorenzo Ramiro , Defelipe Lucas A. , Aliperti Lucio , Niebling Stephan , Custódio Tânia F. , Löw Christian , Schwarz Jennifer J. , Remans Kim , Craig Patricio O. , Otero Lisandro H. , Klinke Sebastián , García-Alai María , Sánchez Ignacio E. , Alonso Leonardo G.
Published: May 2021

The spike is the main protein component of the SARS-CoV-2 virion surface. The spike receptor binding motif mediates recognition of the hACE2 receptor, a critical infection step, and is the preferential target for spike-neutralizing antibodies. Post-translational modifications of the spike receptor binding motif can modulate viral infectivity and immune response. We studied the spike protein in search for asparagine deamidation, a spontaneous event that leads to the appearance of aspartic and isoaspartic residues, affecting both the protein backbone and its charge. We used computational prediction and biochemical experiments to identify five deamidation hotspots in the SARS-CoV-2 spike. Similar deamidation hotspots are frequently found at the spike receptor-binding motifs of related sarbecoviruses, at positions that are mutated in emerging variants and in escape mutants from neutralizing antibodies. Asparagine residues 481 and 501 from the receptor-binding motif deamidate with a half-time of 16.5 and 123 days at 37 °C, respectively. This process is significantly slowed down at 4 °C, pointing at a strong dependence of spike molecular aging on the environmental conditions. Deamidation of the spike receptor-binding motif decreases the equilibrium constant for binding to the hACE2 receptor more than 3.5-fold. A model for deamidation of the full SARS-CoV-2 virion illustrates that deamidation of the spike receptor-binding motif leads to the accumulation in the virion surface of a chemically diverse spike population in a timescale of days. Our findings provide a mechanism for molecular aging of the spike, with significant consequences for understanding virus infectivity and vaccine development.
Golden pompano genome resource enables discovery of valuable gene determining growth traits
Authors: Luo Honglin , Zhang Yongde , Ji Changmian , Zhao Yongzhen , Peng Jinxia , Xu Yuhui , Chen Xiuli , Huang Yin , Liu Qingyun , He Pingping , Feng Pengfei , Yang Chunling , Wei Pinyuan , Yu Haiyan , Zheng Hongkun , Lin Yong , Chen Xiaohan
Published: May 2021

One important goal of fish genetic breeding is to identify valuable loci and genes that can facilitate growth and thereby productivity. Few such loci or genes have been identified in golden pompano (Trachinotus ovatus), a species of significant economic value. In this study, we produced a high-quality chromosome-level genome assembly of the golden pompano byde novosequencing and assemblies for 2 parents and 200 F1offspring by genome re-sequencing. We exploited these assemblies to identify loci and genes by QTL mapping, Kompetitive Allele Specific PCR (KASP) genotyping, and haplotype-based regional association analysis based on growth records of a 64 biparental and 147 individuals from a naturally occurring population. At a locus 291kb from BSNP21031, we identified a somatostatin receptor type 1-like (designated as gpsstr1) gene in which the BSNP1369 of the promoter region was highly associated with growth. Loss of sstr1a, the homolog of gpsstr1 in zebrafish, caused growth retardation. Sstr1a mediated growth via sstr2 and Wnt-gsk-3β signaling pathways. Our findings provide new insights into the underlying mechanisms controlling growth. Our strategy can serve as an effective way to uncover novel genomic information and facilitate improvement of fish growth.
A systematic review and meta-analysis of genetic parameters for complex quantitative traits in aquatic animal species
Authors: Nguyen Nguyen Hong
Published: May 2021

A systematic review and meta-analysis of genetic parameters underlying inheritance and complex biological relationships for quantitative traits are not available for aquatic animal species. I synthesised and conducted a comprehensive meta-analysis of the published information from 1985 to 2017 on heritability, common full-sib effects and genetic correlations for quantitative characters of biological importance (growth, carcass and flesh quality, disease resistance, deformity and reproduction) for aquaculture species. A majority of the studies (73.5%) focussed on growth related traits (body weight), followed by those on disease resistance (15.9%), whereas only a limited number of studies (10.6%) reported heritability estimates for carcass and flesh quality, deformity or reproduction characteristics. The weighted means of heritability for growth (weight, food utilisation efficiency, maturity) and carcass (fillet weight and yield) traits were moderate. Resistance against various bacteria, virus and parasites were moderately to highly heritable. Across aquatic animal species, the weighted heritability for a range of deformity measures and reproductive traits (fecundity, early survival) was low and not significantly different from zero. The common full-sibs (c2) accounted for a large proportion of total variance for body traits but it was of smaller magnitude in later phase of the growth development. The c2 effects however were not significant or in many cases they were not reported for carcass and flesh quality attributes as well as survival and deformity. The maternal genetic effects were not available for all traits studied especially for reproductive and early growth characters. Genetic correlations between body and carcass traits were high and positive, suggesting that selection for rapid growth can improve fillet weight, a carcass trait of paramount importance. Body weight, the most commonly used selection criterion in aquatic animals, showed non-significant genetic correlation with disease resistance, likely because both positive and negative genetic associations between the two types of traits. Interestingly the genetic associations between growth and reproductive performance (fecundity) and fry traits (fry weight, fry survival) were favourable. To date, there are still no published data on genetic relationships of carcass and flesh quality with disease resistance or reproductive performance in any aquaculture species. Additionally, the present study discussed new traits, including functional, immunological, behavioural and social interaction as well as uniformity that are emerging as potential selection criteria and which can be exploited in future genetic improvement programs for aquatic animals.
Endurance Exercise to Improve Physical Function in Adult and Older Mice: High Intensity Interval Training (HIIT) versus Voluntary Wheel Running (VWR)
Authors: Pajski Megan L. , Byrd Chris , Nandigama Nainika , Seguin Emily , Seguin Anna , Fennell Alyssa , Graber Ted G.
Published: May 2021

With age comes a gradual decline in physical function and exercise capacity, concurrent with a progressive propensity for development of sarcopenia /(age-related loss of muscle mass and strength) and frailty (inability of body to thrive and maintain homeostasis). Prior research has demonstrated that exercise, while not a cure, can help mitigate sarcopenia/frailty and restore functional capacity. Reliable, validated, pre-clinical models are necessary to elucidate the underlying molecular mechanisms at the intersection of age, exercise, and functional decline. In this study, we hypothesized that endurance exercise programs mimicking typical human exercise protocols would improve physical function in both adult and older adult mice. Furthermore, our secondary hypothesis was that older mice would receive less benefit from a similar volume of exercise than adult mice. To test these hypotheses, we randomly assigned (with some selection criteria) male C57BL/6 mice either at adult ages during the study (n=24, designated 10m, aged 6 months to 10 months) or at older adult ages (n=18, designated 26m, aged 22 months to 26 months) to a 13-week program of voluntary wheel running (VWR, group termed RUN) or high intensity interval training (HIIT), with an additional 10m sedentary control (CON). The functional aptitude of each mouse was determined pre- and post-training using our composite CFAB (comprehensive functional assessment battery) scoring system consisting of voluntary wheel running (volitional exercise and activity rate), treadmill (endurance), rotarod (overall motor function), grip meter (forelimb strength), and inverted cling (whole body strength/endurance). To measure sarcopenia, we tracked body mass and body composition changes with EchoMRI, and measured muscle wet mass post-training.
Generation of potent cellular and humoral immunity against SARS-CoV-2 antigens via conjugation to a polymeric glyco-adjuvant
Authors: Gray Laura T. , Raczy Michal M. , Briquez Priscilla S. , Marchell Tiffany M. , Alpar Aaron T. , Wallace Rachel P. , Volpatti Lisa R. , Sasso Maria Stella , Cao Shijie , Nguyen Mindy , Mansurov Aslan , Budina Erica , Watkins Elyse A. , Solanki Ani , Mitrousis Nikolaos , Reda Joseph W. , Yu Shann S. , Tremain Andrew C. , Wang Ruyi , Nicolaescu Vlad , Furlong Kevin , Dvorkin Steve , Manicassamy Balaji , Randall Glenn , Wilson D. Scott , Kwissa Marcin , Swartz Melody A. , Hubbell Jeffrey A.
Published: May 2021

The SARS-CoV-2 virus has caused an unprecedented global crisis, and curtailing its spread requires an effective vaccine which elicits a diverse and robust immune response. We have previously shown that vaccines made of a polymeric glyco-adjuvant conjugated to an antigen were effective in triggering such a response in other disease models and hypothesized that the technology could be adapted to create an effective vaccine against SARS-CoV-2. The core of the vaccine platform is the copolymer p(Man-TLR7), composed of monomers with pendant mannose or a toll-like receptor 7 (TLR7) agonist. Thus, p(Man-TLR7) is designed to target relevant antigen-presenting cells (APCs) via mannose-binding receptors and then activate TLR7 upon endocytosis. The p(Man-TLR7) construct is amenable to conjugation to protein antigens such as the Spike protein of SARS-CoV-2, yielding Spike-p(Man-TLR7). Here, we demonstrate Spike-p(Man-TLR7) vaccination elicits robust antigen-specific cellular and humoral responses in mice. In adult and elderly wild-type mice, vaccination with Spike-p(Man-TLR7) generates high and long-lasting titers of anti-Spike IgGs, with neutralizing titers exceeding levels in convalescent human serum. Interestingly, adsorbing Spike-p(Man-TLR7) to the depot-forming adjuvant alum, amplified the broadly neutralizing humoral responses to levels matching those in mice vaccinated with formulations based off of clinically-approved adjuvants. Additionally, we observed an increase in germinal center B cells, antigen-specific antibody secreting cells, activated T follicular helper cells, and polyfunctional Th1-cytokine producing CD4+and CD8+T cells. We conclude that Spike-p(Man-TLR7) is an attractive, next-generation subunit vaccine candidate, capable of inducing durable and robust antibody and T cell responses.
Fides: Reliable Trust-Region Optimization for Parameter Estimation of Ordinary Differential Equation Models
Authors: Fröhlich Fabian , Sorger Peter K.
Published: May 2021

Ordinary differential equation (ODE) models are widely used to describe biochemical processes, since they effectively represent mass action kinetics. Optimization-based calibration of ODE models on experimental data can be challenging, even for low-dimensional problems. However, reliable model calibration is a prerequisite for uncertainty analysis, model comparison, and biological interpretation. Multiple hypotheses have been advanced to explain why optimization based calibration of biochemical models is challenging, but there are few comprehensive studies that test these hypotheses, likely because tools for performing such studies are also lacking.

We implemented an established trust-region method as a modular Python framework (fides) to enable systematic comparison of different approaches to ODE model calibration involving various Hessian approximation schemes. We evaluatedfideson a set of benchmark problems for which real experimental data are available. Unexpectedly, we observed high variability in optimizer performance among different implementations of the same algorithm. Overall,fidesperformed most reliably and efficiently. Our investigation of possible sources of poor optimizer performance identified drawbacks in the widely used Gauss-Newton, BFGS and SR1 Hessian approximations. We address these drawbacks by proposing a novel hybrid Hessian approximation scheme that enhances optimizer performance and outperforms existing hybrid approaches. We expectfidesto be broadly useful for ODE constrained optimization problems and to enable future methods development.

Availability

fidesis published under the permissive BSD-3-Clause license with source code publicly available athttps://github.com/fides-dev/fides. Citeable releases are archived on Zenodo. Code to reproduce results presented in this manuscript is available athttps://github.com/fides-dev/fides-benchmark.
Understanding the complexity of Epimorphic Regeneration in zebrafish: A Transcriptomic and Proteomic approach
Authors: Banu Sarena , Gaur Namami , Nair Sowmya , Ravikrishnan Tanuja , Khan Shahida , Mani Sandhya , Bharathi Swarna , Mandal Komal , Kuram Naga Anusha , Vuppaladadium Sowmya , N. Murthy Ch. Lakshmi , Quoseena Mir , Babu Nukala Sarath , Idris Mohammed M
Published: May 2021

Genomic and Proteomic changes play a crucial role in perpetuating regeneration of complex tissues through differentiation and growth. The complex Epimorphic regeneration of zebrafish caudal fin tissue is hasty and absolute. This study was executed to understand the role of various genes/proteins involved in the regeneration of zebrafish caudal fin tissue through differential expression analysis. High throughput transcriptomics analysis involving Next Generation Sequencing approach and iTRAQ based quantitative proteomics analyses were performed on the regenerating tissue samples for various regenerating time points. Based on our study 1408 genes and 661 proteins were found differentially regulated in the regenerating caudal fin tissue for having at least 1-log fold change in their expression at 12hpa, 1, 2, 3 and 7dpa stages against control non-regenerating tissue. Interleukin, SLC, PRMT, HOX, neurotransmitter and several novel genes were found to be associated with regeneration for its differential regulation during the mechanism. Based on the network and pathway analysis the differentially regulated genes and proteins were found allied with activation of cell proliferation, cell viability, cell survival & cell movement and inactivation of organismal death, morbidity, necrosis, death of embryo & cell death. Network pathways such as Cancer & development disorder, Cell signaling molecular transport, organismal injury & abnormalities and Cellular development, growth & proliferation were found most significantly associated with the zebrafish caudal fin regeneration mechanism. This study has mapped a detailed insight of the genes/proteins expression associated with the epimorphic regeneration more profoundly.
Development and Application of Cas13a-based Diagnostic Assay for Neisseria Gonorrhoeae Detection and Identification of Azithromycin Resistance
Authors: Luo Hao , Chen Wentao , Mai Zhida , Lin Xiaomian , Yang Jianjiang , Zeng Lihong , Pan Yuying , Xie Qinghui , Xu Qingqing , Li Xiaoxiao , Liao Yiwen , Feng Zhanqin , Ou Jiangli , Qin Xiaolin , Zheng Heping
Published: May 2021

Gonorrhea caused by Neisseria gonorrhoeae has spread world-wide. Antimicrobial-resistant strains have emerged to an alarming level to most antibiotics including to the ceftriaxone-azithromycin combination, currently recommended as first-line dual therapy. Rapid testing for antimicrobial resistance will contribute to clinical decision-making for rational drug use and will slow this trend. Herein, we developed a Cas13a-based assay for N. gonorrhoeae detection (porA target) and azithromycin resistance identification (A2059G and C2611T point mutations). We evaluated the sensitivity and specificity of this method, and 10 copies per reaction can be achieved in porA detection and C2611T identification, with no cross-reactions. Comparison of the Cas13a-based assay (porA target) with Roche Cobas 4800 assay (n=23 urine samples) revealed 100% concordance. Isolated N. gonorrhoeae strains were used to validate the identification of A2059G and C2611T resistance mutations. All tested strains (8 A2059G strains, 8 C2611T strains, and 8 wild-type strains) were successfully distinguished by our assay and verified by testing MIC for azithromycin and sequencing the 23S rRNA gene. We adopted lateral flow for the SHERLOCK assay readout, which showed a visible difference between test group and NC group results. To further evaluate the capability of our assay, we tested 27 urethral swabs from patients with urethritis for N. gonorrhoeae detection and azithromycin-resistance identification. Of these, 62.96% (17/27) strains were detected with no mutant strains and confirmed by sequencing. In conclusion, the novel Cas13a-based assay for rapid and accurate N. gonorrhoeae detection combined with azithromycin drug resistance testing is a promising assay for application in clinical practice.