bluuebunny/crossref_metadata_2025 huggingface dataset:
Blenderized Food Tube Feeding for Radioactive Iodine Ablation
Authors: Pritchett Ali , Pierce Leah , Kiser Sarah , Johnson Teresa W. , Barrows Natalie
Published: March 2021

Blenderized tube feeding (BTF), defined as tube feeding substrate derived from whole food, has demonstrated clinical utility to reduce tube feeding intolerance, achieve a physiologic diet, and bridge to oral feeding. BTF use peaked in the 1950s but was displaced by commercial formula (CF) in subsequent decades, as the latter has a consistent nutrient content, is sterile, and is less likely to clog tubes. Interest and use of BTF have reemerged and are largely driven by patients or caregivers reporting improved tolerance to whole-food blends compared with CF. BTF may have additional clinical applications, including preparation for radioactive iodine (RAI) ablation. This article presents a case of an adult male patient with thyroid cancer who utilized BTF to achieve the iodine status needed for effective RAI treatment.
Heart-Healthy Dietary Intake Improved and Maintained 6 Months After Participation in a Cardiac Rehabilitation Program
Authors: Laursen Ulla Bach , Joensen Albert Marni , Johansen Martin Nygård , Overvad Kim , Larsen Mogens Lytken
Published: March 2021

We explored the longitudinal changes in and maintenance of specific food groups among patients with ischemic heart disease who were following a cardiac rehabilitation program. We measured dietary intake of 19 food groups with a validated self-administered food frequency questionnaire before rehabilitation, postrehabilitation, and 6 months after baseline. A total of 186 participants provided data at baseline and postrehabilitation and 157 participants after 6 months. We identified a trend that the quality of most foods was improved and more heart-healthy foods were consumed in patients. Improvements were maintained after 6 months.
An Assessment of Nutrition Education Interventions in Pregnancy Complicated by Diabetes
Authors: Whitcombe Dayna , Ragland Denise , Gauss C. Heath , Tappe Andrea , Dajani Nafisa
Published: March 2021

Diabetes is the most common metabolic dysfunction in pregnancy. The objective of this study was to assess the effectiveness of diabetes knowledge using various educational interventions, including Web-based, traditional in-person class, and a combination of Web-based and in-person education. A quasi-experimental nonequivalent control group pre/posttest design was utilized to assess diabetes and nutrition-related knowledge. There was no statistical difference found among the 3 interventions regarding the mean difference in pretest and posttest scores (P > .05). However, there was a statistically significant mean change in pretest and posttest scores for each intervention group (P < .05), indicating an improvement in nutrition knowledge in each group.
Genetic screening for TLR7 variants in young and previously healthy men with severe COVID-19: a case series
Authors: Solanich Xavier , Vargas-Parra Gardenia , van der Made Caspar I. , Simons Annet , Schuurs-Hoeijmakers Janneke , Antolí Arnau , del Valle Jesús , Rocamora-Blanch Gemma , Setién Fernando , Esteller Manel , Riera-Mestre Antoni , Sabater-Riera Joan , Capellá Gabriel , van de Veerdonk Frank L. , van der Hoven Ben , Corbella Xavier , Hoischen Alexander , Lázaro Conxi
Published: March 2021

Advanced age, male sex and chronic comorbidities are associated with severe COVID-19. However, these general risk factors cannot explain why critical illness occurs in young and apparently healthy individuals. In the past months, several publications have identified susceptibility loci and genes using comprehensive GWAS studies or genome, exome or candidate genes analysis. A recent study reported rare, loss-of-function TLR7 variants in otherwise healthy young brother pairs from two families with severe COVID-19. We aimed to prospectively study the prevalence of rare X-chromosomal TLR7 genetic variants in our cohort of young male patients with severe COVID-19. We recruited 13 patients ≤50 years who had no risk factors known to be associated with severe disease. We studied the entire TLR7 coding region and identified two missense variants (p.Asn215Ser, c.644A>G and p.Trp933Arg, c.2797T>C) in two out of 13 cases (15.4%). These variants were not previously reported in population control databases (gnomAD) and were predicted to be damaging by all in silico predictors. The male index patients were between 25 and 30 years old and had no apparent comorbidities. The TLR7 p.Asn215Ser co-segregated in 2 first-degree relatives severely affected by COVID-19, in a younger previously healthy the variant was found in hemizygous state, and in an older than 60 was in heterozygous state. No family members were available for testing the segregation of the p.Trp933Arg variant. These results further support that susceptibility to severe COVID-19 could be determined by inherited rare genetic variants in TLR7. Understanding the causes and mechanisms of life-threatening COVID-19 is crucial and could lead to novel preventive and therapeutic options. This study supports a rationale for the genetic screening for TLR7 variants in young men with severe COVID-19 in the absence of other relevant risk factors. A diagnosis of TLR7 deficiency could not only inform on treatment options for the patient, but it also enables for pre-symptomatic testing of at-risk male relatives with the possibility of instituting early preventive and therapeutic interventions.
Emergence of porcine delta-coronavirus pathogenic infections among children in Haiti through independent zoonoses and convergent evolution
Authors: Lednicky John A. , Tagliamonte Massimiliano S. , White Sarah K. , Elbadry Maha A. , Alam Md. Mahbubul , Stephenson Caroline J. , Bonny Tania S. , Loeb Julia C. , Telisma Taina , Chavannes Sonese , Ostrov David A. , Mavian Carla , De Rochars Valerie Madsen Beau , Salemi Marco , Morris J. Glenn
Published: March 2021

Coronaviruses have caused three major epidemics since 2003, including the ongoing SARS-CoV-2 pandemic. In each case, coronavirus emergence in our species has been associated with zoonotic transmissions from animal reservoirs1,2, underscoring how prone such pathogens are to spill over and adapt to new species. Among the four recognized genera of the family Coronaviridae – Alphacoronavirus, Betacoronavirus, Deltacoronavirus, Gammacoronavirus, – human infections reported to date have been limited to alpha- and betacoronaviruses3. We identify, for the first time, porcine deltacoronavirus (PDCoV) strains in plasma samples of three Haitian children with acute undifferentiated febrile illness. Genomic and evolutionary analyses reveal that human infections were the result of at least two independent zoonoses of distinct viral lineages that acquired the same mutational signature in the nsp15 and the spike glycoprotein genes by convergent evolution. In particular, structural analysis predicts that one of the changes in the Spike S1 subunit, which contains the receptor-binding domain, may affect protein’s flexibility and binding to the host cell receptor. Our findings not only underscore the ability of deltacoronaviruses to adapt and potentially lead to human-to-human transmission, but also raise questions about the role of such transmissions in development of pre-existing immunity to other coronaviruses, such as SARS-CoV-2.
System-wide hematopoietic and immune signaling aberrations in COVID-19 revealed by deep proteome and phosphoproteome analysis
Authors: Kaneko Tomonori , Esmail Sally , Voss Courtney , Martin Claudio M. , Slessarev Marat , Hovey Owen , Liu Xuguang , Ye Mingliang , Kim Sung , Fraser Douglas , Li Shawn SC
Published: March 2021

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has become a global crisis. To gain systems-level insights into its pathogenesis, we compared the blood proteome and phosphoproteome of ICU patients with or without SARS-CoV-2 infection, and healthy control subjects by quantitative mass spectrometry. We find that COVID-19 is marked with hyperactive T cell and B cell signaling, compromised innate immune response, and dysregulated inflammation, coagulation, metabolism, RNA splicing, transcription and translation pathways. SARS-CoV-2 infection causes global reprogramming of the kinome and kinase-substrate network, resulting in defective antiviral defense via the CK2-OPN-IL-12/IFN-α/β axis, lymphocyte cell death via aberrant JAK/STAT signaling, and inactivation of innate immune cells via inhibitory SIRPA, SIGLEC and SLAM family receptor signaling. Our work identifies CK2, SYK, JAK3, TYK2 and IL-12 as potential targets for immunomodulatory treatment of severe COVID-19 and provides a valuable approach and resource for deciphering the mechanism of pathogen-host interactions.
A Sanger-based approach for scaling up screening of SARS-CoV-2 variants of interest and concern
Authors: Bezerra Matheus Filgueira , Machado Lais Ceschini , de Carvalho Viviane do Carmo Vasconcelos , Docena Cássia , Brandão-Filho Sinval Pinto , Ayres Constância Flávia Junqueira , Paiva Marcelo Henrique Santos , Wallau Gabriel Luz
Published: March 2021

The global spread of new SARS-CoV-2 variants of concern underscore an urgent need of simple deployed molecular tools that can differentiate these lineages. Several tools and protocols have been shared since the beginning of the COVID-19 pandemic, but they need to be timely adapted to cope with SARS-CoV-2 evolution. Although whole-genome sequencing (WGS) of the virus genetic material have been widely used, it still presents practical difficulties such as high cost, shortage of available reagents in the global market, need of a specialized laboratorial infrastructure and well-trained staff. These limitations result in genomic surveillance blackouts across several countries. Here we propose a rapid and accessible protocol based on Sanger sequencing of a single PCR fragment that is able to identify and discriminate all SARS-CoV-2 variants of concern (VOCs) identified so far, according to each characteristic mutational profile at the Spike-RBD region (K417N/T, E484K, N501Y, A570D). Twelve COVID-19 samples from Brazilian patients were evaluated for both WGS and Sanger sequencing: three from P.2, two from P.1 and seven from B.1.1 lineage. All results from the Sanger sequencing method perfectly matched the mutational profile of VOCs and non-VOCs described by WGS. In summary, this approach allows a much broader network of laboratories to perform molecular surveillance of SARS-CoV-2 VOCs and report results within a shorter time frame, which is of utmost importance in the context of rapid public health decisions in a fast evolving worldwide pandemic.
Genomic surveillance of SARS-CoV-2 tracks early interstate transmission of P.1 lineage and diversification within P.2 clade in Brazil
Authors: Lamarca Alessandra P , de Almeida Luiz G P , Francisco Ronaldo da Silva , Lima Lucymara Fassarella Agnez , Scortecci Kátia Castanho , Perez Vinícius Pietta , Brustolini Otavio J. , Sousa Eduardo Sérgio Soares , Secco Danielle Angst , Santos Angela Maria Guimarães , Albuquerque George Rego , Mariano Ana Paula Melo , Maciel Bianca Mendes , Gerber Alexandra L , Guimarães Ana Paula de C , Nascimento Paulo Ricardo , Neto Francisco Paulo Freire , Gadelha Sandra Rocha , Porto Luís Cristóvão , Campana Eloiza Helena , Jeronimo Selma Maria Bezerra , Vasconcelos Ana Tereza R
Published: March 2021

The sharp increase of COVID-19 cases in late 2020 has made Brazil the new epicenter of the ongoing SARS-CoV-2 pandemic. Novel SARS-CoV-2 lineages P.1 and P.2, first identified respectively in Manaus and Rio de Janeiro, have been associated with potentially higher transmission rates and antibody neutralization escape. In this study, we performed a whole-genome sequencing of 185 samples isolated from three out of the five Brazilian regions, including Amazonas (North region), Rio Grande do Norte, Paraíba and Bahia (Northeast region), and Rio de Janeiro (Southeast region) aiming to identify SARS-CoV-2 mutations that could be involved in the surge of COVID19 cases in Brazil. Here, we showed a widespread dispersion of P.1 and P.2 across Brazilian regions. Except for Manaus, P.2 was the predominant lineage identified country-wise. P.2 lineage was estimated to have originated in February, 2020 and has diverged into new clades. Interstate transmission of P.2 was detected since March, but reached its peak in December, 2020 and January, 2021. Transmission of P.1 was also high in December. P.1 origin was inferred to have happened in August 2020. We also confirmed the presence of the variant under investigation (VUI) NP13L, recently described in the southernmost region of Brazil, to have spread across the Northeastern states. P.1, P.2 and NP13L are descended from the ancient B.1.1.28 strain, although during the first phase of the pandemic in Brazil presence of B.1.1.33 strain was also reported. We investigate here the possible occurrence of a new variant of interest descending from B.1.1.33 that also carries the E484K mutation. Indeed, the recurrent report of many novel SARS-CoV-2 genetic variants in Brazil could be due to the absence of effective control measures resulting in high SARS-CoV2 transmission rates. Altogether, our findings provided a landscape of the critical state of SARS-CoV-2 across Brazil and confirm the need to sustain continuous sequencing of the SARS-CoV-2 isolates worldwide in order to early identify novel variants of interest and to monitor for vaccine effectiveness.
Demographic and clinical features associated with in-hospital mortality in Egyptian COVID-19 patients: A retrospective cohort study
Authors: Asem Noha , Hassany Mohamed , Taema Khaled , Masoud Hossam , Elassal Gehan , Kamal Ehab , Amin Wagdy , Abdelbary Akram , Baki Amin Abdel , Zaky Samy , Abdalmohsen Ahmad , Ibrahim Hamdy , Elnady Mohamed , Mohamed Ahmed , Atteia Ehab , Zaid Hala
Published: March 2021

Introduction

Since the worldwide emergence of the COVID-19, several protocols were used by different healthcare organisations. We evaluated in this study the demographic and clinical characteristics of COVID-19 disease in Egyptian population with special consideration for its mortality predictors.

Methodology

8162 participants (mean age 48.7±17.3 years,54.5% males) with RT-PCR positive COVID-19 were included. The electronic medical records were reviewed for demographic, clinical, laboratory, and radiologic features. The primary outcome was the in-hospital mortality rate.

Results

The in-hospital mortality was 11.2%. There was a statistically significant strong association of in-hospital mortality with age >60 years old (OR:4.7; 95% CI 4.1-5.4;p<0.001), diabetes mellitus (OR:4.6; 95% CI 3.99-5.32;p<0.001), hypertension (OR:3.9; 95% CI 3.4-4.5;p<0.001), coronary artery disease (OR:2.7; 95% CI 2.2-3.2;p<0.001), chronic obstructive pulmonary disease (OR:2.1; 95% CI 1.7-2.5;p<0.001), chronic kidney disease (OR:4.8; 95% CI 3.9-5.9;p<0.001), malignancy (OR:3.7; 95% CI 2.3-5.75;p<0.001), neutrophil-lymphocyte ratio >3.1 (OR:6.4; 95% CI 4.4-9.5;P< 0.001), and ground glass opacities (GGOs) in CT chest (OR:3.5; 95% CI 2.84-4.4;P<0.001), respectively. There was a statistically significant moderate association of in-hospital mortality with male gender (OR:1.6; 95% CI 1.38-1.83;p<0.001) and smoking (OR:1.6; 95% CI 1.3-1.9;p<0.001). GGOs was reported as the most common CT finding (occurred in 73.1% of the study participants).

Conclusions

This multicenter, retrospective study ascertained the higher in-hospital mortality rate in Egyptian COVID-19 patients with different comorbidities.
Polygenic basis and biomedical consequences of telomere length variation
Authors: Codd Veryan , Wang Qingning , Allara Elias , Musicha Crispin , Kaptoge Stephen , Stoma Svetlana , Jiang Tao , Hamby Stephen E. , Braund Peter S. , Bountziouka Vasiliki , Budgeon Charley A. , Denniff Matthew , Swinfield Chloe , Papakonstantinou Manolo , Sheth Shilpi , Nanus Dominika E. , Warner Sophie C. , Wang Minxian , Khera Amit V. , Eales James , Ouwehand Willem H. , Thompson John R , Angelantonio Emanuele Di , Wood Angela M. , Butterworth Adam S. , Danesh John N. , Nelson Christopher P. , Samani Nilesh J.
Published: March 2021

Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence1. Here we characterize the genetic architecture of naturally-occurring variation in leucocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized participants in UK Biobank2. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 novel). Genetically-determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular, and inflammatory pathologies. Finally, we estimated that at age 40 years, people with >1-SD shorter compared to ≥1-SD longer LTL than the population mean had 2.5 years lower life expectancy. Overall, we furnish novel insights into the genetic regulation of LTL, reveal LTL’s wide-ranging influences on physiological traits, diseases, and longevity, and provide a powerful resource available to the global research community.
Nasoniasegmentation is regulated by an ancestral insect segmentation regulatory network also present in flies
Authors: Taylor S E , Dearden P K
Published: March 2021

Insect segmentation is a well-studied and tractable system with which to investigate the genetic regulation of development. Though insects segment their germband using a variety of methods, modelling work implies that a single gene regulatory network can underpin the two main types of insect segmentation. This means limited genetic changes are required to explain significant differences in segmentation mode between different insects. Evidence for this idea is limited toDrosophila melanogaster, Tribolium castaneum, and the spiderParasteatoda tepidariorum, and the nature of the gene regulatory network (GRN) underlying this model has not been tested. Some insects, for exampleNasonia vitripennisandApis melliferasegment progressively, a pattern not examined in studies of this segmentation model, producing stripes at different times throughout the embryo, but not from a segment addition zone.

Here we aim to understand the GRNs patterningNasoniausing a simulation-based approach. We found that an existing model ofDrosophilasegmentation (Clark, 2017) can be used to recapitulateNasonia’s progressive segmentation, if provided with altered inputs in the form of expression of the timer genesNν-caudalandNν-odd paired. We also predict limited topological changes to the pair rule network. Together this implies that very limited changes to theDrosophilanetwork are required to simulateNasoniasegmentation, despite the differences in segmentation modes, implying thatNasoniause a very similar version of an ancestral GRN also used byDrosophila.
Aberrant modulation of brain activity underlies impaired working memory following traumatic brain injury
Authors: Taing Abbie S. , Mundy Matthew E. , Ponsford Jennie L. , Spitz Gershon
Published: March 2021

Impaired working memory capacity is a common and disabling consequence of traumatic brain injury (TBI) that is caused by aberrant neural processing. However, due to high heterogeneity in results across studies, it is challenging to conclude whether impaired working memory in this population is driven by neural hypo- or hyper-activation, and the extent to which deficits are perpetuated by specific working memory subprocesses. Using a combined functional magnetic resonance imaging and working memory paradigm, we tested the hypothesis that the pattern of neural activation subserving working memory following TBI would interact with both task demands and specific working memory subcomponents: encoding, maintenance, and retrieval. Behaviourally, we found that working memory deficits were confined to the high cognitive load trials. Our results confirmed our key prediction. Overall, TBI participants showed reduced brain activity while performing the working memory task. However, interrogation of the subcomponents of working memory revealed a more nuanced pattern of activation. When we simply averaged across all task trials, regardless of cognitive load or subcomponent, TBI participants showed reduced neural activation. When examined more closely, patterns of brain activity following TBI were found to interact with both task demands and working memory subcomponent. Participants with TBI demonstrated an inability to appropriately modulate brain activity between low and high demand conditions necessary during encoding and maintenance stages. Therefore, we demonstrate that conclusions about aberrant neural processing are dependent upon the level of analysis and the extent to which general cognitive domains can be parcellated into its constituent parts.
Euchromatin factors HULC and Set1C affect heterochromatin organization for mating-type switching in fission yeastSchizosaccharomyces pombe
Authors: Esquivel-Chávez Alfredo , Maki Takahisa , Tsubouchi Hideo , Handa Testuya , Kimura Hiroshi , Haber James E. , Thon Genevieve , Iwasaki Hiroshi
Published: March 2021

Mating-type (P or M) of fission yeastSchizosaccharomyces pombeis determined by the transcriptionally activemat1cassette and is switched by gene conversion using a donor, eithermat2ormat3, located in an adjacent heterochromatin region (mating-type switching; MTS). In the process, heterochromatic donors of genetic information are selected based on the P or M cell type and on the action of two recombination enhancers,SRE2promoting the use ofmat2-PandSRE3promoting the use ofmat3-M, leading to replacement of the content of the expressedmat1cassette. Recently, we found that the histone H3K4 methyltransferase complex Set1C participates in donor selection, raising the question of how a complex best known for its effects in euchromatin controls recombination in heterochromatin. Here, we report that the histone H2BK119 ubiquitin ligase complex HULC functions with Set1C in MTS, as mutants in theshf1, brl1, brl2andrad6genes showed defects similar to Set1C mutants and belonged to the same epistasis group asset1Δ. Moreover, using H3K4R and H2BK119R histone mutants and a Set1-Y897A catalytic mutant indicated that ubiquitylation of histone H2BK119 by HULC and methylation of histone H3K4 by Set1C are functionally coupled in MTS. Cell-type biases in MTS in these mutants suggested that HULC and Set1C inhibit the use of theSRE3recombination enhancer in M cells, thus favoringSRE2andmat2-P. Consistently, imbalanced switching in the mutants was traced to compromised association of the directionality factor Swi6 with the recombination enhancers in M cells. Based on their known effects at other chromosomal locations, we speculate that HULC and Set1C might control nucleosome mobility and strand invasion near theSREelements. In addition, we uncovered distinct effects of HULC and Set1C on histone H3K9 methylation and gene silencing, consistent with additional functions in the heterochromatic domain.
Mild CF Lung Disease is Associated with Bacterial Community Stability
Authors: Hampton Thomas H. , Thomas Devin , van der Gast Christopher , O’Toole George A. , Stanton Bruce A.
Published: March 2021

Microbial communities in the airways of persons with CF (pwCF) are variable, may include genera that are not typically associated with CF, and their composition can be difficult to correlate with long-term disease outcomes. Leveraging two large datasets characterizing sputum communities of 167 pwCF and associated metadata, we identify five bacterial community types. These communities explain 24% of the variability in lung function in this cohort, far more than single factors like Simpson diversity, which explains only 4%. Subjects withPseudomonas-dominated communities tended to be older and have reduced percent predicted FEV1(ppFEV1) than subjects withStreptococcus-dominated communities, consistent with previous findings. To assess the predictive power of these five communities in a longitudinal setting, we used random forests to classify 346 additional samples from 24 subjects observed 8 years on average in a range of clinical states. Subjects with mild disease were more likely to be observed at baseline, that is, not in the context of a pulmonary exacerbation, and community structure in these subjects was more self-similar over time, as measured by Bray-Curtis distance. Interestingly, we found that subjects with mild disease were more likely to remain in a mixedPseudomonascommunity, providing some support for the climax-attack model of the CF airway. In contrast, patients with worse outcomes were more likely to show shifts among community types. Our results suggest that bacterial community instability may be a risk factor for lung function decline and indicates the need to better understand factors that drive shifts in community composition.
gen3sis: the general engine for eco-evolutionary simulations on the origins of biodiversity
Authors: Hagen Oskar , Flück Benjamin , Fopp Fabian , Cabral Juliano S. , Hartig Florian , Pontarp Mikael , Rangel Thiago F. , Pellissier Loïc
Published: March 2021

Understanding the origins of biodiversity has been an aspiration since the days of early naturalists. The immense complexity of ecological, evolutionary and spatial processes, however, has made this goal elusive to this day. Computer models serve progress in many scientific fields, but in the fields of macroecology and macroevolution, eco-evolutionary models are comparatively less developed. We present a general, spatially-explicit, eco-evolutionary engine with a modular implementation that enables the modelling of multiple macroecological and macroevolutionary processes and feedbacks across representative spatio-temporally dynamic landscapes. Modelled processes can include environmental filtering, biotic interactions, dispersal, speciation and evolution of ecological traits. Commonly observed biodiversity patterns, such as α, β and γ diversity, species ranges, ecological traits and phylogenies, emerge as simulations proceed. As a case study, we examined alternative hypotheses expected to have shaped the latitudinal diversity gradient (LDG) during the Earth’s Cenozoic era. We found that a carrying capacity linked with energy was the only model variant that could simultaneously produce a realistic LDG, species range size frequencies, and phylogenetic tree balance. The model engine is open source and available as an R-package, enabling future exploration of various landscapes and biological processes, while outputs can be linked with a variety of empirical biodiversity patterns. This work represents a step towards a numeric and mechanistic understanding of the physical and biological processes that shape Earth’s biodiversity.
Loss of Nuclear DNA Ligase III Reverts PARP Inhibitor Resistance in BRCA1/53BP1 Double-deficient Cells by Exposing ssDNA Gaps
Authors: Dias Mariana Paes , Tripathi Vivek , van der Heijden Ingrid , Cong Ke , Manolika Eleni-Maria , Bhin Jinhyuk , Gogola Ewa , Galanos Panagiotis , Annunziato Stefano , Lieftink Cor , Andújar-Sánchez Miguel , Chakrabarty Sanjiban , Smith Graeme C. M. , van de Ven Marieke , Beijersbergen Roderick L. , Bartkova Jirina , Rottenberg Sven , Cantor Sharon , Bartek Jiri , Chaudhuri Arnab Ray , Jonkers Jos
Published: March 2021

Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, preclinical and clinical research with PARPi has revealed multiple resistance mechanisms, highlighting the need for identification of novel functional biomarkers and combination treatment strategies. Functional genetic screens performed in cells and organoids that acquired resistance to PARPi by loss of 53BP1 identified loss of LIG3 as an enhancer of PARPi toxicity in BRCA1-deficient cells. Enhancement of PARPi toxicity by LIG3 depletion is dependent on BRCA1 deficiency but independent of the loss of 53BP1 pathway. Mechanistically, we show that LIG3 loss promotes formation of MRE11-mediated post-replicative ssDNA gaps in BRCA1-deficient and BRCA1/53BP1 double-deficient cells exposed to PARPi, leading to an accumulation of chromosomal abnormalities. LIG3 depletion also enhances efficacy of PARPi against BRCA1-deficient mammary tumors in mice, suggesting LIG3 as a potential therapeutic target.
Uncharted biosynthetic potential of the ocean microbiome
Authors: Paoli Lucas , Ruscheweyh Hans-Joachim , Forneris Clarissa C. , Kautsar Satria , Clayssen Quentin , Salazar Guillem , Milanese Alessio , Gehrig Daniel , Larralde Martin , Carroll Laura M. , Sánchez Pablo , Zayed Ahmed A. , Cronin Dylan R. , Acinas Silvia G. , Bork Peer , Bowler Chris , Delmont Tom O. , Sullivan Matthew B. , Wincker Patrick , Zeller Georg , Robinson Serina L. , Piel Jörn , Sunagawa Shinichi
Published: March 2021

Microbes are phylogenetically and metabolically diverse. Yet capturing this diversity, assigning functions to host organisms and exploring the biosynthetic potential in natural environments remains challenging. We reconstructed >25,000 draft genomes, including from >2,500 uncharacterized species, from globally-distributed ocean microbial communities, and combined them with ∼10,000 genomes from cultivated and single cells. Mining this resource revealed ∼40,000 putative biosynthetic gene clusters (BGCs), many from unknown phylogenetic groups. Among these, we discoveredCandidatusEudoremicrobiaceae as one of the most biosynthetically diverse microbes detected to date. Discrete transcriptional states structuring natural populations were associated with a potentially niche-partitioning role for BGC products. Together with the characterization of the first Eudoremicrobiaceae natural product, this study demonstrates how microbiomics enables prospecting for candidate bioactive compounds in underexplored microbes and environments.
Herpesviral induction of germline transcription factor DUX4 is critical for viral gene expression
Authors: Walter Stephanie , Franke Vedran , Drayman Nir , Wyler Emanuel , Tay Savaş , Landthaler Markus , Akalin Altuna , Ensser Armin , Full Florian
Published: March 2021

DUX4 is a transcription factor and a master regulator of embryonic genome activation (EGA). During early embryogenesis, EGA is crucial for maternal to zygotic transition at the 8-cell stage in order to overcome silencing of genes and enable transcription from the zygotic genome. In adult somatic cells, DUX4 expression is largely silenced. Activation is likely pathogenic, and in adult muscle cells causes genetic disorder Facioscapulohumeral Muscular Dystrophy (FSHD).

We identified activation of DUX4 expression upon lytic replication of the herpesviruses HSV-1, HCMV, EBV and KSHV, but not of adenoviruses, negative strand RNA viruses or positive strand RNA viruses. We demonstrate by RNA-Seq analysis that DUX4 expression upon herpesviral replication leads to the induction of hundreds of DUX4 target genes including germline-specific retroelements as well as several members of the TRIM, PRAMEF and ZSCAN protein families. Moreover, we show that DUX4 expression is a direct consequence of herpesviral infection. DUX4 can be stimulated by overexpression of HSV-1 immediate early proteins, indicating active induction of EGA genes by herpesviral infection. We further show that DUX4 expression is critical for driving HSV-1 gene expression.

Our results show that viruses from alpha-, beta- and gamma-herpesvirus subfamilies induce DUX4 expression and downstream germline-specific genes and retroelements. We hypothesize that herpesviruses induce DUX4 expression in order to induce an early embryonic-like transcriptional program that prevents epigenetic silencing of the viral genome and facilitates herpesviral gene expression.
A species-specific retrotransposon drives a conserved Cdk2ap1 isoform essential for preimplantation development
Authors: Modzelewski Andrew , Shao Wanqing , Chen Jingqi , Lee Angus , Qi Xin , Noon Mackenzie , Tjokro Kristy , Sales Gabriele , Biton Anne , Speed Terence , Xuan Zhenyu , Wang Ting , Risso Davide , He Lin
Published: March 2021

Retrotransposons mediate gene regulation in multiple developmental and pathological processes. Here, we characterized the transient retrotransposon induction in preimplantation development of eight mammalian species. While species-specific in sequences, induced retrotransposons exhibit a similar preimplantation profile, conferring gene regulatory activities particularly through LTR retrotransposon promoters. We investigated a mouse-specific MT2B2 retrotransposon promoter, which generates an N-terminally truncated, preimplantation-specific Cdk2ap1ΔN isoform to promote cell proliferation. Cdk2ap1ΔN functionally contrasts to the canonical Cdk2ap1, which represses cell proliferation and peaks in mid-gestation stage. The mouse-specific MT2B2 element is developmentally essential, as its deletion abolishes Cdk2ap1ΔN, reduces cell proliferation and impairs embryo implantation. Intriguingly, Cdk2ap1ΔN is evolutionarily conserved across mammals, driven by species-specific promoters. The distinct preimplantation Cdk2ap1ΔN expression across different mammalian species correlates with their different duration in preimplantation development. Hence, species-specific transposon promoters can yield evolutionarily conserved, alternative protein isoforms, bestowing them with new functions and species-specific expression to govern essential biological divergence.

One Sentence Summary

In mammalian preimplantation embryos, retrotransposon promoters generate conserved gene isoforms, confer species-specific expression, and perform essential developmental functions.
Responses of Oil Palm Pollinator,Elaeidobius kamerunicusto Different Concentrations of Estragoles
Authors: Fahmi-Halil Muhammad , Haris-Hussain Mohamad , Mirad Razali , Idris AB , Jalinas Johari
Published: March 2021

Elaeidobius kamerunicusis the main insect pollinator for oil palm (Elaeis guineensis) worldwide. One of the main reasonE. kamerunicusattracted to oil palm inflorescences is estragole, a volatile organic compound released by the oil palm inflorescences during anthesis stage. However, the amount of estragole released from the oil palm inflorescence is varied due to the influence of abiotic and biotic factors and is seen to have an impact onE. kamerunicuspollination activity on the oil palm. To evaluate the responses ofE. kamerunicus, different types (wild and reared) and sex (male and female) ofE. kamerunicuswere exposed to different concentrations (1, 5, 10, 30, 50, 70, 100, 150 and 200 ppm) of commercial estragole using four-arm olfactometer. Results showed thatE. kamerunicussignificantly preferred 100 ppm of estragole compared to other concentration (F = 139.81; d.f. = 9; P < 0.05). A significant interaction was also recorded between estragole concentrations and sexes ofE. kamerunicus(F = 3.91; d.f. = 9; P < 0.05) where maleE. kamerunicuswas found to be more responsive to 100 ppm of estragole compared femaleE. kamerunicus. TheE. kamerunicusresponses to estragole is in line with the increase of estragole concentration up to 100 ppm. However, the response ofE. kamerunicuswas significantly decreased after the concentration value. The result of this study can be a good platform for future references since the estragole compound plays a significant role in oil palm’s flower pollination byE. kamerunicus. The factor of type and sexes ofE. kamerunicusdid not affect the preferences which indicated thatE. kamerunicusreared in the laboratory have the potential to be released into the oil palm plantation area to overcome the problem of pollination.
Novel cancer subtyping method based on patient-specific gene regulatory network
Authors: Nakazawa Mai Adachi , Tamada Yoshinori , Tanaka Yoshihisa , Ikeguchi Marie , Higashihara Kako , Okuno Yasushi
Published: March 2021

The identification of cancer subtypes is important for the understanding of tumor heterogeneity. In recent years, numerous computational methods have been proposed for this problem based on the multi-omics data of patients. It is widely accepted that different cancer subtypes are induced by different molecular regulatory networks. However, only a few incorporate the differences between their molecular systems into the classification processes. In this study, we present a novel method to classify cancer subtypes based on patient-specific molecular systems. Our method quantifies patient-specific gene networks, which are estimated from their transcriptome data. By clustering their quantified networks, our method allows for cancer subtyping, taking into consideration the differences in the molecular systems of patients. Comprehensive analyses of The Cancer Genome Atlas (TCGA) datasets applied to our method confirmed that they were able to identify more clinically meaningful cancer subtypes than the existing subtypes and found that the identified subtypes comprised different molecular features. Our findings show that the proposed method, based on a simple classification using the patient-specific molecular systems, can identify cancer subtypes even with single omics data, which cannot otherwise be captured by existing methods using multi-omics data.
Whole genome resequencing data enables a targeted SNP panel for conservation and aquaculture ofOreochromiscichlid fishes
Authors: Ciezarek A , Ford AGP , Etherington GJ , Kasozi N , Malinsky M , Mehta T , Penso-Dolfin L , Ngatunga BP , Shechonge A , Tamatamah R , Haerty W , Di Palma F , Genner MJ , Turner GF
Published: March 2021

Cichlid fish of the genusOreochromisform the basis of the global tilapia aquaculture and fisheries industry. Non-native farmed tilapia populations are known to be widely distributed across Africa and to hybridize with nativeOreochromisspecies. However, many species are difficult to distinguish morphologically, hampering attempts to maintain good quality farmed strains or to identify pure populations of native species. Here, we describe the development of a single nucleotide polymorphism (SNP) genotyping panel from whole-genome resequencing data that enables targeted species identification in Tanzania. We demonstrate that an optimized panel of 96 genome-wide SNPs based on FSToutliers performs comparably to whole genome resequencing in distinguishing species and identifying hybrids. We also show this panel outperforms microsatellite-based and phenotype-based classification methods. Case studies indicate several locations where introduced aquaculture species have become established in the wild, threatening nativeOreochromisspecies. The novel SNP markers identified here represent an important resource for assessing broodstock purity and helping to conserve unique endemic biodiversity, and in addition potentially for assessing broodstock purity in hatcheries.
The natural sequence of events in larval settlement and metamorphosis of Hydroides elegans (Polychaeta; Serpulidae)
Authors: Hadfield Michael G. , Freckelton Marnie L. , Nedved Brian T.
Published: March 2021

The broadly distributed serpulid worm Hydroides elegans has become a model organism for studies of marine biofouling, development and the processes of larval settlement and metamorphosis induced by surface microbial films. Contrasting descriptions of the initial events of these recruitment processes, whether settlement is induced by (1) natural multi-species biofilms, (2) biofilms composed of single bacterial species known to induce settlement, or (3) a bacterial extract stimulated the research described here. We found that settlement induced by natural biofilms or biofilms formed by the bacterium Pseudoalteromonas luteoviolacea is invariably initiated by attachment and secretion of an adherent and larva-enveloping primary tube, followed by loss of motile cilia and ciliated cells and morphogenesis. The bacterial extract containing complex tailocin arrays derived from an assemblage of phage genes incorporated into the bacterial genome appears to induce settlement events by destruction of larval cilia and ciliated cells, followed by attachment and primary-tube formation. Similar destruction occurred when precompetent larvae and larvae of a nudibranch gastropod were exposed to the extract, neither of which metamorphosed. We further argue that larvae that lose their cilia before attachment would be swept away from the sites that stimulated settlement by the turbulent flow characteristic of most marine habitats.
Sequence and phylogenetic analysis revealed structurally conserved domains and motifs in lincRNA-p21
Authors: Maulik Aditi , Bandopadhyay Devleena , Singh Mahavir
Published: March 2021

Long Intergenic Non-coding RNAs (lincRNAs) are the largest class of long non-coding RNAs in the eukaryotes, which originate from the intergenic regions of the genome. A ~4kb long lincRNA-p21 is derived from a transcription unit next to the p21/Cdkn1a gene locus. LincRNA-p21 plays key regulatory roles in p53 dependent transcriptional repression and translational repression through its physical association with proteins such as hnRNP-K and HuR.It is also involved in the aberrant gene expression in different cancers. However, detailed information on its structure, recognition, and trans-regulation by proteins is not well known. In this study, we have carried out a complete gene analysis and annotation of lincRNA-p21. This analysis showed that lincRNA-p21 is highly conserved in primates, and its conservation drops significantly in lower organisms. Furthermore, our analysis has revealed two structurally conserved domains in the 5’ and 3’ terminal regions of lincRNA-p21. Phylogenetic analysis has revealed discrete evolutionary dynamics in these conserved domains for orthologous sequences of lincRNA-p21, which have evolved slowly across primates compared to other mammals. Using Infernal based covariance analysis, we have computed the secondary structures of these domains. The secondary structures were further validated by energy minimization criteria for individual orthologous sequences as well as the full-length human lincRNA-p21. In summary, this analysis has led to the identification of sequence and structural motifs in the conserved fragments, indicating the functional importance for these regions.
Characterization of regulatory transcriptional mechanisms in hepatocyte lipotoxicity
Authors: Pérez-Schindler Joaquín , Vargas-Fernández Elyzabeth , Karrer-Cardel Bettina , Ritz Danilo , Schmidt Alexander , Handschin Christoph
Published: March 2021

Non-alcoholic fatty liver disease is a continuum of disorders among which non-alcoholic steatohepatitis (NASH) is particularly associated with a negative prognosis. Hepatocyte lipotoxicity is one of the main pathogenic factors of liver fibrosis and NASH. However, the molecular mechanisms regulating this process are poorly understood. The main aim of this study was to dissect transcriptional mechanisms regulated by lipotoxicity in hepatocytes. We achieved this aim by combining transcriptomic, proteomic and chromatin accessibility analyses from human liver and mouse hepatocytes. This integrative approach revealed several transcription factor networks deregulated by NASH and lipotoxicity. To validate these predictions, genetic deletion of the transcription factors MAFK and TCF4 was performed, resulting in hepatocytes that were better protected against saturated fatty acid oversupply. MAFK- and TCF4-regulated gene expression profiles suggest a mitigating effect against cell stress, while promoting cell survival and growth. Moreover, in the context of lipotoxicity, some MAFK and TCF4 target genes were to the corresponding differentially regulated transcripts in human liver fibrosis. Collectively, our findings comprehensively profile the transcriptional response to lipotoxicity in hepatocytes, revealing new molecular insights and providing a valuable resource for future endeavours to tackle the molecular mechanisms of NASH.
Deep learning-based chest X-ray age serves as a novel biomarker for cardiovascular aging
Authors: Ieki Hirotaka , Ito Kaoru , Saji Mike , Kawakami Rei , Nagatomo Yuji , Koyama Satoshi , Matsunaga Hiroshi , Miyazawa Kazuo , Ozaki Kouichi , Onouchi Yoshihiro , Katsushika Susumu , Matsuoka Ryo , Shinohara Hiroki , Yamaguchi Toshihiro , Kodera Satoshi , Higashikuni Yasutomi , Fujiu Katsuhito , Akazawa Hiroshi , Isobe Mitsuaki , Yoshikawa Tsutomu , Komuro Issei
Published: March 2021

Chest X-ray (CXR) is one of the most commonly performed medical imaging tests. Although aging, sex and disease status have been known to cause changes in CXR findings, the extent of these effects has not been fully characterized. Here, we present a deep neural network (DNN) model trained using more than 100,000 CXRs to estimate the patient’s age and sex solely from CXRs. Our DNN exhibited high performance in terms of estimating age and sex, with Pearson’s correlation coefficient between the actual and estimated age of above 0.9 and an area under the ROC curve of 0.98 for sex estimation. The difference between the actual and estimated age is large in CXRs with abnormal findings, suggesting that the estimated age (“CXR age”) can be a biomarker for disease status. Furthermore, by applying our DNN to CXRs of consecutive 1,562 hospitalized heart failure patients, we demonstrated that an elevated CXR age is not only associated with aging-related diseases, such as hypertension and atrial fibrillation, but also a worse outcome of heart failure. Given these results, our new concept “CXR age” serves as a novel biomarker for cardiovascular aging and can help clinicians to predict, prevent, and manage cardiovascular diseases.
Germ plasm anchors at tight junctions in the early zebrafish embryo
Authors: Rostam Nadia , Goloborodko Alexander , Riemer Stephan , Hertel Andres , Klein Sabine , Riedel Dietmar , Vorbrüggen Gerd , Dosch Roland
Published: March 2021

The zebrafish germline is specified during early embryogenesis by inherited maternal RNAs and proteins collectively called germ plasm. Only the cells containing germ plasm will become part of the germline, whereas other cells will commit to somatic cell fates. Therefore, proper localization of germ plasm is key for germ cell specification and its removal is critical for the development of soma. The molecular mechanism underlying this process in vertebrates is largely unknown. Here we show that germ plasm localization in zebrafish is similar toXenopusand amniotes but distinct fromDrosophila. We identified non muscle myosin II (NMII) and tight junction (TJ) components as interaction candidates of Bucky ball (Buc), which is the germ plasm organizer in zebrafish. Remarkably, we also found that TJ protein ZO1 colocalizes with germ plasm and electron microscopy (EM) of zebrafish embryos uncovered TJ like structures at early cleavage furrows. In addition, injection of the TJ-receptor Claudin-d (Cldn-d) produced extra germ plasm aggregates. Our findings discover for the first time a role of TJs in germ plasm localization.