bluuebunny/crossref_metadata_2025_split huggingface dataset:
A MICROFLUIDIC DEVICE FOR LONG-TERM MAINTENANCE OF ORGANOTYPIC LIVER CULTURES
Authors: de Hoyos Vega José M. , Hong Hye Jin , Loutherback Kevin , Stybayeva Gulnaz , Revzin Alexander 
Published: June 2022

ABSTRACTLiver cultures may be used for modeling disease progression, testing therapies and predicting drug induced liver injury. The complexity of the liver cultures has evolved over the years from monocultures of hepatocytes to co-cultures with non-parenchymal cells and finally to precision cut liver slices. The latter culture format retains biomolecular and cellular complexity of the native liver and therefore holds considerable promise for in vitro testing. However, liver slices remain functional for ~72 h in vitro and hold only limited utility for some of the disease modeling and therapy testing applications that require longer culture times. This paper describes a microfluidic device for longer-term maintenance of functional organotypic liver cultures. Our microfluidic culture system was designed to enable direct injection of liver tissue into a culture chamber through a valve-enabled side port. Liver tissue was embedded in collagen and remained functional for up to 31 days as highlighted by continued production of albumin. These organotypic cultures also produced bile and urea and expressed several enzymes involved in metabolism of xenobiotics. In contrast, matched liver tissue embedded in collagen and cultured in the same media in a 96-well plate lost its phenotype and function on the timescale of 3 to 5 days. The microfluidic organotypic liver cultures described here represent a significant advance in liver cultivation and may be used in the future for modeling liver diseases or for individualized selection of liver-directed therapies.
A Multi-omics Study on the Oncogenic Roles and Clinical Significance of Dynactin Family Gene (DCTN1-6) Expression in Liver Hepatocellular Carcinoma
Authors: Ullah Md. Asad , Tabassum Tahani , Rashid Afrah , Islam Nafisa Nawal , Park Moon Nyeo , Moin Abu Tayab , Kim Bonglee 
Published: June 2022

AbstractIn this study, we employed a comprehensive database mining approach to examine the possible oncogenic roles and clinical relevance of Dynactin family genes (DCTN1-6) in Liver Hepatocellular Carcinoma (LIHC). All the DCTNs were observed to be differentially expressed in LIHC tissues compared to the adjacent normal liver tissues. Most of the DCTNs were discovered to be aberrantly methylated (less methylated) and contain multiple somatic mutations (alteration frequency: 0.2-2.5%) in LIHC tissues. Overexpression of DCTNs was mostly associated with poor overall and relapse-free survival of LIHC patients. Alongside, all the DCTN genes were reported to be overexpressed across different demographic and clinical conditions, i.e., age, cancer stage, tumor grades, and metastatic stages of LIHC patients. DCTN expression was also associated with the infiltration levels of different immune cells, i.e., B cell, T cell, and macrophages in LIHC microenvironment. The co-expressed genes of DCTNs in the LIHC tissues were previously found to be involved in oncogenic processes in different cancer types and control crucial biological processes, i.e., nucleotide metabolism, RNA degradation, and chromosome organization. Later, the expression pattern of DCTNs was validated in two independent microarray datasets (i.e., GSE17856, GSE98383), which also supported our initial findings. All these findings suggest that DCTNs and their transcriptional and translational products are potential prognostic and therapeutic targets for LIHC diagnosis and treatment. This study will help further the development of DCTN-based diagnostic and therapeutic measures for LIHC and translate them into clinical implications.
Autophagy initiation triggers p150Glued-AP-2β interaction on the lysosomes to facilitate their transport
Authors: Tempes Aleksandra , Bogusz Karolina , Brzozowska Agnieszka , Weslawski Jan , Macias Matylda , Tkaczyk Oliver , Lew Aleksandra , Calka-Kresa Malgorzata , Bernas Tytus , Szczepankiewicz Andrzej A. , Orzoł Katarzyna , Mlostek Magdalena , Kumari Shiwani , Bakun Magdalena , Rubel Tymon , Malik Anna R. , Jaworski Jacek 
Published: June 2022

AbstractThe endocytic adaptor protein 2 (AP-2) complex binds dynactin as part of its noncanonical function, which is necessary for dynein-driven autophagosome transport along microtubules in neuronal axons. The absence of this AP-2-dependent transport causes neuronal morphology simplification and neurodegeneration. The mechanisms that lead to formation of the AP-2–dynactin complex have not been studied to date. However, the inhibition of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) enhances the transport of newly formed autophagosomes by influencing the biogenesis and protein interactions of Rab-interacting lysosomal protein (RILP), another dynein cargo adaptor. We tested effects of mTORC1 inhibition on interactions between the AP-2 and dynactin complexes, with a focus on their two essential subunits, AP-2β and p150Glued. We found that the mTORC1 inhibitor rapamycin enhanced p150Glued–AP-2β complex formation in both neurons and non-neuronal cells. Additional analysis revealed that the p150Glued–AP-2β interaction was indirect and required integrity of the dynactin complex. In non-neuronal cells rapamycin-driven enhancement of the p150Glued–AP-2β interaction also required the presence of cytoplasmic linker protein 170 (CLIP-170), the activation of autophagy, and an undisturbed endolysosomal system. The rapamycin-dependent p150Glued–AP-2β interaction occurred on lysosomal-associated membrane protein 1 (Lamp-1)-positive organelles but without the need for autolysosome formation. Rapamycin treatment also increased the acidification and number of acidic organelles and increased speed of the long-distance retrograde movement of Lamp-1-positive organelles. Altogether, our results indicate that autophagy regulates the p150Glued–AP-2β interaction, possibly to coordinate sufficient motor-adaptor complex availability for effective lysosome transport.
Design, development, and preliminary assessment of a novel peripheral intravenous catheter aimed at reducing early failure rates
Authors: Doyle Barry J. , Kelsey Lachlan J. , Shelverton Caroline , Abbate Gabriella , Ainola Carmen , Sato Noriko , Livingstone Samantha , Bouquet Mahe , Passmore Margaret R , Wilson Emily S. , Colombo Sebastiano , Sato Kei , Liu Keibun , Heinsar Silver , Wildi Karin , Carr Peter J. , Suen Jacky , Fraser John , Li Bassi Gianluigi , Keogh Samantha 
Published: June 2022

ABSTRACTBackgroundPeripheral intravenous catheters (PIVCs) are the most commonly used invasive medical device, yet despite best efforts by end-users, PIVCs experience unacceptably high early failure rates. We aimed to design a new PIVC that reduces the early failure rate of in-dwelling PIVCs and we conducted preliminary tests to assess its efficacy and safety in a large animal model of intravenous access.MethodsWe used computer-aided design and simulation to create a PIVC with a ramped tip geometry, which directs the infused fluid away from the vein wall; we called the design the FloRamp™. We created FloRamp prototypes (test device) and tested them against a market-leading device (BD Insyte™; control device) in a highly-controlled setting with five insertion sites per device in four pigs. We measured resistance to infusion and visual infusion phlebitis (VIP) every six hours and terminated the experiment at 48 hours. Veins were harvested for histology and seven pathological markers were assessed.ResultsComputer simulations showed that the optimum FloRamp tip reduced maximum endothelial shear stress by 60%, from 12.7Pa to 5.1Pa, compared to a typical PIVC tip, and improved the infusion dynamics of saline in the blood stream. In the animal study, we found that 2/5 of the control devices were occluded after 24 hours, whereas all test devices remained patent and functional. The FloRamp created less resistance to infusion (0.73±0.81 vs 0.47±0.50, p=0.06) and lower VIP scores (0.60±0.93 vs 0.31±0.70, p=0.09) that the control device, although neither findings were significantly different. Histopathology revealed that 5/7 of the assessed markers were lower in veins with the FloRamp.ConclusionsAs PIVCs are used in almost every hospitalized patient, there is an urgent need to reduce failure rates. Herein we report preliminary assessment of a novel PIVC design, which could be advantageous in clinical settings through decreased device occlusion.
SARS-CoV-2 escapes direct NK cell killing through Nsp1-mediated downregulation of ligands for NKG2D
Authors: Lee Madeline J. , Leong Michelle W. , Rustagi Arjun , Beck Aimee , Zeng Leiping , Holmes Susan , Qi Lei S. , Blish Catherine A. 
Published: June 2022

SummaryNatural killer (NK) cells are cytotoxic effector cells that target and lyse virally-infected cells; many viruses therefore encode mechanisms to escape such NK cell killing. Here, we interrogated the ability of SARS-CoV-2 to modulate NK cell recognition and lysis of infected cells. We found that NK cells exhibit poor cytotoxic responses against SARS-CoV-2-infected targets, preferentially killing uninfected bystander cells. We demonstrate that this escape is driven by downregulation of ligands for the activating receptor NKG2D (“NKG2D-L”). Indeed, early in viral infection, prior to NKG2D-L downregulation, NK cells are able to target and kill infected cells; however, this ability is lost as viral proteins are expressed. Finally, we found that SARS-CoV-2 non-structural protein 1 (Nsp1) mediates downregulation of NKG2D-L and that Nsp1 alone is sufficient to confer resistance to NK cell killing. Collectively, our work reveals that SARS-CoV-2 evades NK cell cytotoxicity and describes a mechanism by which this occurs.Graphical abstract
Wolbachia action in the sperm produces developmentally deferred chromosome segregation defects during the Drosophila mid-blastula transition
Authors: Warecki Brandt , Titen Simon , Alam Mohammad , Vega Giovanni , Lemseffer Nassim , Hug Karen , Sullivan William 
Published: June 2022

ABSTRACTWolbachia, a vertically transmitted endosymbiont infecting many insects, spreads rapidly through uninfected populations by a mechanism known as Cytoplasmic Incompatibility (CI). In CI, embryos from crosses between Wolbachia-infected males and uninfected females fail to develop due to the immediate action of Wolbachia-produced factors in the first zygotic division. In contrast, viable progeny are produced when the female parent is infected. Here, we find ∼1/3 of embryos from CI crosses in Drosophila simulans develop normally beyond the first and subsequent pre-blastoderm divisions. Developing CI-derived embryos then exhibit chromosome segregation errors during the mid-blastula transition and gastrulation. Single embryo PCR and whole genome sequencing reveal a large percentage of the developed CI-derived embryos bypass the first division defect. Using fluorescence in situ hybridization, we find increased chromosome segregation errors in gastrulating CI-derived embryos that had avoided the first division defect. Thus, Wolbachia in the sperm induces independent immediate and developmentally deferred defects. Like the initial immediate defect, the delayed defect is rescued through crosses to infected females.
Distraction and cognitive control independently impact parietal and prefrontal response to pain
Authors: Silvestrini Nicolas , Corradi-Dell’Acqua Corrado 
Published: June 2022

AbstractPrevious studies found that distracting someone through a challenging activity leads to hypoalgesia, an effect mediated by parietal and prefrontal processes. Other studies suggest that challenging activities affect the ability to regulate one’s aching experiences, due to partially-common neural substrate between cognitive control and pain at the level the medial prefrontal cortex. We investigated effects of distraction and cognitive control on pain by delivering noxious stimulations during or after a Stroop paradigm (requiring high cognitive load) or a neutral condition. We found less intense and unpleasant subjective pain ratings during (compared to after) task execution. This hypoalgesia was associated with enhanced activity at the level of the dorsolateral prefrontal cortex and the posterior parietal cortex, which also showed negative connectivity with the insula. Furthermore, multivariate pattern analysis revealed that distraction altered the neural response to pain, by making it more similar to that associated with previous Stroop tasks. All these effects were independent of the nature of the task which, instead, led to a localized neural modulation around the anterior cingulate cortex. Overall, our study underscores the role played by two facets of human executive functions, which exert independent influence in the neural response of pain.
SEMA: Antigen B-cell conformational epitope prediction using deep transfer learning
Authors: Shashkova Tatiana I. , Umerenkov Dmitriy , Salnikov Mikhail , Strashnov Pavel V. , Konstantinova Alina V. , Lebed Ivan , Shcherbinin Dmitrii N. , Asatryan Marina N. , Kardymon Olga L. , Ivanisenko Nikita V. 
Published: June 2022

AbstractOne of the primary tasks in vaccine design and development of immunotherapeutic drugs is to predict conformational B-cell epitopes corresponding to primary antibody binding sites within the antigen tertiary structure. To date, multiple approaches have been developed to address this issue. However, for a wide range of antigens their accuracy is limited. In this paper, we applied the transfer learning approach using pretrained deep learning models to develop a model that predicts conformational B-cell epitopes based on the primary antigen sequence and tertiary structure. A pretrained protein language model, ESM-1b, and an inverse folding model, ESM-IF1, were fine-tuned to quantitatively predict antibody-antigen interaction features and distinguish between epitope and non-epitope residues. The resulting model called SEMA demonstrated the best performance on an independent test set with ROC AUC of 0.76 compared to peer-reviewed tools. We show that SEMA can quantitatively rank the immunodominant regions within the RBD domain of SARS-CoV-2. SEMA is available at https://github.com/AIRI-Institute/SEMAi and the web-interface http://sema.airi.net.
A universal pipeline for the alignment of electrode tracks with slice histology and electrophysiological data
Authors: Montijn Jorrit S. , Heimel J. Alexander 
Published: June 2022

AbstractModern electrophysiological experiments in neuroscience typically measure the activity of hundreds of neurons across multiple brain regions. Each recorded neuron has to be assigned its correct area of origin, which can be estimated using histological reconstructions of electrode tracks. However, this approach has a limited accuracy with which the probe position can be determined. While some tools exist to assist in this process in mice, such tools are scarce for other species, such as rats or macaques. Moreover, even in mice, a more reliable brain area assignment may be achieved by using spiking response properties to delineate area boundaries along the recording probe. Here we present the Universal Probe Finder, which provides multi-species support for reconstructing a probe’s brain area per spike-sorted cluster or recording site. It can use various data formats and can calculate neuronal responsiveness to experimental interventions with only event times and spike times to provide further neurophysiological markers that simplify and improve the reliability of assigning brain areas to neurons. The program can be downloaded here: https://github.com/JorritMontijn/UniversalProbeFinder.
Anaerobic methane oxidizing archaea offset sediment methane concentrations in Arctic thermokarst lagoons
Authors: Yang Sizhong , Anthony Sara E. , Jenrich Maren , In ‘t Zandt Michiel H. , Strauss Jens , Overduin Pier Paul , Grosse Guido , Angelopoulos Michael , Biskaborn Boris K. , Grigoriev Mikhail N. , Wagner Dirk , Knoblauch Christian , Jaeschke Andrea , Rethemeyer Janet , Kallmeyer Jens , Liebner Susanne 
Published: June 2022

AbstractThermokarst lagoons represent the transition state from a freshwater lacustrine to a marine environment, and receive little attention regarding their role for greenhouse gas production and release in Arctic permafrost landscapes. We studied the fate of methane (CH4) in sediments of a thermokarst lagoon in comparison to two thermokarst lakes on the Bykovsky Peninsula in northeastern Siberia through the analysis of sediment CH4concentrations and isotopic signature, methane-cycling microbial taxa, sediment geochemistry, and lipid biomarkers. We specifically assessed whether sulfate-driven anaerobic methane oxidation (S-AOM) through anaerobic methanotrophic archaea (ANMEs), common in marine sediments with constant supply of sulfate and methane, establish after thermokarst lagoon development and whether sulfate-driven ANMEs consequently oxidize CH4that would be emitted to the water column under thermokarst lake conditions. The marine-influenced lagoon environment had fundamentally different methane-cycling microbial communities and metabolic pathways compared to the freshwater lakes, suggesting a substantial reshaping of microbial and carbon dynamics during lagoon formation. Anaerobic sulfate-reducing ANME-2a/2b methanotrophs dominated the sulfate-rich sediments of the lagoon despite its known seasonal alternation between brackish and freshwater inflow. CH4concentrations in the freshwater-influenced sediments averaged 1.34±0.98 µmol g−1, with highly depleted δ13C-CH4values ranging from -89‰ to -70‰. In contrast, the sulfate-affected upper 300 cm of the lagoon exhibited low average CH4concentrations of 0.011±0.005 µmol g−1with comparatively enriched δ13C-CH4values of -54‰ to -37‰ pointing to substantial methane oxidation. Non-competitive methylotrophic methanogens dominated the methanogenic community of the lakes and the lagoon, independent of porewater chemistry and depth. This potentially contributed to the high CH4concentrations observed in all sulfate-poor sediments. Our study shows that S-AOM in lagoon sediments can effectively reduce sediment CH4concentrations and we conclude that thermokarst lake to lagoon transitions have the potential to mitigate terrestrial methane fluxes before thermokarst lakes fully transition to a marine environment.
Retinal metabolism: Evidence for uncoupling of glycolysis and oxidative phosphorylation via Cori-, Cahill-, and mini-Krebs-cycle
Authors: Chen Yiyi , Zizmare Laimdota , Calbiague Victor , Wang Lan , Yu Shirley , Herberg Friedrich W. , Schmachtenberg Oliver , Paquet-Durand François , Trautwein Christoph 
Published: June 2022

AbstractThe retina consumes massive amounts of energy, yet its metabolism and substrate exploitation remain poorly understood. Here, we used a murine explant model to manipulate retinal energy metabolism under entirely controlled conditions and utilized1H-NMR spectroscopy-based metabolomics, in situenzyme detection, and cell viability readouts to uncover the pathways of retinal energy production. Our experimental manipulations resulted in varying degrees of photoreceptor degeneration, while the inner retina and retinal pigment epithelium were essentially unaffected. This selective vulnerability of photoreceptors suggested very specific adaptations in their energy metabolism. Rod photoreceptors were found to rely strongly on oxidative phosphorylation, but only mildly on glycolysis. Conversely, cone photoreceptors were dependent on glycolysis but insensitive to electron transport chain decoupling. Importantly, photoreceptors appeared to uncouple glycolytic and Krebs-cycle metabolism via three different pathways: 1) the mini-Krebs-cycle, fueled by glutamine and branched-chain amino acids, generating N-acetylaspartate; 2) the alanine-generating Cahill-cycle; 3) the lactate-releasing Cori-cycle. Moreover, the metabolomic data indicated a shuttling of taurine and hypotaurine between the retinal pigment epithelium and photoreceptors, likely resulting in an additional net transfer of reducing power to photoreceptors. These findings expand our understanding of retinal physiology and pathology and shed new light on neuronal energy homeostasis and the pathogenesis of neurodegenerative diseases.Graphical abstractRetinal photoreceptors employ both glucose and glutamate as fuels. While rod photoreceptors rely strongly on oxidative phosphorylation and the N-acetylaspartate producing mini-Krebs-cycle, cone photoreceptors rely on the lactate-producing Cori cycle and the oxidative, alanine producing Cahill cycle.HighlightsThe retina utilizes a complex energy switchboard consisting of the Krebs cycle, mini-Krebs cycle, Cahill cycle, and Cori cycle.Mini-Krebs cycle runs more efficiently than ‘full’ Krebs cycle.Alanine transaminase decouples glycolysis from the Krebs cycle.Lactate, alanine, and N-acetylaspartate are distinctive energetic pathway signatures.
Bilateral JNK activation is a hallmark of interface contractility and promotes elimination of aberrant cells
Authors: Prasad Deepti , Illek Katharina , Fischer Friedericke , Holstein Kathrin , Classen Anne-Kathrin 
Published: June 2022

AbstractTissue-intrinsic defence mechanisms eliminate aberrant cells from epithelia and thereby maintain the health of developing tissues or adult organisms. ‘Interface contractility’ comprises one such distinct mechanism that specifically guards against aberrant cells, which undergo inappropriate cell fate and differentiation programs. The cellular mechanisms which facilitate detection and elimination of these aberrant cells are currently unknown. We find that in Drosophila imaginal discs, interface contractility is associated with bilateral JNK activation at the clonal interface of wild type and aberrant cells. Bilateral JNK activation is unique to interface contractility and is not observed in other tissue-intrinsic defence mechanisms, such as cell-cell competition. We find that JNK is activated cell-autonomously by either of the contacting cell types and drives apoptotic elimination of cells at clonal interfaces. Ultimately, JNK interface signalling provides a collective tissue-level mechanism, which ensures elimination of aberrant, misspecified cells that cannot be identified by cell fitness criteria, as in cell-cell competition. Importantly, oncogenic Ras activates interface contractility but evades apoptotic elimination by bilateral JNK activation. Combined, our work establishes bilateral JNK interface signalling and interface apoptosis as a new hallmark of interface contractility, and it highlights how oncogenic mutations evade tumour suppressor function encoded by this tissue-intrinsic surveillance system.