bluuebunny/crossref_metadata_2025 huggingface dataset:
Using LASSO regression to estimate the population-level impact of pneumococcal conjugate vaccines
Authors: Wong Anabelle , Kramer Sarah C. , Piccininni Marco , Rohmann Jessica L. , Kurth Tobias , Escolano Sylvie , Grittner Ulrike , Domenech de Cellès Matthieu
Published: February 2022

The pneumococcal conjugate vaccines (PCVs) protect against diseases caused by Streptococcus pneumoniae, such as meningitis, bacteremia, and pneumonia. It is challenging to estimate their population-level impact due to the lack of a perfect control population and the subtleness of signals when the endpoint – like all-cause pneumonia – is non-specific. Here we present a new approach to estimate PCVs’ impact – using LASSO regression to predict the counterfactual outcome for vaccine impact inference. We first used a simulation study to test the performance of LASSO regression and established methods including the synthetic control (SC) approach. We found that LASSO achieved accurate and precise estimation, even in complex simulation scenarios where the association between outcome and all control variables was non-causal. We then applied LASSO to real-world data and found that it yielded estimates of vaccine impact similar to SC. The LASSO method is accurate, easily implementable, and can be applied to study the impact of PCVs and of other vaccines.
Nitric oxide negatively regulates gibberellin signaling to coordinate growth and salt tolerance in Arabidopsis
Authors: Chen Lichao , Sun Shuhao , Song Chun-Peng , Zhou Jian-Min , Li Jiayang , Zuo Jianru
Published: February 2022

In response to dynamically altered environments, plants must finely coordinate the balance between growth and stress responses for their survival. However, the underpinning regulatory mechanisms remain largely elusive. The phytohormone gibberellin promotes growth via a derepression mechanism by proteasomal degradation of the DELLA transcription repressors. Conversely, the stress-induced burst of nitric oxide (NO) enhances stress tolerance, largely relaying on NO-mediated S-nitrosylation, a redox-based posttranslational modification. Here, we show that S-nitrosylation of Cys-374 in the Arabidopsis RGA protein, a key member of DELLAs, inhibits its interaction with the F-box protein SLY1, thereby preventing its proteasomal degradation under salinity condition. The accumulation of RGA consequently retards growth but enhances salt tolerance. We propose that NO negatively regulates gibberellin signaling via S-nitrosylation of RGA to coordinate the balance of growth and stress responses when challenged by adverse environments.
Faster growth enhances low carbon fuel and chemical production through gas fermentation
Authors: de Lima Lorena Azevedo , Ingelman Henri , Brahmbhatt Kush , Reinmets Kristina , Barry Craig , Harris Audrey , Marcellin Esteban , Köpke Michael , Valgepea Kaspar
Published: February 2022

Gas fermentation offers both fossil carbon-free sustainable production of fuels and chemicals and recycling of gaseous and solid waste using gas-fermenting microbes. Bioprocess development, systems-level analysis of biocatalyst metabolism, and engineering of cell factories are advancing the widespread deployment of the commercialised technology. Acetogens are particularly attractive biocatalysts but effects of the key physiological parameter – specific growth rate (μ) – on acetogen metabolism and the gas fermentation bioprocess have not been established yet. Here, we investigate the μ-dependent bioprocess performance of the model-acetogenClostridium autoethanogenumin CO and syngas (CO+CO2+H2) grown chemostat cultures and assess systems-level metabolic responses using gas analysis, metabolomics, transcriptomics, and metabolic modelling. We were able to obtain steady-states up to μ ~2.8 day-1(~0.12 h-1) and show that faster growth supports both higher yields and productivities for reduced by-products ethanol and 2,3-butanediol. Transcriptomics data revealed differential expression of 1,337 genes with increasing μ and suggest thatC. autoethanogenumuses transcriptional regulation to a large extent for facilitating faster growth. Metabolic modelling showed significantly increased fluxes for faster growing cells that were, however, not accompanied by gene expression changes in key catabolic pathways for CO and H2metabolism. Cells thus seem to maintain sufficient “baseline” gene expression to rapidly respond to CO and H2availability without delays to kick-start metabolism. Our work advances understanding of transcriptional regulation in acetogens and shows that faster growth of the biocatalyst improves the gas fermentation bioprocess.
Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains
Authors: Demontis Ditte , Walters G. Bragi , Athanasiadis Georgios , Walters Raymond , Therrien Karen , Farajzadeh Leila , Voloudakis Georgios , Bendl Jaroslav , Zeng Biao , Zhang Wen , Grove Jakob , Als Thomas D. , Duan Jinjie , Satterstrom F. Kyle , Bybjerg-Grauholm Jonas , Bækved-Hansen Marie , Gudmundsson Olafur O. , Magnusson Sigurdur H. , Baldursson Gisli , Davidsdottir Katrin , Haraldsdottir Gyda S. , Nielsen Trine Tollerup , Agerbo Esben , Hoffman Gabriel E. , Dalsgaard Søren , Martin Joanna , Ribasés Marta , Boomsma Dorret I. , Artigas Maria Soler , Mota Nina Roth , Howrigan Daniel , Medland Sarah E. , Zayats Tetyana , Manikandan Veera ,   ADHD Working Group of the Psychiatric Genomics Consortium,   iPSYCH-Broad Consortium, Nordentoft Merete , Mors Ole , Hougaard David M. , Mortensen Preben Bo , Daly Mark J. , Faraone Stephen V. , Stefansson Hreinn , Roussos Panos , Franke Barbara , Werge Thomas , Neale Benjamin M. , Stefansson Kari , Børglum Anders D.
Published: February 2022

Attention deficit hyperactivity disorder (ADHD) is a prevalent childhood psychiatric disorder, with a major genetic component. Here we present a GWAS meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, which is more than twice the number previously reported. Fine-mapping risk loci highlighted 76 potential risk genes enriched in genes expressed in brain, particularly the frontal cortex, and in early brain development. Overall, ADHD was associated with several brain specific neuronal sub-types and especially midbrain dopaminergic neurons. In a subsample of 17,896 exome-sequenced individuals, we identified increased load of rare protein-truncating variants in cases for a set of risk genes enriched with likely causal common variants, suggesting implication of SORCS3 in ADHD by both common and rare variants. We found ADHD to be highly polygenic, with around seven thousand variants explaining 90% of the SNP heritability. Bivariate gaussian mixture modeling estimated that more than 90% of ADHD influencing variants are shared with other psychiatric disorders (autism, schizophrenia and depression) and phenotypes (e.g. educational attainment) when both concordant and discordant variants are considered. Additionally, we demonstrated that common variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions including attention.
COVID-19 mortality and excess mortality among working-age Californians, by occupational sector: March 2020 through November 2021
Authors: Chen Yea-Hung , Riley Alicia R , Duchowny Kate A , Aschmann Hélène E , Chen Ruijia , Kiang Mathew V , Mooney Alyssa , Stokes Andrew C , Glymour M Maria , Bibbins-Domingo Kirsten
Published: February 2022

Background

During the first year of the pandemic, essential workers faced higher rates of SARS-CoV-2 infection and COVID-19 mortality than non-essential workers. It is unknown whether disparities in pandemic-related mortality across occupational sectors have continued to occur, amidst SARS-CoV-2 variants and vaccine availability.

Methods

We obtained data on all deaths occurring in the state of California from 2016 through 2021. We restricted our analysis to California residents who were working age (18–65 years at time of death) and died of natural causes. Occupational sector was classified into 9 essential sectors; non-essential; or not in the labor market. We calculated the number of COVID-19 deaths in total and per capita that occurred in each occupational sector. Separately, using autoregressive integrated moving average models, we estimated total, per-capita, and relative excess natural-cause mortality by week between March 1, 2020, and November 30, 2021, stratifying by occupational sector. We additionally stratified analyses of occupational risk into regions with high versus low vaccine uptake, categorizing high-uptake regions as counties where at least 50% of the population completed a vaccination series by August 1, 2021.

Findings

From March 2020 through November 2021, essential work was associated with higher COVID-19 and excess mortality compared with non-essential work, with the highest per-capita COVID-19 mortality in agriculture (131.8 per 100,000), transportation/logistics (107.1), manufacturing (103.3), and facilities (101.1). Essential workers continued to face higher COVID-19 and excess mortality during the period of widely available vaccines (March through November 2021). Between July and November 2021, emergency workers experienced higher per-capita COVID-19 mortality (113.7) than workers from any other sector. Essential workers faced the highest COVID-19 mortality in counties with low vaccination rates, a difference that was more pronounced during the period of the Delta surge in Summer 2021.

Interpretation

Essential workers have continued to bear the brunt of high COVID-19 and excess mortality throughout the pandemic, particularly in the agriculture, emergency, manufacturing, facilities, and transportation/logistics sectors. This high death toll has continued during periods of vaccine availability and the delta surge. In an ongoing pandemic without widespread vaccine coverage and anticipated threats of new variants, the US must actively adopt policies to more adequately protect essential workers.
Contribution of deep soil layers to the transpiration of a temperate deciduous forest: quantification and implications for the modelling of productivity
Authors: Maysonnave Jean , Delpierre Nicolas , François Christophe , Jourdan Marion , Cornut Ivan , Bazot Stéphane , Vincent Gaёlle , Morfin Alexandre , Berveiller Daniel
Published: February 2022

Climate change is imposing drier atmospheric and edaphic conditions on temperate forests. Here, we investigated how deep soil (down to 300 cm) water extraction contributed to the provision of water in the Fontainebleau-Barbeau temperate oak forest over two years, including the 2018 record drought. Deep water provision was key to sustain canopy transpiration during drought, with layers below 150 cm contributing up to 60% of the transpired water in August 2018, despite their very low density of fine roots. We further showed that soil databases used to parameterize ecosystem models largely underestimated the amount of water extractable from the soil by trees, due to a considerable underestimation of the tree rooting depth. The consensus database established for France gave an estimate of 207 mm for the soil water holding capacity (SWHC) at Fontainebleau-Barbeau, when our estimate based on the analysis of soil water content measurements was 1.9 times as high, reaching 390±17 mm. Running the CASTANEA forest model with the database-derived SWHC yielded a 350 gC m−2 y−1 average underestimation of annual gross primary productivity under current climate, reaching up to 700 gC m−2 y−1 under climate change scenario RCP8.5. It is likely that the strong underestimation of SWHC that we show at our site is not a special case, and concerns a large number of forest sites. Thus, we argue for a generalisation of deep soil water content measurements in forests, in order to improve the estimation of SWHC and the simulation of the forest carbon cycle in the current context of climate change.

Highlights

Forest-atmosphere carbon exchanges remained insensitive to record drought.

Deep soil (150-300 cm) provisioned up to 60% of the water transpired by the forest during drought.

Soil databases were underestimating soil water holding capacity by a factor of two.

Simulated forest productivity is strongly sensitive to soil water holding capacity parameter.

Deep soil water content measurements are urgently needed to correctly estimate the soil water holding capacity.
Population based selection shapes the T cell receptor repertoire during thymic development
Authors: Camaglia Francesco , Ryvkin Arie , Greenstein Erez , Reich-Zeliger Shlomit , Chain Benny , Mora Thierry , Walczak Aleksandra M. , Friedman Nir
Published: February 2022

One of the feats of adaptive immunity is its ability to recognize foreign pathogens while sparing the self. During maturation in the thymus, T cells are selected through the binding properties of their antigen-specific T-cell receptor (TCR), through the elimination of both weakly (positive selection) and strongly (negative selection) self-reactive receptors. However, the impact of thymic selection on the TCR repertoire is poorly understood. Here, we use transgenic Nur77-mice expressing a T-cell activation reporter to study the repertoires of thymic T cells at various stages of their development, including cells that do not pass selection. We combine high-throughput repertoire sequencing with statistical inference techniques to charactarize the selection of the TCR in these distinct subsets. We find small but significant differences in the TCR repertoire parameters between the maturation stages, which recapitulate known differentiation pathways leading to the CD4+ and CD8+ subtypes. These differences can be simulated by simple models of selection acting linearly on the sequence features. We find no evidence of specific sequences or sequence motifs or features that are suppressed by negative selection. These results are consistent with a collective or statistical model for T-cell specificity, where negative selection biases the repertoire away from self recognition, rather than ensuring lack of self-reactivity at the single-cell level.
Sequentially-reduced representation of artificial neural network to determine cardiovascular intrinsic frequencies
Authors: Alavi Rashid , Wang Qian , Gorji Hossein , Pahlevan Niema M.
Published: February 2022

Analysis of cardiovascular waveforms provides valuable clinical information about the state of health and disease. The intrinsic frequency (IF) method is a recently introduced framework that uses a single arterial pressure waveform to extract physiologically relevant information about the cardiovascular system. The clinical usefulness and physiological accuracy of the IF method have been well-established via several preclinical and clinical studies. However, the computational complexity of the current L2 optimization solver for IF calculations remains a bottleneck for practical deployment of the IF method in real-time settings. In this paper, we propose a machine learning (ML)-based methodology for determination of IF parameters from a single carotid waveform. We use a sequentially-reduced Feedforward Neural Network (FNN) model for mapping carotid waveforms to the output parameters of the IF method, thereby avoiding the non-convex L2 minimization problem arising from the conventional IF approach. Our methodology also includes procedures for data pre-processing, model training, and model evaluation. In our model development, we used both clinical and synthetic waveforms. Our clinical database is composed of carotid waveforms from two different sources: the Huntington Medical Research Institutes (HMRI) iPhone Heart Study and the Framingham Heart Study (FHS). In the HMRI and FHS clinical studies, various device platforms such as piezoelectric tonometry, optical tonometry (Vivio), and an iPhone camera were used to measure arterial waveforms. Our blind clinical test shows very strong correlations between IF parameters computed from the FNN-based method and those computed from the standard L2 optimization-based method (i.e., R≥0.93 and P-value ≤0.005 for each IF parameter). Our results also demonstrate that the performance of the FNN-based IF model introduced in this work is independent of measurement apparatus and of device sampling rate.
BinSPreader: refine binning results for fuller MAG reconstruction
Authors: Tolstoganov Ivan , Kamenev Yuri , Kruglikov Roman , Ochkalova Sofia , Korobeynikov Anton
Published: February 2022

Despite the recent advances in high-throughput sequencing, analysis of the metagenome of the whole microbial population still remains a challenge. In particular, the metagenome-assembled genomes (MAGs) are often fragmented due to interspecies repeats, uneven coverage and vastly different strain abundance. MAGs are usually constructed via a dedicated binning process that uses different features of input data in order to cluster contigs that might belong to the same species. This process has some limitations and therefore binners usually discard input contigs that are shorter than several kilobases. Therefore, binning of even simple metagenome assemblies can miss a decent fraction of contigs and resulting MAGs oftentimes do not contain important conservative sequences that might be of great interest of researcher.

In this work we present BinSPreader — a novel binning refiner tool that exploits the assembly graph topology and other connectivity information to refine the existing binning, correct binning errors, propagate binning from longer contigs to shorter contigs and infer contigs belonging to multiple bins. Furthermore, BinSPreader can split input reads in accordance with the resulting binning, predicting reads potentially belonging to multiple MAGs. We show that BinSPreader could effectively complete the binning, increasing the completeness of the bins without sacrificing the purity and could predict contigs belonging to several MAGs.
Modeling of protein conformational changes with Rosetta guided by limited experimental data
Authors: Sala Davide , del Alamo Diego , Mchaourab Hassane S. , Meiler Jens
Published: February 2022

Conformational changes are an essential component of functional cycles of many proteins such as transporters or receptors. Despite their importance, the characterization of functionally-relevant structural intermediates is often a hard task for both experimental and computational methods. This limitation can be at least partially relieved by integrating experimental data within computational approaches. Such integrative structural biology strategies can yield an ensemble of models consistent with experimental data. While the macromolecular modeling suite Rosetta has been extensively used to predict protein structures de novo using various types of experimental data, an all-purpose conformational change modeling approach has been absent from this suite. Here, we introduce and benchmark ConfChangeMover (CCM), a new Rosetta Mover tailored to model conformational changes in proteins using sparse experimental data. CCM is able to rotate and translate secondary structural elements and modify their backbone dihedral angles in regions of interest. We benchmarked CCM on soluble and membrane proteins with sparse experimental double electron-electron resonance (DEER) restraints and simulated Cα - Cα distance restraints, respectively. In both benchmarks, CCM outperformed state-of-the-art Rosetta methods, showing that it can model a diverse array of conformational changes. In addition, the Rosetta framework allows a wide variety of experimental data to be integrated with CCM, thus extending its capability beyond DEER restraints. Thus, our method will contribute to the biophysical characterization of protein dynamics.
Microbiota-derived aspartate drives pathogenic Enterobacteriaceae expansion in the inflamed gut
Authors: Yoo Woongjae , Zieba Jacob K. , Shealy Nicolas G. , Torres Teresa P. , Thomas Julia D. , Shelton Catherine D. , Foegeding Nora J. , Olsan Erin E. , Byndloss Mariana X.
Published: February 2022

Inflammation boosts the availability of electron acceptors in the intestinal lumen creating a favorable niche for pathogenic Enterobacteriaceae. However, the mechanisms linking intestinal inflammation-mediated changes in luminal metabolites and pathogen expansion remain unclear. Here, we show that mucosal inflammation induced by Salmonella enterica serovar Typhimurium (S. Tm) infection and chemical colitis results in increased intestinal levels of the amino acid aspartate. The S. Tm and E. coli genomes encode an aspartate ammonia-lyase (aspA) which converts aspartate into fumarate, an alternative electron acceptor. S. Tm and pathogenic E. coli used aspA-dependent fumarate respiration for growth in the murine gut only during inflammation. Such growth advantage was abolished in the gut of germ-free mice. However, mono-association of gnotobiotic mice with members of the classes Bacteroidia and Clostridia restored the benefit of aspartate utilization to the pathogens. Our findings demonstrate the role of microbiota-derived amino acids in driving respiration-dependent Enterobacteriaceae expansion during colitis.
In pursuit of the epileptogenic zone in focal epilepsy: A dynamical network biomarker approach
Authors: Runfola Claudio , Sheheitli Hiba , Bartolomei Fabrice , Wang Huifang , Jirsa Viktor
Published: February 2022

The success of resective surgery for drug-resistant epilepsy patients hinges on the correct identification of the epileptogenic zone (EZ) consisting of the subnetwork of brain regions that underlies seizure genesis in focal epilepsy. The dynamic network biomarker (DNB) method is a dynamical systems-based network analysis approach for identifying subnetworks that are the first to exhibit the transition as a complex system undergoes a bifurcation. The approach was devised and validated in the context of complex disease onset where the dynamics is known to be nonlinear and high-dimensional. We here adapt and implement the DNB approach for the identification of the EZ from the analysis of SEEG data. The method is first successfully tested on simulated data generated with a large-scale brain network model of epilepsy using The Virtual Brain neuroinformatic platform and then applied to clinical SEEG data from focal epilepsy patients. The results are compared with those obtained by expert clinicians that designate the EZ using the Epileptogenicity Index (EI) method. High average precision values are obtained and posit the presented approach as a promising candidate tool for the pursuit of EZ in focal epilepsy.

Author Summary

We present a novel SEEG signal analysis tool for the identification of EZ regions in patients with drug-resistant focal epilepsy. The proposed method adapts and implements the dynamic network biomarker approach which builds on dynamical systems theory for complex networked systems. The method is first successfully tested on synthetic seizure data generated with The Virtual Brain modeling framework and then applied to retrospective patients’ clinical SEEG data. High precision values are obtained when the DNB subnetwork is compared with that designated as EZ by expert clinicians using empirical signal analysis measures and indicate that the DNB approach is a promising tool for the identification of EZ regions through SEEG signal analysis.
Neutralization of SARS-CoV-2 Omicron BA.2 by Therapeutic Monoclonal Antibodies
Authors: Zhou Hao , Tada Takuya , Dcosta Belinda M. , Landau Nathaniel R.
Published: February 2022

Monoclonal antibody therapy for the treatment of SARS-CoV-2 infection has been highly successful in decreasing disease severity; however, the recent emergence of the heavily mutated Omicron variant has posed a challenge to this treatment strategy. The Omicron variant BA.1 has been found to evade neutralization by several of the therapeutic monoclonal antibodies authorized for emergency use, while Vir-7831 and a cocktail consisting of monoclonal antibodies AZD8895+AZD1061 retain significant neutralizing activity. A newly emerged variant, Omicron BA.2, containing some of the BA.1 mutations plus an additional 6 mutations and 3 deletions, 3 of which lie in the receptor binding domain, has been found to be spreading with increased transmissibility. We report here, using spike protein-pseudotyped lentiviruses, decreased neutralization of BA.2 by several therapeutic monoclonal antibodies but that the mixture of AZD8895+AZD1061 retained substantial neutralizing activity against BA.2.
Non-productive exposure of PBMCs to SARS-CoV-2 induces cell-intrinsic innate immunity responses
Authors: Kazmierski Julia , Friedmann Kirstin , Postmus Dylan , Fischer Cornelius , Jansen Jenny , Richter Anja , de Jarcy Laure Bosquillon , Schüler Christiane , Sohn Madlen , Sauer Sascha , Drosten Christian , Saliba Antoine-Emmanuel , Sander Leif Erik , Niemeyer Daniela , Goffinet Christine
Published: February 2022

Cell-intrinsic responses mounted in vivo in PBMCs during mild and severe COVID-19 differ quantitatively and qualitatively. Whether they are triggered by signals emitted by productively infected cells of the respiratory tract or are, at least partially, resulting from physical interaction with virus particles, remains unclear. Here, we analyzed susceptibility and expression profiles of PBMCs from healthy donors upon ex vivo exposure to SARS-CoV and SARS-CoV-2. In line with the absence of detectable ACE2 receptor expression, human PBMCs were refractory to productive infection. Bulk and single cell RNA-sequencing revealed JAK/STAT-dependent induction of interferon-stimulated genes, but not pro-inflammatory cytokines. This SARS-CoV-2-specific response was most pronounced in monocytes. SARS-CoV-2-RNA-positive monocytes displayed a lower ISG signature as compared to bystander cells of the identical culture. This suggests a preferential invasion of cells with a low ISG base-line profile or delivery of a SARS-CoV-2-specific sensing antagonist upon efficient particle internalization. Together, non-productive physical interaction of PBMCs with SARS-CoV-2-but not SARS-CoV particles stimulates JAK/STAT-dependent, monocyte-accentuated innate immune responses that resemble those detected in vivo in patients with mild COVID-19.
Reduced antigenicity of Omicron lowers host serologic response
Authors: Tubiana Jérôme , Xiang Yufei , Fan Li , Wolfson Haim J. , Chen Kong , Schneidman-Duhovny Dina , Shi Yi
Published: February 2022

SARS-CoV-2 Omicron variant of concern (VOC) contains fifteen mutations on the receptor binding domain (RBD), evading most neutralizing antibodies from vaccinated sera. Emerging evidence suggests that Omicron breakthrough cases are associated with substantially lower antibody titers than other VOC cases. However, the mechanism remains unclear. Here, using a novel geometric deep-learning model, we discovered that the antigenic profile of Omicron RBD is distinct from the prior VOCs, featuring reduced antigenicity in its remodeled receptor binding sites (RBS). To substantiate our deep-learning prediction, we immunized mice with different recombinant RBD variants and found that the Omicron’s extensive mutations can lead to a drastically attenuated serologic response with limited neutralizing activity in vivo, while the T cell response remains potent. Analyses of serum cross-reactivity and competitive ELISA with epitope-specific nanobodies revealed that the antibody response to Omicron was reduced across RBD epitopes, including both the variable RBS and epitopes without any known VOC mutations. Moreover, computational modeling confirmed that the RBS is highly versatile with a capacity to further decrease antigenicity while retaining efficient receptor binding. Longitudinal analysis showed that this evolutionary trend of decrease in antigenicity was also found in hCoV229E, a common cold coronavirus that has been circulating in humans for decades. Thus, our study provided unprecedented insights into the reduced antibody titers associated with Omicron infection, revealed a possible trajectory of future viral evolution and may inform the vaccine development against future outbreaks.
Pushing the limits of HiFi assemblies reveals centromere diversity between twoArabidopsis thalianagenomes
Authors: Rabanal Fernando A. , Gräff Maike , Lanz Christa , Fritschi Katrin , Llaca Victor , Lang Michelle , Carbonell-Bejerano Pablo , Henderson Ian , Weigel Detlef
Published: February 2022

Although long-read sequencing can often enable chromosome-level reconstruction of genomes, it is still unclear how one can routinely obtain gapless assemblies. In the model plantArabidopsis thaliana, other than the reference accession Col-0, all other accessionsde novoassembled with long-reads until now have used PacBio continuous long reads (CLR). Although these assemblies sometimes achieved chromosome-arm level contigs, they inevitably broke near the centromeres, excluding megabases of DNA from analysis in pan-genome projects. Since PacBio high-fidelity (HiFi) reads circumvent the high error rate of CLR technologies, albeit at the expense of read length, we compared a CLR assembly of accession Ey15-2 to HiFi assemblies of the same sample performed by five different assemblers starting from subsampled data sets, allowing us to evaluate the impact of coverage and read length. We found that centromeres and rDNA clusters are responsible for 71% of contig breaks in the CLR scaffolds, while relatively short stretches of GA/TC repeats are at the core of >85% of the unfilled gaps in our best HiFi assemblies. Since the HiFi technology consistently enabled us to reconstruct gapless centromeres and 5S rDNA clusters, we demonstrate the value of the approach by comparing these previously inaccessible regions of the genome between twoA. thalianaaccessions.
Replication-associated inversions are the dominant form of bacterial chromosome structural variation
Authors: D’Iorio Matthew , Dewar Ken
Published: February 2022

Structural arrangement of a bacterial chromosome varies widely between closely related species and can result in significant phenotypic outcomes. The appearance of large-scale chromosomal inversions that are symmetric relative to the dnaA gene (usually linked to oriC, the origin of replication) has been previously observed; however, the overall prevalence of replication-associated structural rearrangements (RASRs) in bacteria and their causal mechanisms are currently unknown. The decreased cost of full-length genome sequencing has led to a rapidly growing collection of complete genomes spanning multiple different clades, therefore allowing an opportunity to examine chromosomal inversions in the context of species spanning diverse phylogenetic classifications. Here we systematically identify the locations of large, chromosomal inversions in species with multiple complete sequenced genomes using the Refseq and Genbank NCBI databases to investigate potential mediating biological mechanisms. Out of the 239 species available with 10 or more complete genomes, 206 contained sequences with at least one large (≥50Kb) inversion in their set of within-species sequence comparisons. We observed 73.4% of the 127,161 large inversions were centered at a point within 10% proportionate distance to the annotated dnaA gene, which is often nearby the origin of replication. Inversions offset from the annotated dnaA sequence were generally confirmed to be centered on the actual origin of replication. Equidistant breakpoints from the replication origin and prevalence of flanking repeats provide evidence that the breaks that are formed during the replication process are then repaired to opposing positions. We also found a strong relationship between the later stages of replication and the range in variation of distance from symmetry, suggesting that replication fork arrest may be a mechanistic cause for the asymmetry in some inversions.
Canonical Wnt signaling promotes formation of somatic permeability barrier for proper germ cell differentiation
Authors: Chen Ting-An , Lin Kun-Yang , Yang Shun-Min , Tseng Chen-Yuan , Wang Yu-Ting , Lin Chi-Hung , Luo Lichao , Cai Yu , Hsu Hwei-Jan
Published: February 2022

Morphogen-mediated signaling is critical for proper organ development and stem cell function, and well-characterized mechanisms spatiotemporally limit the expression of ligands, receptors, and ligand-binding cell-surface glypicans. Here, we show that in the developing Drosophila ovary, canonical Wnt signaling promotes the formation of somatic escort cells (ECs) and their protrusions, which establish a physical permeability barrier to define morphogen territories for proper germ cell differentiation. The protrusions shield germ cells from Dpp and Wingless morphogens produced by the germline stem cell (GSC) niche and normally only received by GSCs. Genetic disruption of EC protrusions allows GSC progeny to also receive Dpp and Wingless, which subsequently disrupt germ cell differentiation. Our results reveal a role for canonical Wnt signaling in specifying the ovarian somatic cells necessary for germ cell differentiation. Additionally, we demonstrate the morphogen-limiting function of this physical permeability barrier, which may be a common mechanism in other organs across species.
A new bioactive cocrystal of coumarin-3-carboxylic acid and thiourea: detailed structural features and biological activity studies
Authors: Shahbaz Muhammad , Khan Umair Ahmed , Chaudhary M. Iqbal , Yousuf Sammer
Published: February 2022

Cocrystallization is a phenomenon widely used to enhance the biological and physicochemical properties of active pharmaceutical ingredients (APIs). The present study deals with the synthesis of a cocrystal of coumarin-3-carboxylic acid (2-oxochromene-3-carboxylic acid, C10H6O4), a synthetic analogue of the naturally occurring antioxidant coumarin, with thiourea (CH4N2S) using the neat grinding method. The purity and homogeneity of the coumarin-3-carboxylic acid–thiourea (1/1) cocrystal was confirmed by single-crystal X-ray diffraction, FT–IR analysis and thermal stability studies based on differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Detailed geometry analysis via density functional theory (DFT) demonstrated that the 1:1 cocrystal stoichiometry is sustained by N—H...O hydrogen bonding between the amine (–NH2) groups of thiourea and the carbonyl group of coumarin. The synthesized cocrystal exhibited potent antioxidant activity (IC50 = 127.9 ± 5.95 µM) in a DPPH radical scavenger assay in vitro in comparison with the standard N-acetyl-L-cysteine (IC50 = 111.6 ± 2.4 µM). The promising results of the present study highlight the significance of cocrystallization as a crystal engineering tool to improve the efficacy of pharmaceutical ingredients.
Suggestions for takt production subcontract clauses – a conceptual study
Authors: Keskiniva Kimmo , Saari Arto , Junnonen Juha-Matti
Published: February 2022

Purpose

This study aims to provide a foundation for the development of subcontracts that suit takt production in construction.

Design/methodology/approach

This is a non-empiric conceptual study, which integrates takt production and general construction literature into new proposals for subcontract clauses suitable for takt production in construction. This study uses literature reviews, from which proposals regarding takt production viable subcontract clauses are conducted via logical reasoning.

Findings

A total of 13 proposals for takt production applicable subcontracts are provided in this study. The proposals emphasize detailed and collaborative planning, suitable payment methods and flexibility for takt plan modification.

Originality/value

Previous takt literature has not properly addressed the development of subcontracts for takt production, despite regular attempts to use subcontracting in takt production. This study aims to aid main contractors to create fair and suitable subcontracts, so that adhering to takt schedules could be more viable in practice. This study also acts as a foundation for further empirical studies regarding the subject.
Performance implication of exploration and exploitation in foreign markets: the role of marketing capability and operation flexibility
Authors: Ju Min , Gao Gerald Yong
Published: February 2022

Purpose

The purpose of this paper is to examine the performance impact of foreign ventures' exploration and exploitation strategies in emerging markets. Exploration and exploitation represent key strategic choices and have been extensively studied in the context of domestic markets. Yet the implication of such innovation strategies for foreign ventures operating in emerging markets has been under-researched. We aim to investigate whether foreign ventures can realize the value of exploration and exploitation strategies in emerging markets and also the moderating role of marketing capability and operation flexibility to enable the implementation process.

Design/methodology/approach

This study adopts the hierarchical moderated regression approach using a sample of foreign ventures operating in high-tech manufacturing industries in China.

Findings

The authors find that both exploration and exploitation have positive effects on firms' financial performance. Marketing capability strengthens the performance impact of exploration, but exhibits no such impact of exploitation. Moreover, operation flexibility positively moderates the effects of both exploration and exploitation on performance.

Research limitations/implications

This study provides important insights into whether foreign ventures can boost performance through exploration and exploitation strategies in emerging markets as well as the implementation-level factors that can facilitate such positive effects.

Originality/value

The study is novel in revealing the moderating role of marketing capability and operation flexibility in facilitating the performance outcome of exploration and exploitation strategies.
Successful reconfiguration and network evolution within the multinational company
Authors: Valdemarin Stefano , Mayrhofer Ulrike
Published: February 2022

Purpose

This article aims to contribute to a better understanding of how multinational companies can succeed the reconfiguration of their internal structures. The theoretical framework is based on the concept of reconfiguration as a dynamic capability, the Uppsala evolution model and the business network view.

Design/methodology/approach

The authors conducted a case study on the reconfiguration of two vertically-related business units within the Solvay group, a world leader in the chemical industry. The empirical study is based on interviews, observations and secondary data.

Findings

The paper shows how a multinational enterprise can succeed in reorganizing its internal structures to overcome internal liability of outsidership and to be more competitive and profitable. The reconfiguration enabled Solvay to become a fully integrated leader in the polyamide plastics industry.

Originality/value

The paper explains how the internal reorganization has improved the competitiveness and profitability of the integrated business units.
Political sentiment and stock crash risk
Authors: Cao Cathy Xuying , Chen Chongyang
Published: February 2022

Purpose

This paper examines the relation between political sentiment and future stock price crash risk.

Design/methodology/approach

This study employs firm-level political sentiment from earnings conference calls. The empirical analysis applies panel regressions on 40,254 US firm-year observations between 2002 and 2020, controlling for various firm-specific determinants of crash risk and firm-, industry- as well as time-fixed effects.

Findings

The study identifies a negative association between both the level and the change of political sentiment and stock crash risk. Further analysis shows that the predictive power of political sentiment is independent of either non-political sentiment or political risk and remains consistently strong during periods of either high or low economic policy uncertainty. Moreover, the predictive effect of political sentiment is more pronounced for firms with high litigation risk.

Research limitations/implications

The evidence highlights the important role of political sentiment in predicting stock crash risk. The results are consistent with the signaling hypothesis that managers tend to use their tone in conference calls to convey informative messages on firm outlooks.

Practical implications

The study provides a recommendation on risk management: soft information such as political and non-political sentiment in earnings conference calls is useful in managing stock crash risk. The study findings also call for careful consideration of social costs, such as stock crash risk, associated with political policies. Ill-conceived policies may lead to market crashes, which can potentially outweigh the upsides of well-meaning political reforms.

Originality/value

To the authors best knowledge, this is the first study to identify the effect of time-varying firm-level political sentiment conveyed in conference calls on stock price crash.
The impact of COVID-19 pandemic on earnings management and the value relevance of earnings: US evidence
Authors: Liu Guoping , Sun Jerry
Published: February 2022

Purpose

The purpose of this study is to examine whether the COVID-19 pandemic has affected earnings management and the value relevance of earnings in the USA.

Design/methodology/approach

Discretionary accruals, the explanatory power and slope coefficient of earnings are compared between 2019 (prepandemic year) and 2020 (pandemic year). Univariate and regression analyses are performed.

Findings

There was a significant decline in discretionary accruals from 2019 to 2020, suggesting that firms engaged in more income-decreasing earnings management to take a big bath in reporting earnings in the pandemic year. Meanwhile, the explanatory power and slope coefficient of earnings both were lower in 2020 than in 2019, consistent with the notion that the pandemic has impaired the value relevance of earnings.

Originality/value

This study explores the consequences of the pandemic from accounting perspective. It also enriches accounting research on economic crises.
Dead-end jobs or steppingstones? Precarious work in Albania
Authors: Drishti Elvisa , Carmichael Fiona
Published: February 2022

Purpose

This study asks whether lower quality forms of employment lead to career transitions into higher quality forms of employment acting as steppingstones, or bridges or, whether instead they lead to dead-ends, or traps, in which workers move between unstable jobs with low prospects for upward mobility and unemployment.

Design/methodology/approach

This study uses a unique longitudinal dataset recording monthly employment states over 3 years for 373 individuals in the Albanian city of Shkoder. The analysis uses sequence and regression analysis to investigate whether people employed in lower quality, more precarious jobs remain in these kinds of jobs or instead are able to transition into higher quality, permanent and full-time employment.

Findings

In line with previous evidence for the region, the analysis confirms the precarization of many working lives particularly for women, young people and those with lower educational attainment. This evidence is more supportive of the dead-end hypothesis than the idea that a lower quality job can be a steppingstone into a better job.

Originality/value

This study contributes to the limited knowledge of labour market functioning in developing post-socialist Western Balkans countries. Recent flexicurity policies have generated an increased prevalence of more precarious employment arrangements in Albania. This investigation addresses previous research limitations regarding point-in-time transitions and unobserved heterogeneity using retrospective longitudinal data and controlling for personality traits.
Salvage radiotherapy following HiFU: An institutional series and literature review
Authors: Mesci Aruz , Gouran‐Savadkoohi Mohammad , Ribeiro Derek , Dayes Ian , Lukka Himanshu , Schnarr Kara , Quan Kimmen , Goldberg Mira , Hallock Abhirami , Tsakiridis Theodoros
Published: February 2022

Introduction

Algorithms for the treatment of prostate cancer (PrCa) rely on risk grouping, and those who fall into low (LR) and favourable intermediate risk (FIR) categories have multiple options for treatment. High‐intensity focused ultrasound (HiFU) is a local treatment modality that uses ultrasound waves to ablate prostate cancer. In case of treatment failure, optimal salvage modality after HiFU remains unclear.

Methods

Here, we describe a retrospective review of our regional cancer database for men who underwent salvage radiotherapy after failure of HiFU treatment for prostate cancer. Oncologic and toxicity outcomes of the men identified in our database are discussed.

Results

We identified 14 men in our regional database who received salvage radiotherapy (70–74 Gy with or without androgen deprivation therapy (ADT) after primary HiFU, in the period of 2009–2017. No cases of any grade 3 or higher toxicity were observed. In our cohort, 50% (7/14) of patients developed secondary biochemical failure at a median follow‐up of 54 months post‐radiotherapy, with a mean time to biochemical failure of 39 months.

We compare our data to other available reports to date consisting mostly of small, non‐randomized studies. Our biochemical control rates are noticeably lower compared with those reported by other studies but our length of follow‐up is longer, compared with other studies.

Conclusion

The available data to date suggest that salvage radiotherapy after HiFU failure is well‐tolerated albeit with only modest efficacy.
Impairment of a cyanobacterial glycosyltransferase that modifies a pilin results in biofilm development
Authors: Suban Shiran , Sendersky Eleonora , Golden Susan S. , Schwarz Rakefet
Published: February 2022

A biofilm inhibiting mechanism operates in the cyanobacterium Synechococcus elongatus. Here, we demonstrate that the glycosyltransferase homologue, Ogt, participates in the inhibitory process – inactivation of ogt results in robust biofilm formation. Furthermore, a mutational approach shows requirement of the glycosyltransferase activity for biofilm inhibition. This enzyme is necessary for glycosylation of the pilus subunit and for adequate pilus formation. In contrast to wild‐type culture in which most cells exhibit several pili, only 25% of the mutant cells are piliated, half of which possess a single pilus. In spite of this poor piliation, natural DNA competence was similar to that of wild‐type; therefore, we propose that the unglycosylated pili facilitate DNA transformation. Additionally, conditioned medium from wild‐type culture, which contains a biofilm inhibiting substance(s), only partially blocks biofilm development by the ogt‐mutant. Thus, we suggest that inactivation of ogt affects multiple processes including production or secretion of the inhibitor as well as the ability to sense or respond to it.
Surviving sepsis campaign: International guidelines for management of sepsis and septic shock in adults 2021 ‐ endorsement by the Scandinavian society of anaesthesiology and intensive care medicine
Authors: Rehn Marius , Chew Michelle S. , Olkkola Klaus T. , Ingi Sigurðsson Martin , Yli‐Hankala Arvi , Hylander Møller Morten
Published: February 2022

The Clinical Practice Committee of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine endorses the clinical practice guideline Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. The guideline serves as a useful bedside decision aid for clinicians managing adults with suspected and confirmed septic shock and sepsis‐associated organ dysfunction.