bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Cost-Effectiveness of Tocilizumab (Actemra) Therapy in Giant Cell Arteritis
Authors: Jogimahanti Arjun V. , Kini Ashwini T. , Irwin Lauren E. , Lee Andrew G. 
Published: April 2021

Background:
Tocilizumab (Actemra) is a humanized anti–interleukin-6 receptor antibody that has been used as a steroid-sparing agent in giant cell arteritis (GCA). Although the clinical effects are well described in GCA, the cost-effectiveness of the use of tocilizumab in GCA is ill defined. The purpose of this study was to determine the cost-effectiveness of tocilizumab in GCA compared with prednisone alone.

Methods:
A retrospective study of 32 patients with biopsy-proven GCA comparing prednisone alone (16 patients) and prednisone with tocilizumab (16 patients) was performed. The cost for tocilizumab therapy for 26 weeks with mild and severe side effects (Groups 1 and 2, respectively) and for 52 weeks with mild and severe side effects (Group 3 and 4, respectively) was compared with estimated costs of mild and severe steroid-induced side effects (Groups 5 and 6, respectively). Statistical analysis between groups was conducted using independent sample t tests.

Results:
Three out of the 4 group combinations of tocilizumab with prednisone demonstrated a statistically significant (P < 0.05) difference in cost compared with prednisone alone for GCA. Group 2 (26-week tocilizumab therapy with severe steroid-induced side effects), with no statically significant difference in price when compared with steroid therapy alone and far fewer side effects, demonstrated the potential use of tocilizumab in GCA therapy. As expected, longer treatment duration with tocilizumab was associated with greater cost. With respect to side effect severity, the number of side effects of steroid therapy was inversely associated with difference in cost between tocilizumab therapy and steroid side effect treatment.

Conclusion:
This study demonstrates that combination therapy of tocilizumab and prednisone is significantly more expensive than steroids alone with or without accounting for the cost of steroid-induced side effects in treated GCA. The difference in cost between the 2 therapy types is directly related to tocilizumab therapy duration and inversely related to the number or severity of steroid side effects. Patients with GCA who require a shorter duration of steroid therapy and are at risk for a high number of side effects from steroid use may be potential candidates for tocilizumab therapy, from an economic perspective.
Shear Relaxation Governs Dynamic Processes of Biomolecular Condensates
Authors: Ghosh Archishman , Kota Divya , Zhou Huan-Xiang 
Published: April 2021

AbstractPhase-separated biomolecular condensates must respond agilely to biochemical and environmental cues in performing their wide-ranging cellular functions, but our understanding of condensate dynamics is lagging. Ample evidence now indicates biomolecular condensates as viscoelastic fluids, where shear stress relaxes at a finite rate, not instantaneously as in viscous liquids. Yet the fusion dynamics of condensate droplets has only been modeled based on viscous liquids, with fusion time given by the viscocapillary ratio (viscosity over interfacial tension). Here we used optically trapped polystyrene beads to measure the viscous and elastic moduli and the interfacial tensions of four types of droplets. Our results challenge the viscocapillary model, and reveal that the relaxation of shear stress governs fusion and other dynamic processes of condensates.
Visualization of subcortical structures in non-human primates in vivo by Quantitative Susceptibility Mapping at 3T MRI
Authors: Yoshida Atsushi , Ye Frank Q , Yu David K , Leopold David A , Hikosaka Okihide 
Published: April 2021

AbstractMagnetic resonance imaging (MRI) is now an essential tool in the field of neuroscience involving non-human primates (NHP). Structural MRI scanning using T1-weighted (T1w) or T2-weighted (T2w) images provides anatomical information, particularly for experiments involving deep structures such as the basal ganglia and cerebellum. However, for certain subcortical structures, T1w and T2w images fail to reveal important anatomical details. To better visualize such structures in the macaque brain, we applied a relatively new method called quantitative susceptibility mapping (QSM), which enhances tissue contrast based on the local tissue magnetic susceptibility. To evaluate the visualization of important structures, we quantified the the contrast-to-noise ratios (CNRs) of the ventral pallidum (VP), globus pallidus external and internal segments (GPe and GPi), substantia nigra (SN), subthalamic nucleus (STN) in the basal ganglia and the dentate nucleus (DN) in the cerebellum. For these structures, the QSM method significantly increased the CNR, and thus the visibility, beyond that in either the T1w or T2w images. In addition, QSM values of some structures were correlated to the age of the macaque subjects. These results indicate that the QSM method can enable the clear identification of certain subcortical structures that are invisible in more traditional scanning sequences.HighlightsNHP subcortical structures are challenging to see in conventional T1w and T2w imagesWe applied quantitative susceptibility mapping (QSM) to identify them easilyQSM clearly visualized basal ganglia and cerebellar nucleus of high brain iron contentCNRs of some subcortical nucleus were significantly higher in QSMQSM values of several subcortical nucleus increased with age
Identification of a signature of evolutionarily conserved stress-induced mutagenesis in cancer
Authors: Cisneros Luis H. , Vaske Charles , Bussey Kimberly J. 
Published: April 2021

AbstractThe clustering of mutations observed in cancer cells is reminiscent of the stress-induced mutagenesis (SIM) response in bacteria. SIM employs error-prone polymerases resulting in mutations concentrated around DNA double-strand breaks with an abundance that decays with genomic distance. We performed a quantitative study on single nucleotide variant calls for whole-genome sequencing data from 1,950 tumors and non-inherited mutations from 129 normal samples. We introduce statistical methods to identify mutational clusters and quantify their distribution patterns. Our results show that mutations in both normal and cancer samples are indeed clustered and have shapes indicative of SIM. We also found that clusters of mutations colocalize more prevalently in normal samples than in cancer, suggesting loss of regulation leading to increased randomness in the mutational process during carcinogenesis.
RegVar: Tissue-specific Prioritization of Noncoding Regulatory Variants
Authors: Lu Hao , Ma Luyu , Quan Cheng , Li Lei , Lu Yiming , Zhou Gangqiao , Zhang Chenggang 
Published: April 2021

AbstractNoncoding genomic variants constitute the majority of trait-associated genome variations; however, identification of functional noncoding variants is still a challenge in human genetics, and a method systematically assessing the impact of regulatory variants on gene expression and linking them to potential target genes is still lacking. Here we introduce a deep neural network (DNN)-based computational framework, RegVar, that can accurately predict the tissue-specific impact of noncoding regulatory variants on target genes. We show that, by robustly learning the genomic characteristics of massive variant-gene expression associations in a variety of human tissues, RegVar vastly surpasses all current noncoding variants prioritization methods in predicting regulatory variants under different circumstances. The unique features of RegVar make it an excellent framework for assessing the regulatory impact of any variant on its putative target genes in a variety of tissues. RegVar is available as a webserver athttp://regvar.cbportal.org/.
The DNA-to-cytoplasm ratio broadly activates zygotic gene expression in Xenopus
Authors: Jukam David , Kapoor Rishabh R , Straight Aaron F , Skotheim Jan M. 
Published: April 2021

SummaryIn multicellular animals, the first major event after fertilization is the switch from maternal to zygotic control of development. During this transition, zygotic gene transcription is broadly activated in an otherwise quiescent genome in a process known as zygotic genome activation (ZGA). In fast developing embryos, ZGA often overlaps with the slowing of initially synchronous cell divisions at the mid-blastula transition (MBT). Initial studies of the MBT led to the nuclear-to-cytoplasmic ratio model where MBT timing is regulated by the exponentially increasing amounts of some nuclear component ‘N’ titrated against a fixed cytoplasmic component ‘C’. However, more recent experiments have been interpreted to suggest that ZGA is independent of the N/C ratio. To determine the role of the N/C ratio in ZGA, we generatedXenopusfrog embryos with ∼3-fold differences in genomic DNA (i.e., “N”) by usingX. tropicalissperm to fertilizeX. laeviseggs with or without their maternal genome. Resulting embryos have otherwise identicalX. tropicalisgenome template amounts, embryo sizes, andX. laevismaternal environments. We used theX. tropicalispaternally derived mRNA to identify a high confidence set of exclusively zygotic transcripts. Both ZGA and the increase in cell cycle duration are delayed in embryos with ∼3-fold less DNA per cell. Thus, DNA is an important component of the N/C ratio, which is indeed a critical regulator of zygotic genome activation inXenopusembryos.
Alterations in protein translation and carboxylic acid catabolic processes in diabetic kidney disease
Authors: Collins Kimberly S. , Eadon Michael T. , Cheng Ying-Hua , Barwinska Daria , Ferreira Ricardo Melo , McCarthy Thomas W. , Janosevic Danielle , Syed Farooq , Maier Bernhard , El-Achkar Tarek M. , Kelly Katherine J. , Phillips Carrie L. , Hato Takashi , Sutton Timothy A. , Dagher Pierre C. 
Published: April 2021

ABSTRACTDiabetic kidney disease (DKD) remains the leading cause of end stage kidney disease despite decades of study. Alterations in the glomerulus and kidney tubules both contribute to the pathogenesis of DKD although the majority of investigative efforts have focused on the glomerulus. We sought to examine the differential expression signature of human DKD in the glomerulus and proximal tubule and corroborate our findings in the db/db mouse model of diabetes. A transcriptogram network analysis of RNAseq data from laser microdissected (LMD) human glomerulus and proximal tubule of DKD and reference nephrectomy samples revealed enriched pathways including rhodopsin-like receptors, olfactory signaling, and ribosome (protein translation) in the proximal tubule of human DKD biopsy samples. The translation pathway was also enriched in the glomerulus. Increased translation in diabetic kidneys was validated using polyribosomal profiling in the db/db mouse model of diabetes. Using single nuclear RNA sequencing (snRNAseq) of kidneys from db/db mice, we prioritized additional pathways identified in human DKD. The top overlapping pathway identified in the murine snRNAseq proximal tubule clusters and the human LMD proximal tubule compartment was carboxylic acid catabolism. Using ultra-performance liquid chromatography-mass spectrometry, the fatty acid catabolism pathway was also found to be dysregulated in the db/db mouse model. The Acetyl-CoA metabolite was down-regulated in db/db mice, aligning with the human differential expression of the genes ACOX1 and ACACB. In summary, our findings demonstrate that proximal tubular alterations in protein translation and carboxylic acid catabolism are key features in both human and murine DKD.
A biosensor to gauge protein homeostasis resilience differences in the nucleus compared to cytosol of mammalian cells
Authors: Raeburn Candice B. , Ormsby Angelique , Moily Nagaraj S. , Cox Dezerae , Ebbinghaus Simon , Dickson Alex , McColl Gawain , Hatters Danny M. 
Published: April 2021

AbstractAn extensive network of chaperones and other proteins maintain protein homeostasis and guard against inappropriate protein aggregation that is a hallmark of neurodegenerative diseases. Using a fluorescence resonance energy-based biosensor that simultaneously reports on intact cellular chaperone holdase activity and detrimental aggregation propensity, we investigated the buffering capacity of the systems managing protein homeostasis in the nucleus of the human cell line HEK293 compared to the cytosol. We found that the nucleus showed lower net holdase activity and reduced capacity to suppress protein aggregation, suggesting that the nuclear quality control resources are less effective compared to those in the cytosol. Aggregation of mutant huntingtin exon 1 protein (Httex1) in the cytosol appeared to deplete cytosolic chaperone supply by depleting holdase activity. Unexpectedly, the same stress increased holdase activity in the nucleus suggesting that proteostasis stress can trigger a rebalance of chaperone supply in different subcellular compartments. Collectively the findings suggest the cytosol has more capacity to manage imbalances in proteome foldedness than the nucleus, but chaperone supply can be redirected into the nucleus under conditions of proteostasis stress caused by cytosolic protein aggregation.
CRISPR-Cas12a genome editing at the whole-plant level using two compatible RNA virus vectors
Authors: Uranga Mireia , Vazquez-Vilar Marta , Orzáez Diego , Daròs José-Antonio 
Published: April 2021

AbstractThe use of viral vectors that can replicate and move systemically through the host plant to deliver bacterial clustered, regularly interspaced, short palindromic repeats (CRISPR) components enables genome editing at the whole-plant level and avoids the requirement for labor-intensive stable transformation. However, this approach usually relies on previously transformed plants that stably express a CRISPR-associated (Cas) nuclease. Here we describe successful DNA-free genome editing ofNicotiana benthamianausing two compatible RNA virus vectors, derived from tobacco etch virus (TEV; genusPotyvirus) and potato virus X (PVX; genusPotexvirus), which replicate in the same cells. The TEV and PVX vectors respectively express a Cas12a nuclease and the corresponding guide RNA. This novel two-virus vector system improves the toolbox for transformation-free virus-induced genome editing in plants and will advance efforts to breed more nutritious, resistant, and productive crops.
Triggered reversible disassembly of an engineered protein nanocage
Authors: Jones Jesse A. , Cristie-David Ajitha S. , Andreas Michael P. , Giessen Tobias W. 
Published: April 2021

AbstractProtein nanocages play crucial roles in sub-cellular compartmentalization and spatial control in all domains of life and have been used as biomolecular tools for applications in biocatalysis, drug delivery, and bionanotechnology. The ability to control their assembly state under physiological conditions would further expand their practical utility. To gain such control, we introduced a peptide capable of triggering conformational change at a key structural position in the largest known encapsulin nanocompartment. We report the structure of the resulting engineered nanocage and demonstrate its ability to on-demand disassemble and reassemble under physiological conditions. We demonstrate its capacity forin vivoencapsulation of proteins of choice while also demonstratingin vitrocargo loading capabilities. Our results represent a functionally robust addition to the nanocage toolbox and a novel approach for controlling protein nanocage disassembly and reassembly under mild conditions.
Geographical bias in physiological data limits predictions of global change impacts
Authors: White Craig R. , Marshall Dustin J. , Chown Steven L. , Clusella‐Trullas Susana , Portugal Steven J. , Franklin Craig E. , Seebacher Frank 
Published: April 2021

Abstract

Climate affects all aspects of biology. Physiological traits play a key role in mediating these effects, because they define the fundamental niche of each organism.

Climate change is likely to shift environmental conditions away from physiological optima. The consequences for species are significant: they must alter their physiology through plasticity or adaptation, move, or decline to extinction. The ability to understand and predict such organismal responses to global change is, however, only as good as the geographical coverage of the data on which these predictions are based.

Geographical biases in the state of physiological knowledge have been identified, but it has not been determined if these geographical biases are likely to limit our capacity to predict the outcomes of global change. We show that current knowledge of physiological traits is representative of only a limited range of the climates in which terrestrial animals will be required to operate, because data for animals from only a limited range of global climates have been incorporated in existing compilations.

We conclude that geographical bias in existing datasets limits our capacity to predict organismal responses in the vast areas of the planet that are unstudied, and that this geographical bias is a much greater source of uncertainty than the difference between the current climate and the projected future climate. Addressing this bias is urgent to understand where impacts will be most profound, and where the need for intervention is most pressing.

A free Plain Language Summary can be found within the Supporting Information of this article.
Blue consequences of the green bioeconomy: Clear‐cutting intensifies the harmful impacts of land drainage on stream invertebrate biodiversity
Authors: Rajakallio Maria , Jyväsjärvi Jussi , Muotka Timo , Aroviita Jukka 
Published: April 2021

Abstract

Growing bioeconomy is increasing the pressure to clear‐cut drained peatland forests. Yet, the cumulative effects of peatland drainage and clear‐cutting on the biodiversity of recipient freshwater ecosystems are largely unknown.

We studied the isolated and combined effects of peatland drainage and clear‐cutting on stream macroinvertebrate communities. We further explored whether the impact of these forestry‐driven catchment alterations to benthic invertebrates is related to stream size. We quantified the impact on invertebrate biodiversity by comparing communities in forestry‐impacted streams to expected communities modelled with a multi‐taxon niche model.

The impact of clear‐cutting of drained peatland forests exceeded the sum of the independent effects of drainage and clear‐cutting, indicating a synergistic interaction between the two disturbances in small streams. Peatland drainage reduced benthic biodiversity in both small and large streams, whereas clear‐cutting did the same only in small streams. Small headwater streams were more sensitive to forestry impacts than the larger downstream sites.

We found 11 taxa (out of 25 modelled) to respond to forestry disturbances. These taxa were mainly different from those previously reported as sensitive to forestry‐driven alterations, indicating the context dependence of taxonomic responses to forestry. In contrast, most of the functional traits previously identified as responsive to agricultural sedimentation also responded to forestry pressures. In particular, taxa that live temporarily in hyporheic habitats, move by crawling, disperse actively in water, live longer than 1 year, use eggs as resistance form and obtain their food by scraping became less abundant than expected, particularly in streams impacted by both drainage and clear‐cutting.

Synthesis and applications. Drained peatland forests in boreal areas are reaching maturity and will soon be harvested. Clear‐cutting of these forests incurs multiple environmental hazards but previous studies have focused on terrestrial ecosystems. Our results show that the combined impacts of peatland drainage and clear‐cutting may extend across ecosystem boundaries and cause significant biodiversity loss in recipient freshwater ecosystems. This information supports a paradigm shift in boreal forest management, whereby continuous‐cover forestry based on partial harvest may provide the most sustainable approach to peatland forestry.
Genomic and proteomic profiles of biofilms on microplastics are decoupled from artificial surface properties
Authors: Oberbeckmann Sonja , Bartosik Daniel , Huang Sixing , Werner Johannes , Hirschfeld Claudia , Wibberg Daniel , Heiden Stefan E. , Bunk Boyke , Overmann Jörg , Becher Dörte , Kalinowski Jörn , Schweder Thomas , Labrenz Matthias , Markert Stephanie 
Published: April 2021

SummaryMicroplastics in marine ecosystems are colonized by diverse prokaryotic and eukaryotic communities. How these communities and their functional profiles are shaped by the artificial surfaces remains broadly unknown. In order to close this knowledge gap, we set up an in situ experiment with pellets of the polyolefin polymer polyethylene (PE), the aromatic hydrocarbon polymer polystyrene (PS), and wooden beads along a coastal to estuarine gradient in the Baltic Sea, Germany. We used an integrated metagenomics/metaproteomics approach to evaluate the genomic potential as well as protein expression levels of aquatic plastic biofilms. Our results suggest that material properties had a minor influence on the plastic‐associated assemblages, as genomic and proteomic profiles of communities associated with the structurally different polymers PE and PS were highly similar, hence polymer‐unspecific. Instead, it seemed that these communities were shaped by biogeographic factors. Wood, on the other hand, induced the formation of substrate‐specific biofilms and served as nutrient source itself. Our study indicates that, while PE and PS microplastics may be relevant in the photic zone as opportunistic colonization grounds for phototrophic microorganisms, they appear not to be subject to biodegradation or serve as vectors for pathogenic microorganisms in marine habitats.
Desulfovibrio diazotrophicus sp. nov., a sulfate‐reducing bacterium from the human gut capable of nitrogen fixation
Authors: Sayavedra Lizbeth , Li Tianqi , Bueno Batista Marcelo , Seah Brandon K. B. , Booth Catherine , Zhai Qixiao , Chen Wei , Narbad Arjan 
Published: April 2021

SummarySulfate‐reducing bacteria (SRB) are widespread in human guts, yet their expansion has been linked to colonic diseases. We report the isolation, sequencing and physiological characterization of strain QI0027T, a novel SRB species belonging to the class Desulfovibrionia. Metagenomic sequencing of stool samples from 45 Chinese individuals, and comparison with 1690 Desulfovibrionaceae metagenome‐assembled genomes recovered from humans of diverse geographic locations, revealed the presence of QI0027T in 22 further individuals. QI0027T encoded nitrogen fixation genes and based on the acetylene reduction assay, actively fixed nitrogen. Transcriptomics revealed that QI0027T overexpressed 42 genes in nitrogen‐limiting conditions compared to cultures supplemented with ammonia, including genes encoding nitrogenases, a urea uptake system and the urease complex. Reanalyses of 835 public stool metatranscriptomes showed that nitrogenase genes from Desulfovibrio bacteria were expressed in six samples suggesting that nitrogen fixation might be active in the gut environment. Although frequently thought of as a nutrient‐rich environment, nitrogen fixation can occur in the human gut. Animals are often nitrogen limited and have evolved diverse strategies to capture biologically active nitrogen, ranging from amino acid transporters to stable associations with beneficial microbes that provide fixed nitrogen. QI0027T is the first Desulfovibrio human isolate for which nitrogen fixation has been demonstrated, suggesting that some sulfate‐reducing bacteria could also play a role in the availability of nitrogen in the gut.