bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular network analyses implicate death-associated protein kinase 3 (DAPK3) as a key factor in colitis-associated dysplasia progression
Authors: Chen Huey-Miin , MacDonald Justin A. 
Published: September 2021

ABSTRACTUlcerative colitis (UC) is a progressive disorder that elevates the risk of cancer development through a colitis-dysplasia-carcinoma sequence. Differential gene expression (DEGs) profiles of three UC clinical subtypes and healthy controls were developed for the GSE47908 microarray dataset [n = 15 (healthy controls), n = 20 (left-sided colitis), n = 19 (pancolitis), and n = 6 (colitis-associated dysplasia, CAD)] using limma R. Gene ontology (GO) enrichment analysis of DEGs revealed a shift in transcriptome landscape as UC progressed from left-sided colitis to pancolitis to CAD, from being immune-centric to being cytoskeleton-dependent. Hippo signaling (via Yes-associated protein, YAP) and Ephrin receptor signaling were the top canonical pathways progressively altered in concert with the pathogenic progression of UC. Molecular interaction network analysis of DEGs in left-sided colitis, pancolitis, and CAD revealed one pairwise line or edge that was topologically important to the network structure. This edge was found to be highly enriched in actin-based processes, and death-associated protein kinase 3 (DAPK3) was a critical member and sole protein kinase associated with this edge. DAPK3 is a regulator of actin-cytoskeleton reorganization that controls proliferation and apoptosis. Differential correlation analyses revealed a negative correlation for DAPK3-YAP in healthy controls which flipped to positive in left-sided colitis. With UC progression to CAD, the DAPK3-YAP correlation grew progressively more positive. In summary, DAPK3 was identified as a candidate gene involved in UC progression to dysplasia.
Who is at risk of poor mental health following COVID-19 outpatient management?
Authors: Hüfner Katharina , Tymoszuk Piotr , Ausserhofer Dietmar , Sahanic Sabina , Pizzini Alex , Rass Verena , Galffy Matyas , Böhm Anna , Kurz Katharina , Sonnweber Thomas , Tancevski Ivan , Kiechl Stefan , Huber Andreas , Plagg Barbara , Wiedermann Christian , Bellmann-Weiler Rosa , Bachler Herbert , Weiss Günter , Piccoliori Giuliano , Helbok Raimund , Löffler-Ragg Judith , Sperner-Unterweger Barbara 
Published: September 2021

AbstractBackgroundCOVID-19 convalescents are at risk of developing a de novo mental health disorder or of worsening of a pre-existing one. The objectives of our study was to phenotype individuals at highest risk of mental health disorders among COVID-19 outpatients.MethodsWe conducted a binational online survey study with adult non-hospitalized COVID-19 convalescents (Austria/AT: n=1157, Italy/IT: n= 893). Primary endpoints were positive screening for depression and anxiety (PHQ-4, Patient Health Questionnaire) and self-perceived overall mental health and quality of life rated with 4 point Likert scales. Psychosocial stress was surveyed with a modified PHQ stress module. Associations of the mental health with socio-demographic variables, COVID-19 course and recovery data were assessed by multi-parameter random forest and serial univariable modeling. Mental disorder risk subsets were defined by self-organizing map and hierarchical clustering algorithms. The survey analyses are publicly available (https://im2-ibk.shinyapps.io/mental_health_dashboard/).ResultsIn the study cohorts, 4.6 (IT)/6% (AT) of participants reported depression and/or anxiety before to infection. At a median of 79 days (AT)/96 days (IT) post COVID-19 onset, 12.4 (AT)/19.3% (IT) of subjects were screened positive for anxiety and 17.3 (AT)/23.2% (IT) for depression. Over one-fifth of the respondents rated their overall mental health (AT: 21.8%, IT: 24.1%) or quality of life (AT: 20.3%, IT: 25.9%) as fair or poor. In both study collectives, psychosocial stress, high numbers of acute and persistent COVID-19 complaints and the presence of acute neurocognitive symptoms (impaired concentration, confusion, forgetfulness) were the strongest correlates of deteriorating mental health and poor quality of life. In clustering analysis, these variables defined a ‘high risk’ subset with particularly high propensity of post-COVID-19 mental health impairment and decreased quality of life. Pre-existing depression or anxiety was associated with an increased symptom burden during acute COVID-19 and recovery.ConclusionOur study revealed a bidirectional relationship between COVID-19 symptoms and mental health. We put forward specific acute symptoms of the disease as ‘red flags’ of mental health deterioration which should prompt general practitioners to identify COVID-19 patients who may benefit from early psychological and psychiatric intervention.Trial registrationClinicalTrials.gov: NCT04661462.
Preliminary Report of Academic CAR-T (ISIKOK-19) Cell Clinical Trial in Turkey: Characterization of Product and Outcomes of Clinical Application
Authors: Erdogan Ebru , Yalcin Koray , Hemsinlioglu Cansu , Sezgin Aslihan , Seyis Utku , Kancagi Derya Dilek , Tastan Cihan , Yurtsever Bulut , Turan Raife Dilek , Cakirsoy Didem , Abanuz Selen , Karakus Gozde Sir , Elek Muhammer , Bekoz Huseyin Saffet , Gemici Ali İhsan , Sargin Deniz , Arat Mutlu , Ferhanoglu Burhan , Pekguc Ebru , Ornek Serdar , Buyuktas Deram , Birgen Nur , Ratip Siret , Ovali Ercument 
Published: September 2021

AbstractObjectiveChimeric antigen receptor T (CAR-T) cell therapies already made an impact on the treatment of B cell malignancies. Although CAR-T cell therapies are promising, there are concerns with commercial products regarding their affordability and sustainability. In this preliminary study, results of the first productional and clinical data of academic CAR-T cell (ISIKOK-19) from Turkey are presented.Materials and MethodsA pilot clinical trial (NCT04206943) designed to assess the safety and feasibility of ISIKOK-19 T-cell therapy in patients with relapsed and refractory CD19+ tumors was conducted and participating patients received ISIKOK-19 infusions between October 2019 and July 2021. Production data of the first 8 patients and the clinical outcome of 7 patients who received ISIKOK-19 cell infusion is presented in this study.ResultsNine patients were enrolled for the trial (ALL n=5 and NHL n=4) but only 7 patients could receive the treatment. Two out of three ALL patients and three out of four NHL patients had complete/partial response (ORR 72%). Four patients (57%) had CAR-T-related toxicities (CRS, CRES, and pancytopenia). Two patients were unresponsive and had progressive disease following CAR-T therapy. Two patients with partial response had progressive disease during follow-up.ConclusionProduction efficacy and fulfilling the criteria of quality control were satisfactory for academic production. Response rates and toxicity profiles are acceptable for this heavily pretreated/refractory patient group. ISIKOK-19 cells appear to be a safe, economical, and efficient treatment option for CD19 positive tumors. The findings of this study need to be supported by the currently ongoing clinical trial of ISIKOK-19.
Lactoferricins access the cytosol of Escherichia coli within few seconds
Authors: Semeraro Enrico F. , Marx Lisa , Mandl Johannes , Letofsky-Papst Ilse , Mayrhofer Claudia , Frewein Moritz P. K. , Scott Haden L. , Prévost Sylvain , Bergler Helmut , Lohner Karl , Pabst Georg 
Published: September 2021

AbstractWe report the real-time response of E. coli to lactoferricin-derived antimicrobial peptides (AMPs) on length-scales bridging microscopic cell-sizes to nanoscopic lipid packing using millisecond time-resolved synchrotron small-angle X-ray scattering. Coupling a multi-scale scattering data analysis to biophysical assays for peptide partitioning revealed that the AMPs rapidly saturate the bacterial envelope and reach the cytosol within less than three seconds—much faster than previously considered. Final cytosolic AMP concentrations of ~ 100 mM suggest an efficient shut-down of metabolism as primary cause for bacterial killing. On the other hand, the damage of the cell envelope is a collateral effect of AMP activity that does not kill the bacteria. This implies that the impairment of the membrane barrier is a necessary but not sufficient condition for microbial killing by lactoferricins. The most efficient AMP studied exceeds others in both speed of reaching cytoplasm and lowest cytosolic peptide concentration.
Myofibril orientation as a metric for characterizing heart disease
Authors: Ma Weikang , Gong Henry , Jani Vivek , Landim-Vieira Maicon , Papadaki Maria , Pinto Jose R. , Aslam M. Imran , Cammarato Anthony , Irving Thomas 
Published: September 2021

AbstractMyocyte disarray is a hallmark of many cardiac disorders. However, the relationship between alterations in the orientation of individual myofibrils and myofilaments to disease progression has been largely underexplored. This oversight has predominantly been due to a paucity of methods for objective and quantitative analysis. Here we introduce a novel, less-biased approach to quantify myofibrillar and myofilament orientation in cardiac muscle under near physiological conditions and demonstrate its superiority as compared to conventional histological assessments. Using small-angle X-ray diffraction, we first investigated changes in myofibrillar orientation at increasing sarcomere lengths in permeabilized, relaxed, wildtype mouse myocardium by assessing the angular spread of the 1,0 equatorial reflection (angle σ). At a sarcomere length (SL) of 1.9 μm, the angle σ was 0.23±0.01 rad, decreased to 0.19±0.01 rad at a SL of 2.1 μm, and further decreased to 0.15±0.01 rad at a SL of 2.3 μm (p<0.0001). Angle σ was significantly larger in R403Q, a MYH7 hypertrophic cardiomyopathy (HCM) model, porcine myocardium (0.24±0.01 rad) compared to WT myocardium (0.14±0.005 rad, p<0.0001) as well as in human heart failure tissue (0.19±0.006 rad) when compared to non-failing samples (0.17±0.007 rad, p=0.01). These data indicate that diseased myocardium suffers from greater myofibrillar disorientation compared to healthy controls. Finally, we showed that conventional, histology-based analysis of disarray can be subject to user bias and/or sampling error and lead to false positives. Our method for directly assessing myofibrillar orientation avoids the artifacts introduced by conventional histological approaches that assess myocyte orientation and only indirectly evaluate myofibrillar orientation, and provides a precise and objective metric for phenotypically characterizing myocardium. The ability to obtain excellent X-ray diffraction patterns from frozen human myocardium provides a new tool for investigating structural anomalies associated with cardiac diseases.Statement of SignificanceWe introduce a precise and quantitative approach to directly measure myofibrillar and myofilament orientation in cardiac muscle under near physiological conditions as a novel tool for phenotypically characterizing striated muscle systems. We use this technique to demonstrate that myocardium from disease model organisms and failing human myocardium suffers from greater myofibrillar disorientation compared to healthy controls. We also demonstrate that excellent diffraction patterns can be obtained from frozen and thawed human myocardium. Given the ready availability of frozen human heart tissue in tissue banks, this capability opens up a large space of potential experiments relating sarcomere structure to dysfunction in cardiac disorders.
Radial-axial transport coordination enhances sugar translocation in the phloem vasculature of plants
Authors: Nakad Mazen , Domec Jean-Christophe , Sevanto Sanna , Katul Gabriel 
Published: September 2021

AbstractMass transport of photosynthates in the phloem of plants is necessary for describing plant carbon allocation, productivity, and responses to water and thermal stress. Several hypotheses about optimization of phloem structure and function and limitations of phloem transport under drought have been proposed, and tested with models and anatomical data. However, the true impact of radial water exchange of phloem conduits with their surroundings on mass transport of photosynthates has not been addressed. Here, the physics of the Munch mechanism of sugar transport is re-evaluated to include local variations in viscosity resulting from the radial water exchange in two dimensions (axial and radial). Model results show that radial water exchange pushes sucrose away from conduit walls thereby reducing wall frictional stress due to a decrease in sap viscosity and an increase in sugar concentration in the central region of the conduit. These two co-occurring effects lead to increased sugar front speed and axial mass transport across a wide range of phloem conduit lengths. Thus, sugar transport operates more efficiently than predicted by previous models that ignore these two effects. A faster front speed leads to higher phloem resiliency under drought because more sugar can be transported with a smaller pressure gradient.SummaryThe overall speed of sap increased by including a concentrationdependent viscosity in axial and radial directions.
The Fe-S cluster assembly factors NFU4 and NFU5 are primarily required for protein lipoylation in mitochondria
Authors: Przybyla-Toscano Jonathan , Maclean Andrew E. , Franceschetti Marina , Liebsch Daniela , Vignols Florence , Keech Olivier , Rouhier Nicolas , Balk Janneke 
Published: September 2021

ABSTRACTPlants have evolutionarily conserved NFU-domain proteins that are targeted to plastids or mitochondria. The ‘plastid-type’ NFU1, NFU2 and NFU3 in Arabidopsis thaliana play a role in iron-sulfur (Fe-S) cluster assembly in this organelle, whereas the type-II NFU4 and NFU5 proteins have not been subjected to mutant studies in any plant species to determine their biological role. Here we confirm that NFU4 and NFU5 are targeted to the mitochondria. The proteins are constitutively produced in all parts of the plant, suggesting a housekeeping function. Double nfu4 nfu5 knockout mutants were embryonic lethal, and depletion of the proteins led to growth arrest of young seedlings. Biochemical analyses revealed that NFU4 and NFU5 are required for lipoylation of the H proteins of the glycine decarboxylase complex and the E2 subunits of other mitochondrial dehydrogenases, with little impact on Fe-S cluster-containing respiratory complexes and aconitase. Consequently, the Gly-to-Ser ratio was increased in mutant seedlings and early growth was improved by elevated CO2. In addition, pyruvate, 2-oxoglutarate and branched-chain amino acids accumulated in the nfu4 nfu5 mutants, further supporting defects in the other three mitochondrial lipoate-dependent enzyme complexes. NFU4 and NFU5 interacted with mitochondrial lipoyl synthase (LIP1) in yeast 2-hybrid and bimolecular fluorescence complementation assays. These data indicate that NFU4 and NFU5 have a more specific function than previously thought, in providing Fe-S clusters to lipoyl synthase.One sentence summaryA pair of evolutionarily conserved proteins involved in iron-sulfur cofactor assembly have a specific role in lipoate biosynthesis for mitochondrial dehydrogenases.
Genetic interplay between type II topoisomerase enzymes and chromosomal ccdAB toxin-antitoxin in E. coli
Authors: Kim Jay W. , Blay Vincent , Mira Portia , Barlow Miriam , Camps Manel 
Published: September 2021

AbstractFluoroquinolones are one of the most widely used class of antibiotics. They target two type II topoisomerase enzymes: gyrase and topoisomerase IV. Resistance to these drugs, which is largely caused by mutations in their target enzymes, is on the rise and becoming a serious public health risk. In this work, we analyze the sequences of 352 extraintestinal E. coli clinical isolates to gain insights into the selective pressures shaping the type II topoisomerase mutation landscape in E. coli. We identify both Quinolone Resistance-Determining Region (QRDR) and non-QRDR mutations, outline their mutation trajectories, and show that they are likely driven by different selective pressures. We confirm that ciprofloxacin resistance is specifically and strongly associated with QRDR mutations. By contrast, non-QRDR mutations are associated with the presence of the chromosomal version of ccdAB, a toxin-antitoxin operon, where the toxin CcdB is known to target gyrase. We also find that ccdAB and the evolution of QRDR mutation trajectories are partially incompatible. Finally, we identify partial deletions in CcdB and additional mutations that likely facilitate the compatibility between the presence of the ccdAB operon and QRDR mutations. These “permissive” mutations are all found in ParC (a topoisomerase IV subunit). This, and the fact that CcdB-selected mutations frequently map to topoisomerase IV, strongly suggests that this enzyme (in addition to gyrase) is likely a target for the toxin CcdB in E. coli, although an indirect effect on global supercoiling cannot be excluded. This work opens the door for the use of the presence of ccdB and of the proposed permissive mutations in the genome as genetic markers to assess the risk of quinolone resistance evolution and implies that certain strains may be genetically more refractory to evolving quinolone resistance through mutations in target enzymes.
Region-specific KCC2 rescue by rhIGF-1 and oxytocin in a mouse model of Rett syndrome
Authors: Gigliucci Valentina , Teutsch Jasper , Woodbury-Smith Marc , Luoni Mirko , Busnelli Marta , Chini Bice , Banerjee Abhishek 
Published: September 2021

AbstractRett syndrome (RTT) is characterized by dysfunction in neuronal excitation/inhibition (E/I) balance, potentially impacting seizure susceptibility via deficits in K+/Cl- cotransporter 2 (KCC2) function. Mice lacking the Methyl-CpG binding protein 2 (MeCP2) recapitulate many symptoms of RTT, and recombinant human insulin-like growth factor-1 (rhIGF-1) restores KCC2 expression and E/I balance in MeCP2 KO mice. However, clinical trial outcomes of rhIGF-1 in RTT have been variable, and increasing its therapeutic efficacy is highly desirable. To this end, the neuropeptide oxytocin (OXT) is promising, as it also critically modulates KCC2 function during early postnatal development. We measured basal KCC2 expression levels in MeCP2 KO mice and identified three key frontal brain regions showing KCC2 alterations in young adult mice but not in postnatal P10 animals. We thus hypothesized that deficits in an IGF-1/OXT signaling crosstalk modulating KCC2 may occur in RTT during postnatal development. Consistently, we detected alterations of IGF-1 receptor (IGF-1R) and OXT receptor (OXTR) levels in those brain areas. rhIGF-1 and OXT treatments in KO mice rescued KCC2 expression in a region-specific and complementary manner. These results suggest that region-selective combinatorial pharmacotherapeutic strategies could be the most effective at normalizing E/I balance in key brain regions subtending the RTT pathophysiology.
Identification of bacteriophage genome sequences with representation learning
Authors: Bai Zeheng , Zhang Yao-zhong , Miyano Satoru , Yamaguchi Rui , Fujimoto Kosuke , Uematsu Satoshi , Imoto Seiya 
Published: September 2021

AbstractMotivationBacteriophages/Phages are the viruses that infect and replicate within bacteria and archaea, and rich in human body. To investigate the relationship between phages and microbial communities, the identification of phages from metagenome sequences is the first step. Currently, there are two main methods for identifying phages: database-based (alignment-based) methods and alignment-free methods. Database-based methods typically use a large number of sequences as references; alignment-free methods usually learn the features of the sequences with machine learning and deep learning models.ResultsWe propose INHERIT which uses a deep representation learning model to integrate both database-based and alignment-free methods, combining the strengths of both. Pre-training is used as an alternative way of acquiring knowledge representations from existing databases, while the BERT-style deep learning framework retains the advantage of alignment-free methods. We compare INHERIT with four existing methods on a third-party benchmark dataset. Our experiments show that INHERIT achieves a better performance with the F1-score of 0.9932. In addition, we find that pre-training two species separately helps the non-alignment deep learning model make more accurate predictions.AvailabilityThe codes of INHERIT are now available in: https://github.com/Celestial-Bai/INHERIT.Contactyaozhong@ims.u-tokyo.ac.jp and imoto@hgc.jpSupplementary informationSupplementary data are available at BioRxiv online.
Glycerol-driven Denitratation: Process Kinetics, Microbial Ecology, and Operational Controls
Authors: Baideme Matthew P. , Long Chenghua , Plante Luke T. , Starke Jeffrey A. , Butkus Michael A. , Chandran Kartik 
Published: September 2021

ABSTRACTDenitratation, the selective reduction of nitrate to nitrite, is a novel process when coupled with anaerobic ammonium oxidation (anammox) could achieve resource-efficient biological nitrogen removal of ammonium- and nitrate-laden waste streams. Using a fundamentally-based, first principles approach, this study optimized a stoichiometrically-limited, glycerol-driven denitratation process and characterized mechanisms supporting nitrite accumulation with results that aligned with expectations. Glycerol supported selective nitrate reduction to nitrite and near-complete nitrate conversion, indicating its viability in a denitratation system. Glycerol-supported specific rates of nitrate reduction (135.3 mg-N/g-VSS/h) were at least one order of magnitude greater than specific rates of nitrite reduction (14.9 mg-N/g-VSS/h), potentially resulting in transient nitrite accumulation and indicating glycerol’s superiority over other organic carbon sources in denitratation systems. pH and ORP inflection points in nitrogen transformation assays corresponded to maximum nitrite accumulation, indicating operational setpoints to prevent further nitrite reduction. Denitratation conditions supported enrichment of Thauera sp. as the dominant genus. Stoichiometric limitation of influent organic carbon, coupled with differential nitrate and nitrite reduction kinetics, optimized operational controls, and a distinctively enriched microbial ecology, was identified as causal in glycerol-driven denitratation.