bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular dissection of carbapenem-resistant Acinetobacter baumannii circulating in Indian hospitals using Whole Genome Sequencing
Authors: Rose Steffimol , Shamanna Varun , Underwood Anthony , Nagaraj Geetha , Prasanna Akshatha , Govindan Vandana , Dharmavaram Sravani , Shincy M R , Argimón Silvia , Abrudan Monica , Aanensen David M , Ravikumar K. L. 
Published: July 2021

ABSTRACTObjectivesCarbapenem-resistant Acinetobacter baumannii (CRAB) has acquired worldwide recognition as a serious nosocomial infection. It poses a concern to hospitalized patients because of the limited therapeutic options available. Thus, we investigated the molecular epidemiology and antibiotic resistance profiles of A. baumannii isolates in India.Materials and MethodsWe characterized 306 retrospective A. baumannii clinical isolates collected from 18 centers across 10 states and 1 Union Territory of India between 2015 and 2019. Molecular epidemiology, and carbapenem resistance were studied by Whole Genome Sequencing.ResultsA total of 105 different Sequence Types (STs) were identified including 48 reported STs and 57 Novel STs. 99 isolates were classified into Clonal Complex 451 (CC451) among which ST848 and ST1956 were the common STs. Carbapenemase resistance was confirmed in all the isolates with the presence of intrinsic blaOXA-51-like genes, and the acquired blaOXA-23 and blaNDM-1 genes.ConclusionMost of the isolates were grouped under clonal complex 451. ST1053 caused an outbreak in Northern India during 2018 and 2019. Novel MLST alleles and STs were also detected, underlining an evolutionary divergence in India. The carbapenem-resistance was dominated by OXA-type carbapenemases and further surveillance of these carbapenem-resistant A. baumannii and antimicrobial stewardship should be strengthened.
Modeling the mechanics of growing epithelia with a bilayer plate theory
Authors: Ackermann Joseph , Qu Paul-Qiuyang , LeGoff Loïc , Amar Martine Ben 
Published: July 2021

AbstractEpithelia, which consists of cell sheets lying on a substrate, are prevalent structures of multi-cellular organisms. The physical basis of epithelial morphogenesis has been intensely investigated in recent years. However, as 2D mechanics focused most attention, we still lack a rigorous description of how the mechanical interactions between the cell layer and its substrate can lead to 3D distortions. This work provides a complete description of epithelial mechanics using the most straightforward model of an epithelium: a thin elastic bilayer. We first provide experimental evidence inDrosophilatissues that localized alterations of the cell-substrate (the extracellular matrix) can lead to profound 3D shape changes in epithelia. We then develop an analytical model modifying the Föppl-von Kármán equation with growth for bilayers. We provide a complete description of all contributions from biophysical characteristics of epithelia. We show how any localized inhomogeneity of stiffness or thickness drastically changes the bending process when the two layers grow differently. Comparison with finite-element simulations and experiments performed onDrosophilawing imaginal discs validate this approach for thin epithelia.
PROTECTIVE ROLE FOR SMOOTH MUSCLE CELL HEPCIDIN IN ABDOMINAL AORTIC ANEURYSM
Authors: Loick P , Mohammad G , Cassimjee I , Chandrashekar A , Lapolla P , Carrington A , Handa A , Lee R , Lakhal-Littleton S 
Published: July 2021

ABSTRACTRationaleHepcidin (HAMP) is a hormone produced primarily in the liver. It controls systemic iron homeostasis by inhibiting the iron exporter ferroportin (FPN) in the gut and spleen, respective sites of iron absorption and recycling. HAMP and FPN are also found ectopically in tissues not involved in systemic iron homeostasis. The physiological functions of ectopic HAMP and FPN are only just beginning to be uncovered. We observed that HAMP expression is markedly increased in smooth muscle cells (SMCs) of abdominal aortic aneurysms (AAA), both in patients and in an experimental mouse model of AAA.ObjectiveTo understand the role of SMC-derived HAMP in the pathophysiology of AAA.Methods and ResultsWe generated mice harbouring an inducible, SMC-specific deletion of the hamp gene. We then applied the experimental model of AAA and simultaneously induced deletion of hamp in SMCs. We found that these mice developed large aneurysms and had greater incidences of rupture and of fatal dissection than mice with intact hamp in SMCs. A similar phenotype was observed in mice harbouring an inducible SMC-specific knock-in of HAMP-resistant FPNC326Y. Additionally, we observed that expression of Lipocalin-2 (LCN2), a protein known to promote AAA, was suppressed in AAA tissue from patients and from mice with intact hamp in SMCs, but not in mice lacking hamp in SMCs. Treatment of these mice with a LCN2-neutralising antibody protected them from the otherwise detrimental effects of loss of hamp in SMCs.ConclusionsThe present study demonstrates that the rise in SMC-derived HAMP within the aneurysm tissue is protective in the setting of AAA, and that such protection involves the cell-autonomous action of HAMP, and suppression of local LCN2. These findings are the first example of a protective role for ectopic HAMP in disease. They expand understanding of the multifaceted functions of HAMP outside the liver.
Genomic and chemical decryption of the Bacteroidetes phylum for its potential to biosynthesize natural products
Authors: Brinkmann Stephan , Kurz Michael , Patras Maria A. , Hartwig Christoph , Marner Michael , Leis Benedikt , Billion André , Kleiner Yolanda , Bauer Armin , Toti Luigi , Pöverlein Christoph , Hammann Peter E. , Vilcinskas Andreas , Glaeser Jens , Spohn Marius S. , Schäberle Till F. 
Published: July 2021

AbstractWith progress in genome sequencing and data sharing, 1000s of bacterial genomes are publicly available. Genome mining – using bioinformatics tools in terms of biosynthetic gene cluster (BGC) identification, analysis and rating – has become a key technology to explore the capabilities for natural product (NP) biosynthesis. Comprehensively, analyzing the genetic potential of the phylum Bacteroidetes revealed Chitinophaga as the most talented genus in terms of BGC abundance and diversity. Guided by the computational predictions, we conducted a metabolomics and bioactivity driven NP discovery program on 25 Chitinophaga strains. High numbers of peerless strain-specific metabolite buckets confirmed the upfront predicted biosynthetic potential and revealed a tremendous uncharted chemical space. Sourcing this dataset, we isolated the new iron chelating nonribosomally-synthesized cyclic tetradeca- and pentadecalipodepsipeptide antibiotics chitinopeptins with activity against Candida, produced by C. eiseniae DSM 22224 and C. flava KCTC 62435, respectively.TeaserCombination of omics-technologies revealed taxonomical hotspots for specialized metabolites within Bacteroidetes.
A fluorescent sensor for the real-time measurement of extracellular oxytocin dynamics in the brain
Authors: Ino Daisuke , Hibino Hiroshi , Nishiyama Masaaki 
Published: July 2021

ABSTRACTOxytocin (OT), a hypothalamic neuropeptide that acts as a neuromodulator in the brain, orchestrates a variety of animal behaviors. However, the relationship between brain OT dynamics and complex animal behaviors remains largely elusive, partly because of the lack of a suitable technique for its real-time recording in vivo. Here, we describe MTRIAOT, a G protein-coupled receptor-based green fluorescent OT sensor with a large dynamic range, optimal affinity, ligand specificity to OT orthologs, minimal effects on downstream signaling, and long-term fluorescence stability. By combining viral gene delivery and fiber photometry-mediated fluorescence measurements, we demonstrated the utility of MTRIAOT for real-time detection of brain OT dynamics in living mice. Importantly, MTRIAOT-mediated measurements revealed “OT oscillation,” a hitherto unknown rhythmic change in OT levels in the brain. MTRIAOT will allow the analysis of OT dynamics in a wide variety of physiological and pathological processes.
Reduced glutathione decreases cell adhesion and increases cell volume
Authors: Géloën Alain , Berger Emmanuelle 
Published: July 2021

AbstractGlutathione is the most abundant thiol in animal cells. Reduced glutathione (GSH) is a major intracellular antioxidant neutralizing free radicals and detoxifying electrophiles. It plays important roles in many cellular processes, including cell differentiation, proliferation, and apoptosis. In the present study we demonstrate that extracellular concentration of reduced glutathione markedly increases cell volume within few hours, in a dose-response manner. Pre-incubation of cells with BSO, the inhibitor of γ-glutamylcysteine synthetase, responsible for the first step in intracellular glutathione synthesis did not change the effect of reduced glutathione on cell volume suggesting a mechanism limited to the interaction of extracellular reduced glutathione on cell membrane. Similarly, inhibition of γ-glutamylcyclotransferase involved in intracellular glutamate production had no effect on the action of reduced glutathione. Oxidized glutathione exerted no effect on cell volume. Results show that reduced GSH decreases cell adhesion resulting in an increased cell volume. Since many cell types are able to export GSH, the present results suggest that this could be a fundamental self-regulation of cell volume, giving the cells a self-control on their adhesion proteins.
Directed biosynthesis of fluorinated polyketides
Authors: Rittner Alexander , Joppe Mirko , Schmidt Jennifer J. , Mayer Lara Maria , Heid Elia , Sherman David H. , Grininger Martin 
Published: July 2021

AbstractModification of polyketides with fluorine offers a promising approach to develop new pharmaceuticals. While synthetic chemical methods for site-specific incorporation of fluorine in complex molecules have improved in recent years, approaches for the direct biosynthetic fluorination of natural compounds are still rare. Herein, we present a broadly applicable approach for site-specific, biocatalytic derivatization of polyketides with fluorine. Specifically, we exchanged the native acyltransferase domain (AT) of a polyketide synthase (PKS), which acts as the gatekeeper for selection of extender units, with an evolutionarily related but substrate tolerant domain from metazoan type I fatty acid synthase (FAS). The resulting PKS/FAS hybrid can utilize fluoromalonyl coenzyme A and fluoromethylmalonyl coenzyme A for polyketide chain extension, introducing fluorine or fluoro-methyl disubstitutions in polyketide scaffolds. Addition of a fluorine atom is often a decisive factor toward developing superior properties in next-generation antibiotics, including the macrolide solithromycin. We demonstrate the feasibility of our approach in the semisynthesis of a fluorinated derivative of the macrolide antibiotic YC-17.
Phosphoproteomic analysis of chondrocytes after short-term exposure to inorganic polyphosphate
Authors: Kuzmanov Uros , Gawri Rahul , Zelinka Alena , Russell Keith A , Lee Shin-Haw , Gramolini Anthony , Kandel Rita 
Published: July 2021

AbstractOsteoarthritis is a debilitating disease of the joint that affects over 230 million people worldwide. Currently there are no treatments that slow the progression of this disease. For these reasons, new biological treatment options are currently being explored. Inorganic polyphosphates are naturally occurring biological molecules that have an anabolic effect on chondrocytes grown in vitro in the presence of Ca2+. We hypothesized that when examining significant changes in protein phosphorylation, key candidates would emerge that could help to elucidate the anabolic effects of polyphosphate on chondrocytes. Therefore, we conducted a large-scale quantitative proteomic and phosphoproteomic study of bovine primary articular chondrocytes after 30-minute treatment with inorganic polyphosphate and Ca2+. Mass spectrometry identified more than 6000 phosphorylation sites on ∼1600 chondrocyte phosphoproteins while proteomic analysis detected approximately 4100 proteins. Analysis of the data revealed a swift and dynamic response to polyphosphate after 30 minutes. What emerged from the list of proteins most affected by the treatment were proteins with key roles in chondrogenesis including TNC, IGFBP-5, and CTGF, indicating that polyphosphate plays an important role in chondrocyte metabolism. This phosphoproteome serves as a meaningful resource to help elucidate the molecular events that contribute to extracellular matrix production in cartilage.
PERK inhibition blocks metastasis initiation by limiting UPR-dependent survival of dormant disseminated cancer cells
Authors: Calvo Veronica , Zheng Wei , Staschke Kirk A. , Cheung Julie , Nobre Ana Rita , Farias Eduardo F. , Nowacek Ari , Mulvihill Mark , Rigby Alan C. , Aguirre-Ghiso Julio A. 
Published: July 2021

AbstractThe unfolded protein response (UPR) kinase PERK has been shown to serve as a survival factor for HER2-driven breast and prostate cancers as well as for dormant cancer cells. However, its role in metastasis is not understood. Here we found in the MMTV-HER2 mouse model that quiescent HER2+ disseminated cancer cells (DCCs) displayed unresolved ER stress as revealed by high expression of the PERK-inducible GADD34 gene. Single cell gene expression profiling and imaging confirmed that a significant proportion of DCCs in lungs were dormant and displayed an active UPR. In human breast cancer metastasis biopsies, GADD34 expression and quiescence were also positively correlated. Importantly, PERK inhibition with a specific inhibitor (HC4) blunted metastasis development by selectively killing UPRhigh quiescent but not proliferative DCCs. We also show that PERK inhibition altered optimal HER2 activity in primary tumors as a result of sub-optimal HER2 trafficking and phosphorylation in response to EGF. Our data identify PERK as a unique “Achilles heel” in dormant DTCs, supporting a requisite role for PERK in DTCs. Taken together, these data identify novel strategies to eliminate quiescent DCCs in patients with disseminated cancer disease.
Identification of the Global miR-130a Targetome Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML
Authors: Krivdova Gabriela , Voisin Veronique , Schoof Erwin M , Marhon Sajid A , Murison Alex , McLeod Jessica L , Gabra Martino , Zeng Andy GX , Van Nostrand Eric L , Aigner Stefan , Shishkin Alexander A , Yee Brian A , Hermans Karin G , Trotman-Grant Aaron G , Mbong Nathan , Kennedy James A , Gan Olga I , Wagenblast Elvin , De Carvalho Daniel D , Salmena Leonardo , Minden Mark D , Bader Gary D , Yeo Gene W , Dick John E , Lechman Eric R 
Published: July 2021

SUMMARYGene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells (HSC) point to shared core stemness properties. However, discordance between mRNA and protein signatures underscores an important role for post-transcriptional regulation by miRNAs in governing this critical nexus. Here, we identified miR-130a as a regulator of HSC self-renewal and differentiation. Enforced expression of miR-130a impaired B lymphoid differentiation and expanded long-term HSC. Integration of protein mass spectrometry and chimeric AGO2 eCLIP-seq identified TBL1XR1 as a primary miR-130a target, whose loss of function phenocopied miR-130a overexpression. Moreover, we found that miR-130a is highly expressed in t(8;21) AML where it is critical for maintaining the oncogenic molecular program mediated by AML1-ETO. Our study establishes that identification of the comprehensive miRNA targetome within primary cells enables discovery of novel genes and molecular networks underpinning stemness properties of normal and leukemic cells.HIGHLIGHTSmiR-130a is a regulator of HSC self-renewal and lineage commitmentTBL1XR1 is a principal target of miR-130aTBL1XR1 loss of function in HSPC phenocopies enforced expression of miR-130aElevated miR-130a levels maintain the AML1-ETO repressive program in t(8;21) AML
Synthetic and biological surfactant effects on freshwater biofilm community composition and metabolic activity
Authors: Gill Stephanie P. , Hunter William R. , Coulson Laura E. , Banat Ibrahim M. , Schelker Jakob 
Published: July 2021

AbstractSurfactants are used to control microbial biofilms in industrial and medical settings. Their known toxicity on aquatic biota and their longevity in the environment has encouraged research on biodegradable alternatives such as rhamnolipids. While previous research has investigated the effects of biological surfactants on single species biofilms, there remains a lack of information regarding the effects of synthetic and biological surfactants in freshwater ecosystems. We conducted a mesocosm experiment to test how the surfactant sodium dodecyl sulphate (SDS) and the biological surfactant rhamnolipid altered community composition and metabolic activity of freshwater biofilms. Biofilms were cultured in the flumes using lake water from Lake Lunz in Austria, under high (300 ppm) and low (150 ppm) concentrations of either surfactant over a four-week period. Our results show that both surfactants significantly affected microbial diversity. Up to 36% of microbial operational taxonomic units were lost after surfactant exposure. Rhamnolipid exposure also increased the production of the extracellular enzymes, leucine aminopeptidase and glucosidase, while SDS exposure reduced leucine aminopeptidase and glucosidase. This study demonstrates that exposure of freshwater biofilms to chemical and biological surfactants caused a reduction of microbial diversity and changes in biofilm metabolism, exemplified by shifts in extracellular enzyme activities.Key PointsMicrobial biofilm diversity decreased significantly after surfactant exposure.Exposure to either surfactant altered extracellular enzyme activity.Overall metabolic activity was not altered, suggesting functional redundancy.
Tissue-specific heteroplasmy dynamics is accompanied by a sharp drop in mtDNA copy number during development
Authors: Tsyba Nikita , Patel Maulik R. 
Published: July 2021

AbstractMitochondrial mutation phenotypes are highly unpredictable as they depend on 3 variables; mutant-to-wildtype ratio (heteroplasmy level), total number of mitochondrial genomes (mtDNA), and the tissue affected. The exact phenotype experienced is governed by the combination of these variables, but current models lack the capability to examine the three variables simultaneously. We have established a C. elegans muscle and neuron system to overcome this challenge. Using this system, we measure heteroplasmy level and mtDNA copy number throughout development. Our results show that neurons accumulate significantly higher heteroplasmy level than muscles. These tissue-specific differences arise late in development, and are dependent on AMP-activated protein kinase (AMPK). Importantly, we find that somatic tissues lose more than half of their mtDNA content during development. These findings show that heteroplasmy levels can remain stable, or even increase, despite acute mtDNA losses.
Generation of a new six1-null line in Xenopus tropicalis for study of development and congenital disease
Authors: Coppenrath Kelsey , Tavares Andre L.P. , Shaidani Nikko-Ideen , Wlizla Marcin , Moody Sally A. , Horb Marko 
Published: July 2021

ABSTRACTThe vertebrate Six (Sine oculis homeobox) family of homeodomain transcription factors play critical roles in the development of several organs. Six1 plays a central role in cranial placode development, including the precursor tissues of the inner ear, as well as other cranial sensory organs and the kidney. In humans, mutations in SIX1 underlie some cases of branchio-oto-renal syndrome (BOR), which is characterized by moderate to severe hearing loss. We utilized CRISPR/Cas9 technology to establish a six1 mutant line in Xenopus tropicalis that is available to the research community. We demonstrate that at larval stages, the six1-null animals show severe disruptions in gene expression of putative Six1 target genes in the otic vesicle, cranial ganglia, branchial arch and neural tube. At tadpole stages, six1-null animals display dysmorphic Meckel’s, ceratohyal and otic capsule cartilage morphology. This mutant line will be of value for the study of the development of several organs as well as congenital syndromes that involve these tissues.
Shedding of Infectious SARS-CoV-2 Despite Vaccination
Authors: Riemersma Kasen K. , Haddock Luis A. , Wilson Nancy A. , Minor Nicholas , Eickhoff Jens , Grogan Brittany E. , Kita-Yarbro Amanda , Halfmann Peter J. , Segaloff Hannah E. , Kocharian Anna , Florek Kelsey R. , Westergaard Ryan , Bateman Allen , Jeppson Gunnar E. , Kawaoka Yoshihiro , O’Connor David H. , Friedrich Thomas C. , Grande Katarina M. 
Published: July 2021

AbstractThe SARS-CoV-2 Delta Variant of Concern is highly transmissible and contains mutations that confer partial immune escape. The emergence of Delta in North America caused the first surge in COVID-19 cases after SARS-CoV-2 vaccines became widely available. To determine whether individuals infected despite vaccination might be capable of transmitting SARS-CoV-2, we compared RT-PCR cycle threshold (Ct) data from 20,431 test-positive anterior nasal swab specimens from fully vaccinated (n = 9,347) or unvaccinated (n=11,084) individuals tested at a single commercial laboratory during the interval 28 June – 1 December 2021 when Delta variants were predominant. We observed no significant effect of vaccine status alone on Ct value, nor when controlling for vaccine product or sex. Testing a subset of low-Ct (<25) samples, we detected infectious virus at similar rates, and at similar titers, in specimens from vaccinated and unvaccinated individuals. These data indicate that vaccinated individuals infected with Delta variants are capable of shedding infectious SARS-CoV-2 and could play a role in spreading COVID-19.
Balancing unity and diversity in a not-for-profit inter-organizational partnership through lateral accountability mechanisms
Authors: Chen Jinhua , Harrison Graeme , Jiao Lu 
Published: July 2021

PurposeThis paper examines how lateral accountability mechanisms may be used to address the unity–diversity tension in a large not-for-profit (NFP) inter-organizational partnership governed under a lead organization model.Design/methodology/approachA case study was conducted in the New South Wales Settlement Partnership comprising 23 NFP organizations providing settlement services for migrants and humanitarian entrants. Multiple data sources included semi-structured interviews, proprietary and publicly available documents and observation.FindingsThe paper demonstrates (1) the usefulness of a strength-based approach that the lead organization adopts in enacting lateral accountability mechanisms, which enables a balance between unity and diversity in the partnership; and (2) the capability of the lead organization governance model to address the unity–diversity tension.Research limitations/implicationsThe paper (1) identifies the importance of a strength-based approach in implementing lateral accountability mechanisms to address the unity–diversity tension; and (2) challenges prior research that advocates the network administrative organization governance model in addressing the tension.Practical implicationsFor practice, the paper identifies a suite of lateral accountability practices designed to address the unity–diversity tension. For policy, it provides confidence for government in promulgating the lead organization governance model in “purchasing” public services.Originality/valueThe paper demonstrates how lateral accountability mechanisms may be used to provide a balance between the objectives of preserving and leveraging the benefits of partner diversity and achieving unity. The strength-based approach (used in enacting the accountability mechanisms), while having a history in psychology and social work research, has not been recognized in prior partnership accountability and governance studies.