bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synthetic STING agonists elicit powerful vaccine adjuvancy providing robust central memory and anti-tumour effects
Authors: Towner Laurence D. , Dahal Lekh N. , Taylor Martin C. , Cox Kerry L. , Inzhelevskaya Tatyana , Mack Matthias , Wedge Stephen R , Richardson Caroline , Cragg Mark S. , Beers Stephen A. 
Published: January 2023

AbstractDrugs that target the innate immune sensor STING are known to be effective in modulating the immune infiltrate of the tumour microenvironment. STING agonists have potential to enhance responses to checkpoint inhibitor therapy, however, their ability to influence and shape adaptive immune responses is poorly understood. Here, we investigated the impact of a range of synthetic STING agonists on antigen specific CD8+T-cell responses to soluble antigen using the murine OT-1 adoptive transfer model with Ovalbumin as the antigen to monitor T cell responses. Our data demonstrate that synthetic STING agonists are able to stimulate antigen specific T-cell expansion in response to challenge in mice. This effect required expression of STING, an intact myeloid compartment and Type-I IFN and TNFα signalling. Expanded T-cells post treatment differed from those induced by the established immune adjuvant, anti-CD40 antibody through lower induction of the immune checkpoint receptor PD-1. Furthermore, our data revealed a marked increase in the induction and persistence of CD8+central memory cells after STING agonist and antigen challenge. Finally, we demonstrate that following rechallenge, STING agonism produced larger secondary responses that could be translated into enhanced tumour protection and survival. Therefore, synthetic STING agonists are capable of acting as potent immune adjuvants and can induce robust memory formation leading to better recall and tumour control. Critically, these benefits along with the lower expression of PD-1, have implications for their use as adjuvants for multiple immunotherapy and vaccine applications.
Dietary Restriction Impacts Peripheral Circadian Clock Output Important for Longevity inDrosophila
Authors: Hwangbo Dae-Sung , Kwon Yong-Jae , Iwanaszko Marta , Jiang Peng , Abbasi Ladan , Wright Nicholas , Alli Sarayu , Hutchison Alan L. , Dinner Aaron R. , Braun Rosemary I , Allada Ravi 
Published: January 2023

AbstractCircadian clocks may mediate lifespan extension by caloric or dietary restriction (DR). We find that the core clock transcription factorClockis crucial for a robust longevity and fecundity response to DR inDrosophila. To identify clock-controlled mediators, we performed RNA-sequencing from abdominal fat bodies across the 24 h day after just 5 days under control or DR diets. In contrast to more chronic DR regimens, we did not detect significant changes in the rhythmic expression of core clock genes. Yet we discovered that DR induced de novo rhythmicity or increased expression of rhythmic clock output genes. Network analysis revealed that DR increased network connectivity in one module comprised of genes encoding proteasome subunits. Adult, fat body specific RNAi knockdown demonstrated that proteasome subunits contribute to DR-mediated lifespan extension. Thus, clock control of output links DR-mediated changes in rhythmic transcription to lifespan extension.
Cold tolerance and diapause within and across trophic levels: endoparasitic wasps and their fly host have similar phenotypes
Authors: McIntyre Trinity , Andaloori Lalitya , Hood Glen Ray , Feder Jeffrey L. , Hahn Daniel A. , Ragland Gregory J. , Toxopeus Jantina 
Published: January 2023

AbstractLow temperatures associated with winter can limit the survival of organisms, especially ectotherms whose body temperature is similar to their environment. Important adaptations for overwintering such as cold hardiness and diapause have been well-explored in many insect taxa. However, there is a gap in understanding how overwintering may vary among groups of species that interact closely, such as multiple parasitoid species that attack the same host insect. Our study investigated cold tolerance and diapause phenotypes in three endoparasitoid wasps of the apple maggot flyRhagoletis pomonella(Diptera: Tephritidae):Utetes canaliculatus, Diachasma alloeum, andDiachasmimorpha mellea(Hymenoptera: Braconidae). Using a combination of respirometry and eclosion tracking, we detected diapause phenotypes in all three wasp species, remarkably similar to the fly host. Weak diapause was rare (< 5%) in all three wasp species, and while mostD. mellea(93%) entered prolonged diapause under warm conditions, the majority ofU. canaliculatus(92%) andD. alloeum(72%) averted diapause (non-diapause). There was limited interspecific variation in acute cold tolerance among the three wasp species: wasps and flies had similarly high survival (>87%) following exposure to extreme low temperatures (- 20°C) as long as their body fluids did not freeze. The wasp species showed little interspecific variation in survival following prolonged exposure to mild chilling of 8 or more weeks at 4°C. This study shows remarkable conservation of cold tolerance and diapause phenotypes within and across trophic levels. The interaction between diapause phenotype and cold hardiness in these parasitoids is an interesting direction for future research.Graphical Abstract and HighlightsThe apple maggot fly and its parasitoids exhibit the same three diapause phenotypesEach parasitoid wasp species exhibits different proportions of these phenotypesUtetes canaliculatusandDiachasma alloeumare freeze-avoidant, like their host flyThese wasps and flies survive to similarly extreme low temperatures (c. -20°C)Each wasp species survives prolonged exposure to mild chilling (4°C) similarly well
Indel driven rapid evolution of core nuclear pore protein gene promoters
Authors: Mcquarrie David W. J. , Read Adam M. , Stephens Frannie H. S. , Civetta Alberto , Soller Matthias 
Published: January 2023

AbstractNuclear pore proteins (Nups) prominently are among the few genes linked to speciation from hybrid incompatibility inDrosophila. It was previously found that neuronal wiring underlying the female post-mating response induced by male-derived sex-peptide requires channel Nup54 functionality. A hot spot for rapid evolution in the promoter ofNup54suggests a critical role for regulatory elements at the onset of speciation. Systematic analysis of Nup coding and promoter regions usingDrosophilaphylogenomics reveals that polymorphism differences between closely relatedDrosophilaspecies in Nup coding regions do not generally evolve rapidly. Consistent with findings forNup54, additional channel Nups 58 and 62 promotors are also hotpots for rapid accumulation of insertions/deletions (indels). Examination of Nup upstream regions reveals that core nuclear pore complex gene promoters accumulate indels rapidly. Since changes in promoters can have dominant effects (effects which directly impact gene expression of associated genes), these results indicate an evolutionary mechanism driven by indel accumulation in core Nup promoters. Compensation of such deleterious changes could lead to altered neuronal wiring, rapid fixation of adaptive traits and subsequently the rise of new species. Hence, the nuclear pore complex may act as a nexus for species-specific changesvianucleo-cytoplasmic transport regulated gene expression.
Establishing a causal role for left ventrolateral prefrontal cortex in value-directed memory encoding with high-definition transcranial direct current stimulation
Authors: Han Linfeng Tony , Cohen Michael S. , He Liqin Ken , Green Laura M. , Knowlton Barbara J. , Castel Alan D. , Rissman Jesse 
Published: January 2023

AbstractOne critical approach for promoting the efficiency of memory is to adopt selective encoding strategies to prioritize more valuable information. Past neuroimaging studies have shown that value-directed modulation of verbal memory depends heavily on engagement of left-lateralized semantic processing regions, particularly in ventrolateral prefrontal cortex (VLPFC). In the present study, we used high-definition direct current stimulation (HD-tDCS) to seek evidence for a causal role of left VLPFC in supporting the memory advantage for high-value items. Three groups of healthy young adult participants were presented with lists of words to remember, with each word accompanied by an arbitrarily assigned point value. During the first session, all participants received sham stimulation as they encoded five lists of 30 words each. Two of these lists were immediately tested with free recall, with feedback given to allow participants to develop metacognitive insight and strategies to maximize their point total. The second session had the exact same structure as the first, but the groups differed in whether they received continued sham stimulation (N=22) or anodal stimulation of the left VLPFC (N=21) or right VLPFC (N=20). Those lists not tested with immediate recall were tested with recognition judgments after a one-day delay. Since no brain stimulation was applied during this Day 2 test, any performance differences can be attributed to the effects of stimulation on Day 1 encoding processes. Anodal stimulation of left VLPFC significantly boosted participants’ memory encoding selectivity. In comparison, no such effect was seen in participants who received right VLPFC or sham stimulation. Estimates of recollection- and familiarity-based responding revealed that left VLPFC stimulation specifically amplified the effects of item value on recollection. These results demonstrate a causal role for left VLPFC in the implementation of selective value-directed encoding strategies, putatively by boosting deep semantic processing of high-value words. Our findings also provide further evidence on the hemispheric lateralization of value-directed verbal memory encoding.
Biomolecular condensates modulate membrane lipid packing and hydration
Authors: Mangiarotti Agustín , Siri Macarena , Tam Nicky , Zhao Ziliang , Malacrida Leonel , Dimova Rumiana 
Published: January 2023

AbstractMembrane wetting by biomolecular condensates recently emerged as a key phenomenon in cell biology, playing an important role in a diverse range of processes across different organisms. However, an understanding of the molecular mechanisms behind condensate formation and interaction with lipid membranes is still missing. To study this, we exploited the properties of the dyes ACDAN and LAURDAN as nano-environmental sensors in combination with phasor analysis of hyperspectral and lifetime imaging microscopy. Using glycinin as a model condensate-forming protein and giant vesicles as model membranes, we obtained vital information on the process of condensate formation and membrane wetting. Our results reveal that glycinin condensates display differences in water dynamics when changing the salinity of the medium as a consequence of rearrangements in the secondary structure of the protein. Remarkably, analysis of membrane-condensates interaction with protein as well as polymer condensates indicated a correlation between increased wetting affinity and enhanced lipid packing. This is demonstrated by a decrease in the dipolar relaxation of water across all membrane-condensate systems, suggesting a general mechanism to tune membrane packing by condensate wetting.
MNK1 and MNK2 expression in the human dorsal root and trigeminal ganglion
Authors: Shiers Stephanie , Sahn James J. , Price Theodore J. 
Published: January 2023

AbstractMitogen activated protein kinase interacting kinases (MNK) 1 and 2 are serine/threonine protein kinases that play an important role in translation of mRNAs through their phosphorylation of the RNA 5’-cap binding protein, eukaryotic translation initiation factor (eIF) 4E. These kinases are downstream targets for mitogen activated protein kinases (MAPKs), extracellular activity regulated protein kinase (ERK) and p38. MNKs have been implicated in the sensitization of peripheral nociceptors of the dorsal root and trigeminal ganglion (DRG and TG) using transgenic mouse lines and through the use of specific inhibitors of MNK1 and MNK2. While specific knockout of theMknk1gene suggests that it is the key isoform for regulation of nociceptor excitability and nociceptive behaviors in mice, bothMKNK1andMKNK2genes are expressed in the DRG and TG of mice and humans based on RNA sequencing experiments. Single cell sequencing in mice suggests thatMknk1andMknk2may be expressed in different populations of nociceptors. We sought to characterize mRNA expression in human DRG and TG for both MNK1 and MNK2. Our results show that both genes are expressed by nearly all neurons in both human ganglia with expression in other cell types as well. Our findings provide evidence that MNK1 and MNK2 are expressed by human nociceptors and suggest that efforts to pharmacologically target MNKs for pain would likely be translatable due its conserved expression in both species.
Hybrid epigenomes reveal extensive local genetic changes to chromatin accessibility contribute to divergence in embryonic gene expression between species
Authors: Devens Hannah R. , Davidson Phillip L. , Byrne Maria , Wray Gregory A. 
Published: January 2023

ABSTRACTChromatin accessibility plays an important role in shaping gene expression patterns across development and evolution; however, little is known about the genetic and molecular mechanisms that influence chromatin configuration itself. Becausecisandtransinfluences can both theoretically influence the accessibility of the epigenome, we sought to better characterize the role that both of these mechanisms play in altering chromatin accessibility in two closely related sea urchin species. Using hybrids of the two species, and adapting a statistical framework previously developed for the analysis ofcisandtransinfluences on the transcriptome, we examined how these mechanisms shape the regulatory landscape at three important developmental stages, and compared our results to similar patterns in the transcriptome. We found extensivecis- andtrans-based influences on evolutionary changes in chromatin, withciseffects slightly more numerous and larger in effect. Genetic mechanisms influencing gene expression and chromatin configuration are correlated, but differ in several important ways. Maternal influences also appear to have more of an effect on chromatin accessibility than on gene expression, persisting well past the maternal-to-zygotic transition. Furthermore, chromatin accessibility near GRN genes appears to be regulated differently than the rest of the epigenome, and indicates thattransfactors may play an outsized role in the configuration of chromatin near these genes. Together, our results represent the first attempt to quantifycisandtransinfluences on evolutionary divergence in chromatin configuration in an outbred natural study system, and suggest that the regulation of chromatin is more genetically complex than was previously appreciated.
Multiphoton imaging of glucose, galactose, and fructose-induced formation of fluorescent advanced glycation end products in tissues
Authors: Lin Chih-Ju , Mondal Sohidul , Lee Sheng-Lin , Kang Jeon-Woong , So Peter T. C. , Dong Chen-Yuan 
Published: January 2023

AbstractBlood glucose and HbA1c, intermediate glycation products of hemoglobin, remain the two clinical biomarkers for monitoring disease progression in diabetics. However, the formation of advanced glycation end products (AGEs) has been implicated in diabetic pathogenesis and the use of AGEs in tissues as long-term glycemic markers may be of value in the clinical setting. Therefore, it is necessary to understand how different tissue constituents respond to dietary monosaccharides. In this study, we studied thein vitrorate of fluorescent AGEs (fAGEs) formation with multiphoton microscopy in different porcine tissues (aorta, cornea, kidney, dermis, and tendon). These tissues were treated with D-glucose, D-galactose, and D-fructose, three primary monosaccharides found in human diets. We found that the use of D-fructose resulted in the highest glycation rate, followed by D-galactose and then D-glucose. Moreover, compared to non-collagen tissue constituents such as elastic fibers and cells, the rate of tissue glycation was consistently higher in collagen, suggesting that collagen is a more sensitive target for fAGE formation. However, we also found that collagen in different tissues exhibits different rates of fAGE formation, with slower rates observed in tightly packed tissues such as cornea and tendon. Our study suggests that for fAGE to be developed into a long-term glycemic biomarker, loosely organized collagen tissues located in the proximity of vasculature may be the best targets.
Cost & Cost-Effectiveness of Implementing SD Biosensor Antigen Detecting SARs-CoV-2 Rapid Diagnostic Tests in Kenya
Authors: Arwah Brian , Mbugua Samuel , Ngure Jane , Makau Mark , Mwaura Peter , Kamau David , Nshimirimana Desire Aime , Barasa Edwine , Gitaka Jesse 
Published: January 2023

AbstractThe COVID-19 pandemic has created a need to rapidly scale-up testing services. In Kenya, services for SARS-CoV-2 nucleic acid amplifying test (NAAT) have often been unavailable or delayed, precluding the clinical utility of the results. The introduction of antigen-detecting rapid diagnostic tests (Ag-RDT) has had the potential to fill at least a portion of the ‘testing gap’. We, therefore, evaluated the cost-effectiveness of implementing SD Biosensor Antigen Detecting SARs-CoV-2 Rapid Diagnostic Tests in Kenya.We conducted a cost and cost-effectiveness of implementing SD biosensor antigen-detecting SARS-CoV-2 rapid diagnostic test using a decision tree model following the Consolidated Health Economic Evaluation Standards (CHEERS) guidelines under two scenarios. In the first scenario, we compared the use of Ag-RDT as a first-line diagnostic followed by using NAAT assay, to the use of NAAT only. In the second scenario, we compared the use of Ag-RDT to clinical judgement. We used a societal perspective and a time horizon of patient care episodes. Cost and outcomes data were obtained from primary and secondary data. We used one-way and probabilistic sensitivity analysis to assess the robustness of the results.At the point of care, Ag-RDT use for case management in settings with access to delayed confirmatory NAAT testing, the use of Ag-RDT was cost-effective (ICER = US$ 964.63 per DALY averted) when compared to Kenya’s cost-effectiveness threshold (US$ 1003.4). In a scenario with no access to NAAT, comparing the Ag-RDT diagnostic strategy with the no-test approach, the results showed that Ag-RDT was a cost-saving and optimal strategy (ICER = US$ 1490.33 per DALY averted).At a higher prevalence level and resource-limited setting such as Kenya, implementing Ag-RDT to complement NAAT testing will be a cost-effective strategy in a scenario with delayed access to NAAT and a cost-saving strategy in a scenario with no access to NAAT assay.
The SARS-CoV-2 Spike protein induces long-term transcriptional perturbations of mitochondrial metabolic genes, causes cardiac fibrosis, and reduces myocardial contractile in obese mice
Authors: Cao Xiaoling , Nguyen Vi , Tsai Joseph , Gao Chao , Tian Yan , Zhang Yuping , Carver Wayne , Kiaris Hippokratis , Cui Taixing , Tan Wenbin 
Published: January 2023

AbstractBackgroundAs the pandemic evolves, post-acute sequelae of CoV-2 (PACS) including cardiovascular manifestations have emerged as a new health threat. This study aims to study whether the Spike protein plus obesity can exacerbate PACS-related cardiomyopathy.MethodsA Spike protein-pseudotyped (Spp) virus with the proper surface tropism of SARS-CoV-2 was developed for viral entry assayin vitroand administration into high fat diet (HFD)-fed mice. The systemic viral loads and cardiac transcriptomes were analyzed at 2 and 24 hrs, 3, 6, and 24 weeks post introducing (wpi) Spp using RNA-seq or real time RT-PCR. Echocardiography was used to monitor cardiac functions.ResultsLow-density lipoprotein cholesterol enhanced viral uptake in endothelial cells, macrophages, and cardiomyocyte-like H9C2 cells. Selective cardiac and adipose viral depositions were observed in HFD mice but not in normal-chow-fed mice. The cardiac transcriptional signatures in HFD mice at 3, 6, and 24 wpi showed systemic suppression of mitochondria respiratory chain genes including ATP synthases and nicotinamide adenine dinucleotide:ubiquinone oxidoreductase gene members, upregulation of stress pathway-related crucial factors such as nuclear factor-erythroid 2-related factor 1 and signal transducer and activator of transcription 5A, and increases in expression of glucose metabolism-associated genes. As compared with the age-matched HFD control mice, cardiac ejection fraction and fractional shortening were significantly decreased, while left ventricular end-systolic diameter and volume were significantly elevated, and cardiac fibrosis was increased in HFD mice at 24 wpi.ConclusionOur data demonstrated that the Spike protein could induce long-term transcriptional suppression of mitochondria metabolic genes and cause cardiac fibrosis and myocardial contractile impairment, providing mechanistic insights to PACS-related cardiomyopathy.
Outage probability analysis of power domain ordered NOMA under various channel conditions
Authors: Koteeshwari RS. , Malarkodi B. 
Published: January 2023

PurposeAmong the proposed radio access strategies for improving system execution in 5G networks, the non-orthogonal multiple access (NOMA) scheme is the prominent one.Design/methodology/approachAmong the most fundamental NOMA methods, power-domain NOMA is the one where at the transmitter, superposition coding is used, and at the receiver, successive interference cancellation (SIC) is used. The importance of power allocation (PA) in achieving appreciable SIC and high system throughput cannot be overstated.FindingsThis research focuses on an outage probability analysis of NOMA downlink system under various channel conditions like Rayleigh, Rician and Nakagami-m fading channel. The system design's objectives, techniques and constraints for NOMA-based 5G networks' PA strategies are comprehensively studied.Practical implicationsFrom the results of this study, it is found that the outage probability performance of downlink ordered NOMA under Rayleigh, Rician and Nakagami-m fading channel was good.Originality/valueOutage probability analysis of downlink ordered NOMA under various channel conditions like Rayleigh, Rician and Nakagami-m fading channels were employed. Though the performance of Nakagami-m fading channel is lesser compared to Rayleigh channel, the performance for user 1 and user 2 are good.