bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct patterns of mutational sensitivity for λ resistance and maltodextrin transport in Escherichia coli LamB
Authors: Andrews Bryan , Fields Stanley
Published: April 2020

Bacteria can evade cohabiting phages through mutations in phage receptors, but these mutations may come at a cost if they disrupt the receptor’s native cellular function. To investigate the relationship between these two conflicting activities, we generated sequence–function maps of

Escherichia coli

LamB with respect to sensitivity to phage λ and transport of maltodextrin. By comparing 413 missense mutations whose effect on both traits could be analysed, we find that these two phenotypes were correlated, implying that most mutations affect these phenotypes through a common mechanism such as loss of protein stability. However, individual mutations could be found that specifically disrupt λ-sensitivity without affecting maltodextrin transport. We identify and individually assay nine such mutations, whose spatial positions implicate loop L6 of LamB in λ binding. Although missense mutations that lead to λ-resistance are rare, they were approximately as likely to be maltodextrin-utilizing (Mal+) as not (Mal-), implying that

E. coli

can adapt to λ while conserving the receptor’s native function. We propose that in order for

E. coli

and λ to stably cohabitate, selection for λ-resistance and maltose transport must be spatially or temporally separated.
Comparative genomics suggests limited variability and similar evolutionary patterns between major clades of SARS-CoV-2
Authors: Chiara Matteo , Horner David S. , Gissi Carmela , Pesole Graziano
Published: April 2020

Phylogenomic analysis of SARS-CoV-2 as available from publicly available repositories suggests the presence of 3 prevalent groups of viral episomes (super-clades), which are mostly associated with outbreaks in distinct geographic locations (China, USA and Europe). While levels of genomic variability between SARS-CoV-2 isolates are limited, to our knowledge, it is not clear whether the observed patterns of variability in viral super-clades reflect ongoing adaptation of SARS-CoV-2, or merely genetic drift and founder effects. Here, we analyze more than 1100 complete, high quality SARS-CoV-2 genome sequences, and provide evidence for the absence of distinct evolutionary patterns/signatures in the genomes of the currently known major clades of SARS-CoV-2. Our analyses suggest that the presence of distinct viral episomes at different geographic locations are consistent with founder effects, coupled with the rapid spread of this novel virus. We observe that while cross species adaptation of the virus is associated with hypervariability of specific protein coding regions (including the RDB domain of the spike protein), the more variable genomic regions between extant SARS-CoV-2 episomes correspond with the 3’ and 5’ UTRs, suggesting that at present viral protein coding genes should not be subjected to different adaptive evolutionary pressures in different viral strains. Although this study can not be conclusive, we believe that the evidence presented here is strongly consistent with the notion that the biased geographic distribution of SARS-CoV-2 isolates should not be associated with adaptive evolution of this novel pathogen.
Co-evolution between codon usage and Protein-Protein Interaction Networks in Bacterial genomes
Authors: Dilucca Maddalena , Cimini Giulio , Forcelloni Sergio , Giansanti Andrea
Published: April 2020

In this work, we study the correlation between codon usage and the network features of the PPI in bacteria genomes. We want to extend the information by Dilucca et al. (2015) about E.Coli’s genome for a set of other 34 bacteria. We use PCA techniques in the space of codon bias indices (compAI, compAI_w, tAI, NC) and GC content to show that genes with similar patterns of codon usage feature have a significantly higher probability that their encoded proteins interact within the PPI. And vice-versa, we show that interacting in the PPI have a coherent codon usage. This work could allow for future investigations into the possible effects that codon bias signal can have on the topology of protein interaction network and, as such, to improve existing bioinformatics methods for predicting protein interactions.
Pan-cancer Drivers are Recurrent Transcriptional Regulatory Heterogeneities in Early-stage Luminal Breast Cancer
Authors: Singh Shambhavi , Sutcliffe Matthew D. , Repich Kathy , Atkins Kristen A. , Harvey Jennifer A. , Janes Kevin A.
Published: April 2020

The heterogeneous composition of solid tumors is known to impact disease progression and response to therapy. Malignant cells coexist in different regulatory states that can be accessed transcriptomically by single-cell RNA sequencing, but these methods have many caveats related to sensitivity, noise, and sample handling. We revised a statistical fluctuation analysis called stochastic profiling to combine with 10-cell RNA sequencing, which was designed for laser-capture microdissection (LCM) and extended here for immuno-LCM. When applied to a cohort of late-onset, early-stage luminal breast cancers, the integrated approach identified thousands of candidate regulatory heterogeneities. Intersecting the candidates from different tumors yielded a relatively stable set of 710 recurrent heterogeneously expressed genes (RHEGs) that were significantly variable in >50% of patients. RHEGs were not strongly confounded by dissociation artifacts, cell cycle oscillations, or driving mutations for breast cancer. Rather, we detected RHEG enrichments for epithelial-to-mesenchymal transition genes and, unexpectedly, the latest pan-cancer assembly of driver genes across cancer types other than breast. Heterogeneous transcriptional regulation conceivably provides a faster, reversible mechanism for malignant cells to evaluate the effects of potential oncogenes or tumor suppressors on cancer hallmarks.

Statement of significance

Profiling intratumor heterogeneity of luminal breast carcinoma cells identifies a recurrent set of genes suggesting sporadic activation of pathways known to drive other types of cancer.
Metagenomic sequencing as a clinical diagnostic tool for infectious diseases: a systematic review and meta-analysis
Authors: Govender Kumeren N. , Street Teresa L. , Sanderson Nicholas D. , Eyre David W.
Published: April 2020

Background

Metagenomics has the potential to revolutionise infectious diseases diagnostics, from rapid species and antimicrobial resistance prediction, to finding unrecognised and sometimes untreated infections. Our aim was to summarise all literature on culture-independent metagenomic sequencing to describe the accuracy of species and antimicrobial resistance prediction and, describe the challenges and progress in the field.

Methods

We conducted a systematic review with meta-analysis from eligible studies retrieved from PubMed, Google Scholar and bioRxiv and, assessed risk of bias and quality using the QUADAS-2 tool. This study is registered with PROSPERO, number CRD42020163777.

Findings

We identified 36 studies, 22 of which used a species-agnostic approach to identify all possible pathogens. In these studies, the overall sensitivity and specificity of pathogen species detection were 88% (95%CI 81-92%) and 86% (95%CI 70-94%) respectively. Antimicrobial resistance prediction and comparison to phenotypic results was undertaken in six studies. Categorical agreement was 83% (95%CI 68-92%), very major (prediction sensitive, phenotype resistant) and major error (prediction resistant, phenotype sensitive) rates were 9% (95%CI 2-27%) and 1% (95%CI 0-20%) respectively. We report limited use of negative controls in studies 61% (22/36) which contribute to a major challenge of discriminating true pathogens from contamination, where there is no convergence on methodology. More efficient human DNA depletion methods are required as a median of 79% (IQR 62-96) [Range 7-98] of sequences were classified as human despite laboratory depletion techniques. The median time from sample to result was 23·5 hours (7-31) [4-144], with sequencing time accounting 10 hours (4·8-16) [1-16]. The average reported consumables cost per sample ranged from $128 to $685.

Interpretation

The science and regulatory environment are rapidly developing, and its role as a routine test or test of last resort still needs to be determined, however it is likely that clinical metagenomics will be an increasing part of the clinician’s armamentarium to diagnose infectious diseases in the near future.

Funding

None.
Genetic risk scores of disease and mortality capture differences in longevity, economic behavior, and insurance outcomes
Authors: Linnér Richard Karlsson , Koellinger Philipp D.
Published: April 2020

Widespread genetic testing for diseases may cause adverse selection, escalating premiums, or discrimination in various insurance markets. Here, without systematically informing study participants of their genetic predisposition, we estimate to what extent genetic data are informative about differences in longevity, health expectations, and economic behavior. We compute measures of genetic liability (polygenic scores) for 27 common diseases and mortality risks in 9,272 participants of the Health and Retirement Study (HRS). Survival analysis suggests that the highest decile of cumulative genetic risk can distinguish a median lifespan up to 4.5 years shorter, a difference that is similar to or larger than that distinguished by conventional actuarial risk factors, including sex. Furthermore, greater genetic liability is associated with less long-term care insurance, among other economic behaviors. We conclude that the rapid developments in genetic epidemiology pose new challenges for regulating consumer genetics and insurance markets, requiring urgent attention from policymakers.
A framework for network-based epidemiological modeling of tuberculosis dynamics using synthetic datasets
Authors: Renardy Marissa , Kirschner Denise E.
Published: April 2020

We present a framework for discrete network-based modeling of TB epidemiology in US counties using publicly available synthetic datasets. We explore the dynamics of this modeling framework by simulating the hypothetical spread of disease over two years resulting from a single active infection in Washtenaw County, MI. We find that for sufficiently large transmission rates that active transmission outweighs reactivation, disease prevalence is sensitive to the contact weight assigned to transmissions between casual contacts (that is, contacts that do not share a household, workplace, school, or group quarter). Workplace and casual contacts contribute most to active disease transmission, while household, school, and group quarter contacts contribute relatively little. Stochastic features of the model result in significant uncertainty in the predicted number of infections over time, leading to challenges in model calibration and interpretation of model-based predictions. Finally, predicted infections were more localized by household location than would be expected if they were randomly distributed. This modeling framework can be refined in later work to study specific county and multi-county TB epidemics in the US.
Flattening the curve is not enough, we need to squash it: An explainer using a simple model
Authors: McBryde ES , Meehan MT , Trauer JM
Published: April 2020

Background

Around the world there are examples of both effective control (e.g., South Korea, Japan) and less successful control (e.g., Italy, Spain, United States) of COVID-19 with dramatic differences in the consequent epidemic curves. Models agree that flattening the curve without controlling the epidemic completely is insufficient and will lead to an overwhelmed health service. A recent model, calibrated for the UK and US, demonstrated this starkly.

Methods

We used a simple compartmental deterministic model of COVID-19 transmission in Australia, to illustrate the dynamics resulting from shifting or flattening the curve versus completely squashing it.

Results

We find that when the reproduction number is close to one, a small decrease in transmission leads to a large reduction in burden (i.e., cases, deaths and hospitalisations), but achieving this early in the epidemic through social distancing interventions also implies that the community will not reach herd immunity.

Conclusions

Australia needs not just to shift and flatten the curve, but to squash it by getting the reproduction number below one. This will require Australia to achieve transmission rates at least two thirds lower than those seen in the most severely affected countries.

The known

COVID-19 has been diagnosed in over 4,000 Australians. Up until mid-March, most were from international travel, but now we are seeing a rise in locally acquired cases.

The new

This study uses a simple transmission dynamic model to demonstrate the difference between moderate changes to the reproduction number and forcing the reproduction number below one.

The implications

Lowering local transmission is becoming important in reducing the transmission of COVID-19. To maintain control of the epidemic, the focus should be on those in the community who do not regard themselves as at risk.
Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in non-human primates
Authors: Page Nicholas F. , Gandal Michael , Estes Myka , Cameron Scott , Buth Jessie , Parhami Sepideh , Ramaswami Gokul , Murray Karl , Amaral David , Van de Water Judy , Schumann Cynthia M. , Carter Cameron S. , Bauman Melissa D. , McAllister A. Kimberley , Geschwind Daniel H.
Published: April 2020

Background

Maternal immune activation (MIA) is a proposed risk factor for multiple neurodevelopmental and psychiatric disorders, including schizophrenia. However, the molecular and neurobiological mechanisms through which MIA imparts risk for these disorders remain poorly understood. A recently developed nonhuman primate model of exposure to the viral mimic poly:ICLC during pregnancy shows abnormal social and repetitive behaviors and elevated striatal dopamine, a molecular hallmark of human psychosis, providing an unprecedented opportunity for mechanistic dissection.

Methods

We performed RNA-sequencing across four psychiatrically-relevant brain regions (prefrontal cortex, anterior cingulate, hippocampus, and primary visual cortex) from 3.5-4-year old male MIA-exposed and control offspring—an age comparable to mid adolescence in humans.

Results

We identify 266 unique genes differentially expressed (DE) in at least one brain region with the greatest number observed in hippocampus. Co-expression networks identified region-specific alterations in synaptic signaling and oligodendrocytes. Across regions, we observed temporal and regional differences, but transcriptomic changes were largely similar across 1stor 2ndtrimester MIA exposures, including for the top DE genes—PIWIL2 and MGARP. In addition to PIWIL2, several other known regulators of retrotransposition, as well as endogenous transposable elements were dysregulated in MIA offspring.

Conclusions

Together, these results begin to elucidate the brain-level molecular mechanisms through which MIA may impart risk for psychiatric disease.
Clinical features and outcomes of 2019 novel coronavirus-infected patients with high plasma BNP levels
Authors: Liu Youbin , Liu Dehui , Song Huafeng , Chen Chunlin , Lv Mingfang , Pei Xing , Hu Zhongwei , Qin Zhihui , Li Jinglong
Published: April 2020

Aims

To explore clinical features and outcome of 2019 novel coronavirus(2019-nCoV)-infected patients with high BNP levels

Methods and results

Data were collected from patients’ medical records, and we defined high BNP according to the plasma BNP was above > 100 pg/mL. In total,34 patients with corona virus disease 2019(COVID-19)were included in the analysis. Ten patients had high plasma BNP level. The median age for these patients was 60.5 years(interquartile range, 40-80y), and 6/10 (60%) were men. Underlying comorbidities in some patients were coronary heart disease (n=2, 20%), hypertesion (n=3,30%), heart failure (n=1,10%)and diabetes (n=2, 20%). Six (60%) patients had a history of Wuhan exposure. The most common symptoms at illness onset in patients were fever (n=7, 70%), cough (n=3, 30%), headache or fatigue(n=4,40%). These patients had higher aspartate aminotransferase(AST), troponin I, C reactive protein and lower hemoglobin, and platelet count,compared with patients with normal BNP, respectively. Compared with patients with normal BNP, patients with high BNP were more likely to develop severe pneumonia, and receive tracheal cannula, invasive mechanical ventilation, continuous renal replacement therapy, extracorporeal membrane oxygenation, and be admitted to the intensive care unit. One patient with high BNP died during the study.

Conclusion

High BNP is a common condition among patients infected with 2019-nCoV. Patients with high BNP showed poor clinical outcomes
Monitoring trends and differences in COVID-19 case-fatality rates using decomposition methods: Contributions of age structure and age-specific fatality
Authors: Dudel Christian , Riffe Tim , Acosta Enrique , van Raalte Alyson , Strozza Cosmo , Myrskylä Mikko
Published: April 2020

The population-level case-fatality rate (CFR) associated with COVID-19 varies substantially, both across countries time and within countries over time. We analyze the contribution of two key determinants of the variation in the observed CFR: the age-structure of diagnosed infection cases and age-specific case-fatality rates. We use data on diagnosed COVID-19 cases and death counts attributable to COVID-19 by age for China, Germany, Italy, South Korea, Spain, the United States, and New York City. We calculate the CFR for each population at the latest data point and also for Italy over time. We use demographic decomposition to break the difference between CFRs into unique contributions arising from the age-structure of confirmed cases and the age-specific case-fatality. In late April 2020, CFRs varied from 2.2% in South Korea to 13.0% in Italy. The age-structure of detected cases often explains more than two thirds of cross-country variation in the CFR. In Italy, the CFR increased from 4.2% to 13.0% between March 9 and April 22, 2020, and more than 90% of the change was due to increasing age-specific case-fatality rates. The importance of the age-structure of confirmed cases likely reflects several factors, including different testing regimes and differences in transmission trajectories; while increasing age-specific case-fatality rates in Italy could indicate other factors, such as the worsening health outcomes of those infected with COVID-19. Our findings lend support to recommendations for data to be disaggregated by age, and potentially other variables, to facilitate a better understanding of population-level differences in CFRs. They also show the need for well designed seroprevalence studies to ascertain the extent to which differences in testing regimes drive differences in the age-structure of detected cases.
Bioinformatics analysis and collection of protein post-translational modification sites in human viruses
Authors: Xiang Yujia , Zou Quan , Zhao Lilin
Published: April 2020

In viruses, post-translational modifications (PTMs) are essential for their life cycle. Recognizing viral PTMs is very important for better understanding the mechanism of viral infections and finding potential drug targets. However, few studies have investigated the roles of viral PTMs in virus-human interactions using comprehensive viral PTM datasets. To fill this gap, firstly, we developed a viral post-translational modification database (VPTMdb) for collecting systematic information of viral PTM data. The VPTMdb contains 912 PTM sites that integrate 414 experimental-confirmed PTM sites with 98 proteins in 45 human viruses manually extracted from 162 publications and 498 PTMs extracted from UniProtKB/Swiss-Prot. Secondly, we investigated the viral PTM sequence motifs, the function of target human proteins, and characteristics of PTM protein domains. The results showed that (i) viral PTMs have the consensus motifs with human proteins in phosphorylation, SUMOylation and N-glycosylation. (ii) The function of human proteins that targeted by viral PTM proteins are related to protein targeting, translation, and localization. (iii) Viral PTMs are more likely to be enriched in protein domains. The findings should make an important contribution to the field of virus-human interaction. Moreover, we created a novel sequence-based classifier named VPTMpre to help users predict viral protein phosphorylation sites. Finally, an online web server was implemented for users to download viral protein PTM data and predict phosphorylation sites of interest.

Author summary

Post-translational modifications (PTMs) plays an important role in the regulation of viral proteins; However, due to the limitation of data sets, there has been no detailed investigation of viral protein PTMs characteristics. In this manuscript, we collected experimentally verified viral protein post-translational modification sites and analysed viral PTMs data from a bioinformatics perspective. Besides, we constructed a novel feature-based machine learning model for predicting phosphorylation site. This is the first study to explore the roles of viral protein modification in virus infection using computational methods. The valuable viral protein PTM data resource will provide new insights into virus-host interaction.
Characterizing sensitivity and coverage of clinical WGS as a diagnostic test for genetic disorders
Authors: Sun Yan , Liu Fengxia , Fan Chunna , Wang Yaoshen , Song Lijie , Fang Zhonghai , Han Rui , Wang Zhonghua , Wang Xiaodan , Yang Ziying , Xu Zhenpeng , Peng Jiguang , Shi Chaonan , Zhang Hongyun , Dong Wei , Huang Hui , Li Yun , Le Yanqun , Sun Jun , Peng Zhiyu
Published: April 2020

Background

With the reduce of cost and incomparable advantages, WGS is likely to change the way of clinical diagnosis of rare and undiagnosed diseases. However, the sensitivity and breadth of coverage of clinical WGS as a diagnostic test for genetic disorders has not been fully evaluated, especially for CNV detection.

Methods

All the samples underwent WGS using MGISEQ-2000. The performance of NA12878, YH cell line, and the Chinese trios were measured for sensitivity, PPV, depth and breadth of coverage. We also compared the performance of WES and WGS using NA12878. The sensitivity and PPV were tested using family-based trio design in the Chinese trios. We also developed a systematic WGS pipeline for the analysis of 8 clinical cases with known disease-causing variants.

Results

In general, the sensitivity and PPV for SNV/indel detection increased with mean depth, and reached a plateau at a ~40X mean depth using down-sampling samples of NA12878. With a mean depth of 40X, the sensitivity of homozyous and heterozygous SNPs of NA12878 was >99.25% and >99.50% respectively, and PPVs were 99.97% and 98.96%. Homozygous and heterozygous indels showed lower sensitivity and PPV. The sensitivity and PPV is still not 100% even with a mean depth of ~150X. We also observed a substantial variation in the sensitivity of CNV detection across different tools, especially in CNVs with a size of less than 1kb. In general, the breadth of coverage for disease-associated genes and CNVs increased with mean depth. The sensitivity and coverage of WGS (~40X) is better than WES (~120X). Among the Chinese trios with ~40X mean depth, the sensitivity in the offspring was >99.48% and >96.36% for SNP and indel detection, and PPVs were 99.86% and 97.93%. All the 12 previously validated variants in the 8 clinical cases were successfully detected by our WGS pipeline.

Conclusions

The current standard of a mean depth of 40X may be sufficient for SNV/indel detection and identification of most CNVs. Clinical scientists should know the range of sensitivity and PPV for different classes of variants for a particular WGS pipeline, which would be useful when interpreting and delivering clinical reports.
Cellular senescence and quiescence are associated with altered ribosomal RNA methylation and processing
Authors: Yang Guohuan , Heisenberger Clemens , Kos-Braun Isabelle C. , Polacek Norbert , Grillari Johannes , Schosserer Markus , Koš Martin
Published: April 2020

The 2’-O-methylation (2’-O-Me) of ribosomal RNA (rRNA) shows plasticity potentially associated with specific cell phenotypes. We used RiboMeth-seq profiling to reveal 2’-O-Me patterns specific to stress induced premature senescent (SIPS), quiescent and proliferating human dermal fibroblasts. The altered methylation levels in SIPS and quiescence partially correlated with the expression of specific snoRNAs but not fibrillarin. Senescence and quiescence were accompanied by a trend towards preferred usage of one of the two alternative ribosome biogenesis pathways.
Resources for genome editing in livestock: Cas9-expressing chickens and pigs
Authors: Bartsch Denise , Sid Hicham , Rieblinger Beate , Hellmich Romina , Schlickenrieder Antonina , Lengyel Kamila , Flisikowski Krzysztof , Flisikowska Tatiana , Simm Nina , Grodziecki Alessandro , Perleberg Carolin , Kupatt Christian , Wolf Eckhard , Kessler Barbara , Kettler Lutz , Luksch Harald , Hagag Ibrahim T. , Wise Daniel , Kaufman Jim , Kaufer Benedikt B. , Schnieke Angelika , Schusser Benjamin
Published: April 2020

Genetically modified animals continue to provide important insights in biomedical sciences. Research has focused mostly on genetically modified mice so far, but other species like pigs resemble more closely the human physiology. In addition, cross-species comparisons with phylogenetically distant species such as chickens provide powerful insights into fundamental biological and biomedical processes. One of the most versatile genetic methods applicable across species is CRISPR/Cas9. Here, we report for the first time the generation of Cas9 transgenic chickens and pigs that allowin vivogenome editing in these two important agricultural species. We demonstrated that Cas9 is constitutively expressed in all organs of both species and that the animals are healthy and fertile. In addition, we confirmed the functionality of Cas9 for a number of different target genes and for a variety of cell types. Taken together, these transgenic animal species expressing Cas9 provide an unprecedented tool for agricultural and biomedical research, and will facilitate organ specific reverse genetics as well as cross-species comparisons.

Significance statement

Genome engineering of animals is crucial for translational medicine and the study of genetic traits. Here, we generated transgenic chickens and pigs that ubiquitously express the Cas9 endonuclease, providing the basis forin vivogenome editing. We demonstrated the functionality of this system by successful genome editing in chicken and porcine cells and tissues. These animals facilitate organ specificin vivogenome editing in both species without laborious germ line modifications, which will reduce the number of animals needed for genetic studies. They also provide a new tool for functional genomics, developmental biology and numerous other applications in biomedical and agricultural science.
Large domains of heterochromatin direct the formation of short mitotic chromosome loops
Authors: Fitz-James Maximilian H. , Tong Pin , Pidoux Alison L. , Ozadam Hakan , Yang Liyan , White Sharon A. , Dekker Job , Allshire Robin C.
Published: April 2020

During mitosis chromosomes reorganise into highly compact, rod-shaped forms, thought to consist of consecutive chromatin loops around a central protein scaffold. Condensin complexes are involved in chromatin compaction, but the contribution of other chromatin proteins, DNA sequence and histone modifications is less understood. A large region of fission yeast DNA inserted into a mouse chromosome was previously observed to adopt a mitotic organisation distinct from that of surrounding mouse DNA. Here we show that a similar distinct structure is common to a large subset of insertion events in both mouse and human cells and is coincident with the presence of high levels of heterochromatic H3 lysine 9 trimethylation (H3K9me3). Hi-C and microscopy indicate that the heterochromatinised fission yeast DNA is organised into smaller chromatin loops than flanking euchromatic mouse chromatin. We conclude that heterochromatin alters chromatin loop size, thus contributing to the distinct appearance of heterochromatin on mitotic chromosomes, such as at centromeres.
Fast protein database as a service with kAAmer
Authors: Déraspe Maxime , Boisvert Sébastien , Laviolette François , Roy Paul H , Corbeil Jacques
Published: April 2020

Identification of proteins is one of the most computationally intensive steps in genomics studies. It usually relies on aligners that don’t accommodate rich information on proteins and require additional pipelining steps for protein identification. We introduce kAAmer, a protein database engine based on amino-acid k-mers, that supports fast identification of proteins with complementary annotations. Moreover, the databases can be hosted and queried remotely.
Mapping shifts in nanopore signal to changes in protein and protein-DNA conformation
Authors: Carlsen A. T. , Tabard Cossa V.
Published: April 2020

Solid-state nanopores have been used extensively in biomolecular studies involving DNA and proteins. However, the interpretation of signals generated by the translocation of proteins or protein-DNA complexes remains challenging. Here, we investigate the behavior of monovalent streptavidin and the complex it forms with short biotinylated DNA over a range of nanopore sizes, salts and voltages. We describe a simple geometric model that is broadly applicable and employ it to explain observed variations in conductance blockage and dwell time with experimental conditions. The general approach developed here underscores the value of nanopore-based protein analysis and represents progress toward the interpretation of complex translocation signals.

STATEMENT OF SIGNIFICANCE

Nanopore sensing allows investigation of biomolecular structure in aqueous solution, including electricfield-induced changes in protein conformation. This nanopore-based study probes: (1) the tetramerdimer transition of streptavidin, observing the effects of increasing voltage with varying salt type and concentration; (2) the possible conformational states of DNA-streptavidin complexes when confined inside a pore. We describe a broadly applicable geometric approach that maps stepwise changes in the nanopore signal to real-time conformational transitions. These results represent progress toward accurate interpretation of nanopore signals generated by molecular complexes.
Evolution-based design of chorismate mutase enzymes
Authors: Russ William P. , Figliuzzi Matteo , Stocker Christian , Barrat-Charlaix Pierre , Socolich Michael , Kast Peter , Hilvert Donald , Monasson Remi , Cocco Simona , Weigt Martin , Ranganathan Rama
Published: April 2020

The rational design of enzymes is an important goal for both fundamental and practical reasons. Here, we describe a design process in which we learn the constraints for specifying proteins purely from evolutionary sequence data, build libraries of synthetic genes, and test them for activityin vivousing a quantitative complementation assay. For chorismate mutase, a key enzyme in the biosynthesis of aromatic amino acids, we demonstrate the design of natural-like catalytic function with substantial sequence diversity. Further optimization focuses the generative model towards function in a specific genomic context. The data show that sequence-based statistical models suffice to specify proteins and provide access to an enormous space of synthetic functional sequences. This result provides a foundation for a general process for evolution-based design of artificial proteins.

One-sentence summary

An evolution-based, data-driven engineering process can build synthetic functional enzymes.
Cross-talk between individual phenol soluble modulins inS. aureusbiofilm formation
Authors: Zaman Masihuz , Andreasen Maria
Published: April 2020

The infective ability of the opportunistic pathogenStaphylococcus aureusis associated with biofilm mediated resistance to host immune response and even disinfectants and indeedS. aureusis recognized as the most frequent cause of biofilm associated infections. Phenol-soluble modulin (PSM) peptides serve various roles in pathogenicity while also comprising the structural scaffold ofS. aureusbiofilms through self-assembly into functional amyloids, but the role of the individual PSMs during biofilm formation remains poorly understood and the molecular pathways of PSM self-assembly have proved challenging to identify. Here, we show a high degree of cooperation between individual PSMs during the formation of functional amyloids in biofilm formation. The fast aggregating PSMα3 initiates the aggregation by forming unstable aggregates capable of seeding the formation of aggregates by other PSM peptides into the formation of stable amyloid structures. Using chemical kinetics along with spectroscopic techniques we dissect the molecular mechanism of aggregation of the individual peptides to show that PSMα1, PSMα3 and PSMβ1 display secondary nucleation whereas βPSM2 aggregates through primary nucleation and elongation. Our findings suggest that the various PSMs have evolved to ensure fast and efficient biofilm formation through cooperation between individual peptides.
Ecology and molecular targets of hypermutation in the global microbiome
Authors: Roux Simon , Paul Blair G. , Bagby Sarah C. , Allen Michelle A. , Attwood Graeme , Cavicchioli Ricardo , Chistoserdova Ludmila , Hallam Steven J. , Hernandez Maria E. , Hess Matthias , Liu Wen-Tso , O’Malley Michelle A. , Peng Xuefeng , Rich Virginia I. , Saleska Scott , Eloe-Fadrosh Emiley A.
Published: April 2020

Changes in the sequence of an organism’s genome, i.e. mutations, are the raw material of evolution1. The frequency and location of mutations can be constrained by specific molecular mechanisms, such as Diversity-generating retroelements (DGRs)2–4. DGRs introduce mutations in specific target genes, and were characterized from several cultivated bacteria and bacteriophages2. Whilst a larger diversity of DGR loci has been identified in genomic data from environmental samples, i.e. metagenomes, the ecological role of these DGRs and their associated evolutionary drivers remain poorly understood5–7. Here we built and analyzed an extensive dataset of >30,000 metagenome-derived DGRs, and determine that DGRs have a single evolutionary origin and a universal bias towards adenine mutations. We further identified six major lineages of DGRs, each associated with a specific ecological niche defined as a genome type, i.e. whether the DGR is encoded on a viral or cellular genome, a limited set of taxa and environments, and a distinct type of target. Finally, we leverage read mapping and metagenomic time series to demonstrate that DGRs are consistently and broadly active, and responsible for >10% of all amino acid changes in some organisms at a conservative estimate. Overall, these results highlight the strong constraints under which DGRs diversify and expand, and elucidate several distinct roles these elements play in natural communities and in shaping microbial community structure and function in our environment.
Transcriptome Analysis in Yeast Reveals the Externality of Position Effect
Authors: Gui Qian , Deng Shuyun , Shi Wenjun , Cai Xiujuan , Zhou Zhen-Zhen , Yang Jian-Rong , Chen Xiaoshu
Published: April 2020

When a gene is integrated into the chromosome, its activity depends on the genomic context. Although this phenomenon of “position effect” was widely reported, how the integration event affects the local environment, or the “externality” of position effect, remained largely unexplored, let alone the mechanism or phenotypic consequence of such externality. Here, we examined the transcriptome profiles of ∼250Saccharomyces cerevisiaestrains, each withGFPinserted into a different locus of the wild-type strain. We found that the GFP expression level and the change of expression of genes near the integration site decreases in genomic regions with high density of essential genes. This observation was found associated with H3K4me2 by further joint-analysis with public genome-wide histone modification profiles. More importantly, we found that the expression changes of neighboring genes, but not the GFP expression, exerted a significant impact on cellular growth rate. As a result, genomic loci that grant higher GFP expression immediately after the integration will have lower total yield of GFP in the long run. Our results, which were consistent with the competition for transcriptional resources among neighboring genes, revealed a previously unappreciated facet of the position effect, and highlighted its impact on the fate of genomic integration of exogenous genes, which has profound implications for biological engineering and pathology of virus integrative to host genome.
Systematic Chromatin Architecture Analysis inXenopus tropicalisReveals Conserved Three-Dimensional Folding Principles of Vertebrate Genomes
Authors: Niu Longjian , Shen Wei , Shi Zhaoying , He Na , Wan Jing , Sun Jialei , Zhang Yuedong , Huang Yingzhang , Wang Wenjing , Fang Chao , Li Jiashuo , Zheng Piaopiao , Cheung Edwin , Chen Yonglong , Li Li , Hou Chunhui
Published: April 2020

Metazoan genomes are folded into 3D structures in interphase nuclei. However, the molecular mechanism remains unknown. Here, we show that topologically associating domains (TADs) form in two waves duringXenopus tropicalisembryogenesis, first at zygotic genome activation and then as the expression of CTCF and Rad21 is elevated. We also found TAD structures continually change for at least three times during development. Surprisingly, the directionality index is preferentially stronger on one side of TADs where orientation-biased CTCF and Rad21 binding are observed, a conserved pattern that is found in human cells as well. Depletion analysis revealed CTCF, Rad21, and RPB1, a component of RNAPII, are required for the establishment of TADs. Overall, our work shows thatXenopusis a powerful model for chromosome architecture analysis. Furthermore, our findings indicate that cohesin-mediated extrusion may anchor at orientation-biased CTCF binding sites, supporting a CTCF-anchored extrusion model as the mechanism for TAD establishment.
Glycan analysis of human neutrophil granules implicates a maturation-dependent glycosylation machinery
Authors: Venkatakrishnan Vignesh , Dieckmann Regis , Loke Ian , Tjondro Harry , Chatterjee Sayantani , Bylund Johan , Thaysen-Andersen Morten , Karlsson Niclas G. , Karlsson-Bengtsson Anna
Published: April 2020

Protein glycosylation is essential to trafficking and immune functions of human neutrophils. During granulopoeisis in the bone marrow, distinct neutrophil granules are successively formed. Distinct receptors and effector proteins, many of which are glycosylated, are targeted to each type of granule according to their time of expression, a process called ‘targeting-by-timing’. Therefore, these granules are time capsules reflecting different times of maturation that can be used to understand how glycosylation evolves during granulopoiesis. Herein, neutrophil subcellular granules were fractionated by Percoll density gradient centrifugation andN- andO-glycans present in each compartment were analyzed by liquid chromatography and tandem mass spectrometry. We found abundant paucimannosidicN-glycans and lack ofO-glycans in early-formed azurophil granules (AG), whereas later-formed specific and gelatinase granules (SG and GG) contained complexN- andO-glycans with remarkably elongatedN-acetyllactosamine repeats with Lewis-x and sialyl-Lewis-x epitopes. Many glycans identified are unique to neutrophils and their complexity increased progressively from AG to SG and then to GG, suggesting temporal changes in the glycosylation machinery indicative of ‘glycosylation-by-timing’ during granulopoiesis. In summary, this comprehensive neutrophil granule glycome map, the first of its kind, highlights novel granule-specific glycosylation features and is a crucial first step towards a better understanding of the mechanisms regulating protein glycosylation during neutrophil granulopoiesis and a more detailed understanding of neutrophil biology and function.
Geometric realizations of abstract regular polyhedra with automorphism group H
3
Authors: Aranas Jonn Angel L. , Loyola Mark L.
Published: April 2020

A geometric realization of an abstract polyhedron {\cal P} is a mapping that sends an i-face to an open set of dimension i. This work adapts a method based on Wythoff construction to generate a full rank realization of an abstract regular polyhedron from its automorphism group Γ. The method entails finding a real orthogonal representation of Γ of degree 3 and applying its image to suitably chosen (not necessarily connected) open sets in space. To demonstrate the use of the method, it is applied to the abstract polyhedra whose automorphism groups are isomorphic to the non-crystallographic Coxeter group H
3.
The mediating role of human capital and management accounting information system in the relationship between innovation strategy and internal process performance and the impact on corporate financial performance
Authors: Hutahayan Benny
Published: April 2020

Purpose

Analyze the importance of sustainable innovation strategy applied in manufacturing companies in Indonesia which affects the company's financial performance through several mediating variables.

Design/methodology/approach

The population in this research was medium and large manufacturing company business units in East Java. Business units are part of a company considered as the profit center. The business unit as the unit of analysis in this research is part of the organization that: (1) is responsible for the production and marketing of a product or set of products; (2) is formed by product type; (3) has its own competitors which are different from competitors of other business units or divisions within a parent company; (4) has a manager who is responsible and has authority over the planning and implementation of strategies to achieve the specified profit target.

Findings

Innovation strategy has a significant effect on financial performance. Human capital does not significantly mediate the relationship between innovation strategy and financial performance. Capital performance and internal performance do not mediate the relationship between innovation strategy and financial performance. Management accounting information system does not mediate the relationship between innovation strategy and financial performance. Internal process performance mediates the relationship between innovation strategy and financial performance. Management accounting information system and internal process performance mediate the relationship between innovation strategy and financial performance.

Originality/value

The difference in findings confirms that this research needs to be conducted. On the other hand, there is no research that has comprehensively tested the mediating effects of Human Capital and Management Accounting Information System in the relationship between Innovation Strategy and Internal Process Performance and the Impact on Corporate Financial Performance. The originality of this research can be seen in the use of contingency theory which narrows the gap between the industrial organization (I/O) paradigm and the resource-based view (RBV) regarding competitive advantage and performance. Specifically, this research introduces innovation strategy, human capital, management accounting information system, and internal business process performance as the contingency factors that affect financial performance. Second, empirically, this research tries to reduce the gap in empirical research by offering new research model and new research establishment at the level of strategic business units (SBU) in manufacturing companies in East Java. This research is expected to be useful for policy decision making, especially for managers who want to improve strategic business unit's financial performance.
Green human resource management and corporate social responsibility
Authors: Freitas Wesley Ricardo de Souza , Caldeira-Oliveira Jorge Henrique , Teixeira Adriano Alves , Stefanelli Nelson Oliveira , Teixeira Talita Borges
Published: April 2020

Purpose

In the past, simply fulfilling economic performance alone was critical to ensuring the success of companies and their shareholders, but this traditional perspective is not compatible with society's current demands, as there is increasing social pressure on organizations to become more sustainable and reduce impacts on the environment, promoting sustainable results in their business processes. In this context, the specialized literature states that human resources management (HRM) is considered a central aspect for building sustainable organizations, in particular, the area of green human resources management (GHRM). Thus, this study analyzes the relationship between GHRM and corporate social responsibility (CSR) in Brazilian companies. Company's age, size, ISO 9001 and 14001 certifications are the control variables.

Design/methodology/approach

The authors adopted a quantitative approach in conducting the survey. Four waves of email were sent to HR and CSR managers from 853 Brazilian companies from the metallurgical, automotive and chemical industries. In total, 79 questionnaires were fully answered, higher than the minimum sample calculated by theG*Power 3.1 software, which corresponds to a return rate of 9.26%. For the analysis of the results, the partial least squares method was used.

Findings

This research identifies that GHRM practices, in fact, positively influence CSR practices. The findings evidence that practices of performance evaluation, teamwork and recruitment and selection are the most important for a better CSR performance. The research results indicate that the “ISO 9001 certification” control variable also has a positive and significant effect on CSR and that the size of the company, the age of the company and the ISO 14001 certification, in the analyzed sample, were not relevant (as control variables) for CSR.

Originality/value

Current literature highlights the gap between GHRM and CSR. This relationship is not explored in Brazil. The study uses a new theoretical model, and it fills the gap identified in the literature. This paper brings important theoretical and managerial contributions. It is the first in the literature to show, in an empirical way, the positive relationship between GHRM and CSR, contributing in an original way to the state of the art of the GHRM and CSR theme. In addition, this research adds empirical evidence on GHRM and CSR in Latin America/South America/Brazil.
HMSolution en búsqueda del “Product-Market fit”
Authors: Kuschel Katherina , Leiva Fernando
Published: April 2020

Learning outcomes

Pivotear, Producto Mínimo Viable, Alianzas estratégicas, ROE, Burn-rate

Case overview/synopsis

HMSolution tiene la misión de remover el arsénico del agua potable. El caso cuenta cómo HMS ha pivoteado su modelo de negocio durante 2014 y 2015 y, el desafío que presenta varias alternativas de crecimiento. La primera empresa propone adoptar su tecnología como alianza u outsourcing y la segunda empresa desea adquirir HMSolution. Sin embargo, Margaret, la fundadora, maneja una tercera opción con una importante empresa sanitaria de tratamiento de aguas servidas en Chile con presencia internacional, con la que podría alcanzar un territorio más amplio en su país de origen y otros países donde ese grupo está presente. El caso propone el dilema de Margaret para determinar el mejor curso a seguir y encontrar el mejor ajuste de su producto con las necesidades del mercado.

Complexity Academic Level

Nivel de pregrado y formación contínua en Curso de Emprendimiento y Curso de Administración y Estrategia.

Supplementary materials

Teaching Notes are available for educators only.

Subject code

CSS 3: Entrepreneurship.