bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel plasma exosome biomarkers for prostate cancer progression in co-morbid metabolic disease
Authors: Jafari Naser , Chen Andrew , Kolla Manohar , Pompa Isabella R. , Qiu Yuhan , Yu Rebecca , Llevenes Pablo , Ennis Christina S. , Mori Joakin , Mahdaviani Kiana , Halpin Meredith , Gignac Gretchen A. , Heaphy Christopher M. , Monti Stefano , Denis Gerald V. 
Published: February 2022

AbstractComorbid Type 2 diabetes (T2D), a metabolic complication of obesity, associates with worse cancer outcomes for prostate, breast, head and neck, colorectal and several other solid tumors. However, the molecular mechanisms remain poorly understood. Emerging evidence shows that exosomes carry miRNAs in blood that encode the metabolic status of originating tissues and deliver their cargo to target tissues to modulate expression of critical genes. Exosomal communication potentially connects abnormal metabolism to cancer progression. Here, we hypothesized that T2D plasma exosomes induce epithelial-mesenchymal transition (EMT) and immune checkpoints in prostate cancer cells. We demonstrate that plasma exosomes from subjects with T2D induce EMT features in prostate cancer cells and upregulate the checkpoint genesCD274andCD155. We demonstrate that specific exosomal miRNAs that are differentially abundant in plasma of T2D adults compared to nondiabetic controls (miR374a-5p, miR-93-5p and let-7b-3p) are delivered to cancer cells, thereby regulating critical target genes. We build on our previous reports showing BRD4 controls migration and dissemination of castration-resistant prostate cancer, and transcription of key EMT genes, to show that T2D exosomes require BRD4 to drive EMT and immune ligand expression. We validate our findings with gene set enrichment analysis of human prostate tumor tissue in TGCA genomic data. These results suggest novel, non-invasive approaches to evaluate and potentially block progression of prostate and other cancers in patients with comorbid T2D.
Platinum-Induced Mitochondrial OXPHOS Contributes to Cancer Stem Cell Enrichment in Ovarian Cancer
Authors: Sriramkumar Shruthi , Sood Riddhi , Huntington Thomas D. , Ghobashi Ahmed H. , Wang Weini , Nephew Kenneth P. , O’Hagan Heather M. 
Published: February 2022

AbstractBackgroundPlatinum based agents – cisplatin and carboplatin in combination with taxanes are used for the treatment of ovarian cancer (OC) patients. However, the majority of OC patients develop recurrent, platinum resistant disease that is uniformly fatal. Acute platinum treatment enriches for chemoresistant aldehyde dehydrogenase (ALDH) + ovarian cancer stem cells (OCSCs), which contribute to tumor recurrence and disease relapse. Acquired platinum resistance includes metabolic reprograming and switching to oxidative phosphorylation (OXPHOS). Chemosensitive cells rely on glycolysis while chemoresistant cells have the ability to switch between glycolysis and OXPHOS, depending on which pathway drives a selective advantage for growth and chemoresistance. High expression of genes involved in OXPHOS and high production of mitochondrial ROS are characteristics of OCSCs, suggesting that OCSCs favor OXPHOS over glycolysis. Based on connections between OCSCs, chemoresistance and OXPHOS, we hypothesize that platinum treatment induces changes in metabolism that contribute to platinum-induced enrichment of OCSCs.MethodsThe effect of cisplatin on mitochondrial activity was assessed by JC1 staining and expression of OXPHOS genes by quantitative RTPCR. Cisplatin-induced changes in Sirtuin 1 (SIRT1) levels and activity were assessed by Western blot. Small molecule inhibitors of mitochondrial complex I and SIRT1 were used to determine if their enzymatic activity contributes to the platinum-induced enrichment of OCSCs. The percentage of ALDH+ OCSCs in OC cells and tumor tissue from xenograft models across different treatment conditions was analyzed using ALDEFLUOR assay and flow cytometry.ResultsWe demonstrate that acute platinum treatment increases mitochondrial activity. Combined treatment of platinum agents and OXPHOS inhibitors blocks the platinum-induced enrichment of ALDH+ OCSCs in vitro and in vivo. Furthermore, platinum treatment increases SIRT1 levels and subsequent deacetylase activity, which likely contributes to the increase in platinum-induced mitochondrial activity.ConclusionsThese findings on metabolic pathways altered by platinum-based chemotherapy have uncovered key targets that can be exploited therapeutically to block the platinum-induced enrichment of OCSCs, ultimately improving the survival of OC patients.
The Longitudinal Aging Study Amsterdam COVID-19 exposure index: a cross-sectional analysis of the impact of the pandemic on daily functioning of older adults
Authors: Hoogendijk Emiel O. , Schuster Noah A. , van Tilburg Theo G. , Schaap Laura A. , Suanet Bianca , de Breij Sascha , Kok Almar A.L. , van Schoor Natasja M. , Timmermans Erik J. , de Jongh Renate T. , Visser Marjolein , Huisman Martijn 
Published: February 2022

ABSTRACTObjectivesThe aim of this study was to develop an index to measure older adults’ exposure to the COVID-19 pandemic, and to study its association with various domains of functioning.DesignCross-sectional study.SettingThe Longitudinal Aging Study Amsterdam (LASA), a cohort study in the Netherlands.ParticipantsCommunity dwelling older adults aged 62-102 years (n=1089) who participated in the LASA COVID-19 study (June-September 2020), just after the first wave of the pandemic.Primary outcome measuresA 35-item COVID-19 exposure index with a score ranging between 0 and 1 was developed, including items that assess the extent to which the COVID-19 situation affected daily lives of older adults. Descriptive characteristics of the index were studied, stratified by several socio-demographic factors. Logistic regression analyses were performed to study associations between the exposure index and several indicators of functioning (functional limitations, anxiety, depression, and loneliness).ResultsThe mean COVID-19 exposure index score was 0.20 (SD 0.10). Scores were relatively high among women and in the southern region of the Netherlands. In models adjusted for socio-demographic factors and pre-pandemic functioning (2018-2019), those with scores in the highest tertile of the exposure index were more likely to report functional limitations (OR: 2.23; 95% CI: 1.48 to 3.38), anxiety symptoms (OR: 3.87; 95% CI: 2.27 to 6.61), depressive symptoms (OR: 2.45; 95% CI: 1.53 to 3.93) and loneliness (OR: 2.97; 95% CI: 2.08-4.26) than those in the lowest tertile.ConclusionsAmong older adults in the Netherlands, those with higher scores on a COVID-19 exposure index reported worse functioning in the physical, mental and social domain. The index may be used to identify persons for whom targeted interventions are needed to maintain or improve functioning during the pandemic or post-pandemic.Strengths and limitations of this studyThis study was based on a representative sample of older adults from three culturally different regions in the Netherlands.The Longitudinal Aging Study Amsterdam COVID-19 study provides unique data on functioning of older adults in various life domains during the COVID-19 pandemic.The items of the COVID-19 exposure index that was developed were based on self-report, more objective sources such as medical records were lacking.The study covered the first months of the pandemic in the Netherlands, longitudinal data is needed to monitor functioning of older adults in later stages of the pandemic.
Enhancing high-temperature degradation of polyethylene terephthalate through a synergistic division of enzyme labour between a solid-degrading thermostable cutinase and a reaction intermediate-degrading thermostable carboxylesterase
Authors: Mrigwani Arpita , Thakur Bhishem , Guptasarma Purnananda 
Published: February 2022

AbstractCutinases degrade PET (polyethylene terephthalate) into various degradation intermediates (DIs) such as OET (oligoethylene terephthalate), BHET (bis-hydroxyethyl terephthalate), and MHET (mono-hydroxyethyl terephthalate), and eventually into TPA (terephthalic acid), which is the terminal product of degradation. Unlike PET, which is insoluble, TPA and the DIs are sparingly soluble in water. This causes both DIs and TPA to be partitioned into aqueous solution, where DIs accumulate without undergoing significant further degradation, despite being better substrates of cutinase than solid PET. This frustrates the creation of a circular economy involving PET and TPA (since TPA must be separated from DIs before re-condensation into PET). We argue that the non-degradation of DIs owes to cutinase becoming progressively depleted from solution, through binding to solid PET. This creates a conundrum, in that degradation of PET is anticipated to be inversely correlated with degradation of DIs (at least while solid PET remains available to deplete cutinase from solution), causing any improvement of the cutinase’s PET-binding efficiency to only further ensure non-degradation of released DIs. Here, we propose the deployment of a second DI-degrading enzyme; one that remains in solution, and acts as an ‘assistant’ to the ‘master’ PET-invading cutinase acting upon PET’s surface. We demonstrate that one such dual-enzyme system, consisting of a thermostable Thermus thermophilus carboxylesterase (TTCE), characterized here for the first time, and the already-used thermostable leaf-branch compost cutinase (LCC), allows complete degradation of all products of PET hydrolysis into TPA in solution, at 60 °C, even in the presence of residual solid PET.
Chromatin sequesters pioneer transcription factor Sox2 from exerting force on DNA
Authors: Nguyen Tuan , Li Sai , Chang Jeremy , Watters John , Ng Htet , Osunsade Adewola , David Yael , Liu Shixin 
Published: February 2022

AbstractFormation of biomolecular condensates constitutes an emerging mechanism for transcriptional regulation. Recent studies suggest that the co-condensation between transcription factors (TFs) and DNA can generate mechanical forces driving genome rearrangements. However, the reported forces generated by such protein-DNA co-condensation are typically below one piconewton (pN), questioning its physiological significance. Moreover, the force-generating capacity of these condensates in the chromatin context remains unknown. Using single-molecule biophysical techniques, we show that Sox2, a nucleosome-binding pioneer TF, forms co-condensates with DNA, thereby exerting considerable mechanical tension on DNA strands both in cis and trans. Sox2 can generate forces up to 7 pN—similar in magnitude to other cellular forces. Sox2:DNA condensates are highly stable, withstanding disruptive forces high enough to melt DNA. We find that the disordered domains of Sox2 are required for maximum force generation but not condensate formation per se. Finally, we show that nucleosomes dramatically attenuate the mechanical stress exerted by Sox2 via sequestering it from coalescing on bare DNA. Our findings reveal that TF-mediated DNA condensation can exert significant mechanical stress which can nonetheless be alleviated by the chromatin organization, suggesting a new function of eukaryotic chromatin in protecting the genome from potentially deleterious nuclear forces.
Extinction Risk of Sonoran Desert Annuals Following Potential Changes in Precipitation Regimes
Authors: Cuello William S. , Schreiber Sebastian J. , Gremer Jennifer R. , Venable D. Lawrence , Trimmer Pete C. , Sih Andrew 
Published: February 2022

AbstractRapid environmental change can affect both the mean and variability in environmental conditions. Natural selection tends to favour those organisms that best respond to such changes. Here, we consider delayed germination as bet hedging strategies for 10 Sonoran Desert annuals. We use a germination model parameterized with long-term demographic and climate data to explore potential effects of changes in the mean and variance in precipitation on the evolution of germination strategies, as well as the risk of extinction. We then explored the potential for evolutionary rescue in response to these changes. As expected, results indicate that as rainfall declines, or uncertainty in rainfall increases, all species have higher extinction risk (the former being more detrimental). These shifts also increased the benefit of delayed germination. Results also indicate that evolutionary rescue can often occur for small shifts, especially for more variable rainfall regimes, but would not likely save populations experiencing larger environmental changes. Finally, we identified life history traits and functional responses to precipitation that were most strongly correlated to the ability to cope with changes in rainfall and with potential for evolutionary rescue: dormant seed survivorship and, to a smaller degree, chance of reproduction and seed yield sensitivity to precipitation.
Primary macrophages exhibit a modest inflammatory response early in SARS-CoV-2 infection
Authors: Zhang Ziyun , Penn Rebecca , Barclay Wendy S , Giotis Efstathios S 
Published: February 2022

AbstractInvolvement of macrophages in the SARS-CoV-2-associated cytokine storm, the excessive secretion of inflammatory/anti-viral factors leading to the acute respiratory distress syndrome (ARDS) in COVID-19 patients, is unclear. In this study, we sought to characterize the interplay between the virus and primary human monocyte-derived macrophages (MDM). MDM were stimulated with recombinant IFN-α and/or infected with either live or UV-inactivated SARS-CoV-2 or with two reassortant influenza viruses containing external genes from the H1N1 PR8 strain and heterologous internal genes from a highly pathogenic avian H5N1 or a low pathogenic human seasonal H1N1 strain. Virus replication was monitored by qRT-PCR for theEviral gene for SARS-CoV-2 orMgene for influenza and TCID50or plaque assay, and cytokine levels were assessed semiquantitatively with qRT-PCR and a proteome cytokine array. We report that MDM are not susceptible to SARS-CoV-2 whereas both influenza viruses replicated in MDM, albeit abortively. We observed a modest cytokine response in SARS-CoV-2 infected MDM with notable absence of IFN-β induction, which was instead strongly induced by the influenza viruses. Pre-treatment of MDM with IFN-α enhanced proinflammatory cytokine expression upon infection. Together, the findings concur that the hyperinflammation observed in SARS-CoV-2 infection is not driven by macrophages.
In silico structure-based analysis of the predicted protein-protein interaction of Syntaxin-18, a putative receptor of Peregrinus maidis Ashmead (Hemiptera: Delphacidae) with Maize mosaic virus glycoprotein
Authors: Castrosanto Melvin A. , Clemente Apel Jae N. , Whitfield Anna E. , Alviar Karen B. 
Published: February 2022

ABSTRACTThe corn planthopper, Peregrinus maidis, is a widely distributed insect pest which serves as a vector of two phytopathogenic viruses, Maize mosaic virus (MMV) and Maize stripe virus (MStV). It transmits the viruses in a persistent and propagative manner. MMV is an alphanucleorhabdovirus with a negative-sense, single-stranded (ss) RNA unsegmented genome. One identified insect vector protein that may serve as receptor to MMV is Syntaxin-18 (PmStx18) which belongs to the SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors). SNAREs play major roles in the final stage of docking and subsequent fusion of diverse vesicle-mediated transport events. In this work, in silico analysis of the interaction of MMV glycoprotein (MMV G) and PmStx18 was performed. Various freely available protein-protein docking web servers were used to predict the 3D complex of MMV G and PmStx18. Analysis and protein-protein interaction (PPI) count showed that the complex predicted by the ZDOCK server has the highest number of interaction and highest affinity, as suggested by the calculated solvation free energy gain upon formation of the interface (ΔiG = −31 kcal/mol). Molecular dynamics simulation of the complex revealed important interactions at the interface over the course of 50 ns. This is the first in silico analysis performed for the interaction on a putative receptor of P. maidis and MMV G. The results of the protein-protein interaction prediction provide novel information for studying the role of STX18 in the transport, docking and fusion events involved in virus particle transport in the insect vector cells and its release.
Rapid aggregation of Staphylococcus aureus in synovial fluid is influenced by synovial fluid concentration, viscosity, and fluid dynamics-with evidence of polymer bridging
Authors: Staats Amelia , Burback Peter W. , Schwieters Andrew , Li Daniel , Sullivan Anne , Horswill Alexander R. , Stoodley Paul 
Published: February 2022

AbstractEarly bacterial survival in the post-surgical joint is still a mystery. Recently, synovial fluid-induced aggregation was proposed as a potential mechanism of bacterial protection upon entry into the joint. As synovial fluid is secreted back into the joint cavity following surgery, rapid fluctuations in synovial fluid concentration, composition, and viscosity occur. These changes, along with fluid movement from post-operative joint motion, will modify the environment and potentially affect the kinetics of aggregate formation. Through this work, we sought to evaluate the influence of exposure time, synovial fluid concentration, viscosity, and fluid dynamics on aggregation. Furthermore, we aimed to elucidate the primary mechanism of aggregate formation by assessing the interaction of bacterial adhesins with synovial fluid polymer, fibrinogen. Following incubation in each simulated post-operative joint condition, the aggregates were imaged using confocal microscopy. Our analysis revealed the formation of two distinct aggregate phenotypes dependent on whether the incubation was conducted under static or dynamic conditions. Using a surface adhesin mutant, we have narrowed down the genetic determinants for synovial fluid aggregate formation and identified essential host polymers required. We report here that synovial fluid-induced aggregation is influenced by various changes specific to the post-surgical joint environment. While we now have evidence that select synovial fluid polymers facilitate bridging aggregation through essential bacterial adhesins, we suspect that their utility is limited by the increasing viscosity under static conditions. Furthermore, dynamic fluid movement recovers the ability of the bacteria with present surface proteins to aggregate under high viscosity conditions, yielding large, globular aggregates.ImportanceInfection is a major complication of knee and hip joint replacement surgery which is used to treat arthritis or joint damage. We have shown that Staphylococcus aureus, a common bacterial pathogen, aggregates upon contact with synovial fluid. Within seconds, the bacterial cells will interact with synovial fluid polymers in the joint fluid through their cell wall adhesins. The rapid formation of these aggregates likely aids in early bacterial survival in the joint-potentially contributing to the likelihood of developing an infection. By strengthening our basic understanding of the mechanics of synovial fluid aggregate formation under clinically relevant conditions, we hope to expand the knowledge of how to prevent or disrupt aggregation and reduce and more successfully treat these joint infections.
BNT162b2, mRNA-1273, and Sputnik V vaccines induce comparable immune responses on a par with severe course of COVID-19
Authors: Kaznadzey Anna , Tutukina Maria , Bessonova Tatiana , Kireeva Maria , Mazo Ilya 
Published: February 2022

AbstractVaccines against the severe acute respiratory syndrome coronavirus 2, which have been in urgent need and development since the beginning of 2020, are aimed to induce a prominent immune system response capable of recognizing and fighting future infection. Here we analyzed the levels of IgG antibodies against the receptor-binding domain (RBD) of the viral spike protein after the administration of three types of popular vaccines, BNT162b2, mRNA-1273, or Sputnik V, using the same ELISA assay to compare their effects. An efficient immune response was observed in the majority of cases. The obtained ranges of signal values were wide, presumably reflecting specific features of the immune system of individuals. At the same time, these ranges were comparable among the three studied vaccines. The anti-RBD IgG levels after vaccination were also similar to those in the patients with moderate/severe course of the COVID-19, and significantly higher than in the individuals with asymptomatic or light symptomatic courses of the disease. No significant correlation was observed between the levels of anti-RBD IgG and sex or age of the vaccinated individuals. The signals measured at different time points for several individuals after full Sputnik V vaccination did not have a significant tendency to lower within many weeks. The rate of neutralization of the interaction of the RBD with the ACE2 receptor after vaccination with Sputnik V was on average slightly higher than in patients with a moderate/severe course of COVID-19. The importance of the second dose administration of the two-dose Sputnik V vaccine was confirmed: while several individuals had not developed detectable levels of the anti-RBD IgG antibodies after the first dose of Sputnik V, after the second dose the antibody signal became positive for all tested individuals and raised on average 5.4 fold. Finally, we showed that people previously infected with SARS-CoV-2 developed high levels of antibodies, efficiently neutralizing interaction of RBD with ACE2 after the first dose of Sputnik V, with almost no change after the second dose.
Proteostasis in ice: The role of heat shock proteins and ubiquitin in the freeze tolerance of the intertidal mussel, Mytilus trossulus
Authors: Gill Lauren T. , Kennedy Jessica R. , Marshall Katie E. 
Published: February 2022

AbstractThe bay mussel, Mytilus trossulus, is one of the few animals that can survive internal ice formation. Freeze tolerant intertidal animals, like M. trossulus, may freeze and thaw many times during the winter, depending on air and ocean temperatures. Freezing can cause protein denaturation, leading to an induction of the heat shock response with expression of proteins like HSP70, and an increase in ubiquitin conjugated proteins. There has been little work on the mechanisms of freeze tolerance in intertidal species, limiting our understanding of this survival strategy. Additionally, this limited research has focused solely on the effects of single freezing events, but the act of repeatedly crossing the freezing threshold may present novel physiological or biochemical stressors that have yet to be discovered. We predicted that repeated freeze exposures would increase mortality, upregulate HSP70 expression, and increase ubiquitin conjugates in mussels, relative to single, prolonged freeze exposures. Mytilus trossulus from Vancouver, Canada were repeatedly frozen for a combination of 1 × 8 hours, 4 × 2 hours, or 2 × 4 hours. We then compared mortality, HSP70 expression, and ubiquitin quantity across experimental groups. We found a single 8-hour freeze caused significantly more mortality than repeated freeze-thaw cycles. We also found that HSP70 and ubiquitin expression was upregulated exclusively after freeze-thaw cycles, suggesting that freeze-thaw cycles offer a period of damage repair between freezes. This indicates that freeze-thaw cycles, which happen naturally in the intertidal, are crucial for M. trossulus survival in sub-zero temperatures.