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In skeletal muscle, the health and adaptive capacity of the mitochondrial network is regulated by mitochondrial quality control (MQC) mechanisms (1). The Mitochondrial Integrated Stress Response (ISR) and Unfolded Protein Response (UPRmt) are conserved regulatory processes that can become activated in response to a variety of organellar stressors (2). This quality control architype is primarily regulated by the transcription factors, ATF4 and ATF5, which can coordinate a nuclear response to promote the restoration of mitochondrial homeostasis (3). Beyond these canonical functions, both ATF4 and ATF5 can also mediate other mitochondrial quality control processes and thereby influence the adaptive and restorative capacity of the network (4, 5). While a dynamic and efficient mitochondrial reticulum is essential for skeletal muscle function, with age, mitochondrial quality becomes disrupted contributing to aberrations in muscle health (6). Although previous work has demonstrated a role for both ATF4 and ATF5 in propagating mitochondrial health via the mediation of MQC processes in young skeletal muscle (4, 5), this regulation has not been evaluated with age. To therefore investigate the importance of such transcription factors in maintaining mitochondrial and muscle health with age, we utilized aged ATF4 and ATF5 KO mice with associated WT counterparts (results summarized in Figure 1). We first assessed muscle mass and contractile kinetics using an acute contractile activity protocol of mouse hindlimb muscle via sciatic nerve stimulation. Interestingly, the canonical decline in muscle mass typically associated with age was prevented in the absence of both ATF4 and ATF5. To ascertain the molecular mechanisms underlying this preservation, we next assessed the expression of muscle atrophy markers, MuRF-1, GADD45α, p21, and p53, which were similarly blunted in aged ATF4 and ATF5 KO mice. This suggests a regulatory role for both transcription factors in mediating muscle protein degradation with age. Muscle quality, reflected by reduced maximal twitch and tetanic force per muscle weight, was impaired by the loss of ATF4 but not ATF5, indicating a greater reliance on ATF4 for age-related muscle health. To examine the functional capacity and thus health of the mitochondrial reticulum, we next investigated mitochondrial respiration and ROS emission. We observed a stark reduction in active respiration and mitochondrial H2O2 emission in young ATF4 and ATF5 KO mice, however with age, these parameters were only perturbed in the absence of ATF4. These findings indicate that both ATF4 and ATF5 support mitochondrial health in young muscle, however, the presence of ATF4 becomes more critical with age for the maintenance of mitochondrial functioning. In order to ascertain the precise roles of both ATF4 and ATF5 in governing mitochondrial quality with age, we next analyzed the expression of autophagy and lysosomal related proteins. Interestingly, deficits in this quality control program were only evident in ATF4 KO muscle, represented by a blunted expression of various related proteins. Similarly, antioxidant-related proteins, which are also responsive to changes in mitochondrial ROS during stress conditions, were only blunted in ATF4 KO muscle. These findings emphasize the requirement for ATF4 to modulate mitochondrial quality control mechanisms in aging muscle. Lastly, the canonical regulation of the ISR/UPRmt was negatively altered solely in ATF4 KO muscle, demonstrating a hierarchal regulation of the mitochondrial stress response. In sum, these data thereby suggest that ATF4 and ATF5 are required to mediate mitochondrial muscle health with age, however, ATF4 is more critical in this determination, alongside the regulation of other quality control processes. Future work will reveal the precise underlying mechanisms that contribute to the importance of ATF4 signaling in aging muscle.

Purpose This study aims to develop a framework to identify the drivers underpinning food tourists' behavioral intentions (BIs). This framework centers on examining how local food consumption value (TLFCV), local food experiential value (TLFEV) and social media influencers (SMIs) impact upon tourists’ attitudes toward local food (ATLF) and food destination image (FDI). The impact of ATLF and FDI on tourists’ BIs is also examined. Design/methodology/approach PLS-SEM was used to test the hypothesized relationships using survey responses from 379 tourists visiting Rasht, Iran. Findings The results demonstrate that TLFCV, TLFEV and SMIs can be used to populate a theoretical framework for predicting and understanding the factors influencing tourists’ ATLF and FDI. Specifically, positive ATLF and FDI stimulated positive BIs (e.g., intending to recommend Iranian food to others and intending to revisit Iran in future for culinary tourism purposes). Practical implications The findings provide managers and practitioners within the culinary tourism industry with suggestions for how best to strategically market their offerings to increase inbound food tourism. Originality/value This study is one of the first to empirically evaluate the drivers of food tourists' BIs, presenting a newly developed model for deployment in future research. Originality is also established by simultaneously investigating TLFCV and TLFEV within the context of food tourism.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. It is the fourth leading cause of cancer-related death worldwide. Deregulation of the ATF/CREB family is associated with the progression of metabolic homeostasis and cancer. Because the liver plays a central role in metabolic homeostasis, it is critical to assess the predictive value of the ATF/CREB family in the diagnosis and prognosis of HCC. Using data from The Cancer Genome Atlas (TCGA), this research evaluated the expression, copy number variations, and frequency of somatic mutations of 21 genes in the ATF/CREB family in HCC. A prognostic model based on the ATF/CREB gene family was developed via Lasso and Cox regression analyses, with the TCGA cohort serving as the training dataset and the International Cancer Genome Consortium (ICGC) cohort serving as the validation set. Kaplan-Meier and receiver operating characteristic analyses verified the accuracy of the prognostic model. Furthermore, the association among the prognostic model, immune checkpoints, and immune cells was examined. High-risk patients exhibited an unfavorable outcome as opposed to those in the low-risk category. Multivariate Cox analysis revealed that the risk score calculated based on the prognostic model was an independent prognostic factor for HCC. Analysis of immune mechanisms revealed that the risk score had a positive link to the expression of immune checkpoints, particularly CD274, PDCD1, LAG3, and CTLA4. Differences in immune cells and immune-associated roles were found between the high- and low-risk patients, as determined by single-sample gene set enrichment analysis. The core genes ATF1, CREB1, and CREB3 in the prognostic model were shown to be upregulated in HCC tissues as opposed to adjoining normal tissues, and the 10-year overall survival (OS) rate was worse among patients with elevated expression levels of ATF1, CREB1, and CREB3. Elevated expression levels of ATF1, CREB1, and CREB3 in HCC tissues were confirmed by qRT-PCR and immunohistochemistry studies. According to the results of our training set and test set, the risk model based on the six ATF/CREB gene signatures predicting prognosis has certain predictive accuracy in predicting the survival of HCC patients. This study provides novel insights into the individualized treatment of patients with HCC.

Respiratory diseases including influenza A virus (IAV) infections represent a major threat to human health. While the development of a vaccine requires a lot of time, a fast countermeasure could be the use of defective interfering particles (DIPs) for antiviral therapy. IAV DIPs are usually characterized by a large internal deletion in one viral RNA segment. Consequentially, DIPs can only propagate in presence of infectious standard viruses (STVs), compensating the missing gene function. Here, they interfere with and suppress the STV replication and might act “universally” against many IAV subtypes. We recently reported a production system for purely clonal DIPs utilizing genetically modified cells. In the present study, we established an automated perfusion process for production of a DIP, called DI244, using an alternating tangential flow filtration (ATF) system for cell retention. Viable cell concentrations and DIP titers more than 10 times higher than for a previously reported batch cultivation were observed. Furthermore, we investigated a novel tubular cell retention device for its potential for continuous virus harvesting into the permeate. Very comparable performances to typically used hollow fiber membranes were found during the cell growth phase. During the virus replication phase, the tubular membrane, in contrast to the hollow fiber membrane, allowed 100% of the produced virus particles to pass through. To our knowledge, this is the first time a continuous virus harvest was shown for a membrane-based perfusion process. Overall, the process established offers interesting possibilities for advanced process integration strategies for next-generation virus particle and virus vector manufacturing.Key points• An automated perfusion process for production of IAV DIPs was established.• DIP titers of 7.40E + 9 plaque forming units per mL were reached.• A novel tubular cell retention device enabled continuous virus harvesting.

To cope with the shortcomings of nuclear fuel design exposed during the Fukushima Nuclear Accident, researchers around the world have been directing their studies towards accident-tolerant fuel (ATF), which can improve the safety of fuel elements. Among the several ATF cladding concepts, surface coatings comprise the most promising strategy to be specifically applied in engineering applications in a short period. This review presents a comprehensive introduction to the latest progress in the development of Cr-based surface coatings based on zirconium alloys. Part I of the review is a retrospective look at the application status of zirconium alloy cladding, as well as the development of ATF cladding. Following this, the review focuses on the selection process of ATF coating materials, along with the advantages and disadvantages of the current mainstream preparation methods of Cr-based coatings worldwide. Finally, the characteristics of the coatings obtained through each method are summarized according to some conventional performance evaluations or investigations of the claddings. Overall, this review can help assist readers in getting a thorough understanding of the selection principle of ATF coating materials and their preparation processes.

Understanding the environmental drivers of movement of potentially dangerous shark species can help inform mitigation strategies. Bull sharks are known to undertake seasonal migrations from tropical to temperate waters along the east coast of Australia. However, the environmental drivers of their movements from sub-tropical to temperate waters are unknown. Using multi-year (2010–2016) acoustic telemetry data from 68 bull sharks and generalised additive models, we evaluate the (1) temporal and (2) environmental variables that drive shark abundance, presence/absence and residency along the south-eastern coast of Australia. Bull sharks were detected in sub-tropical waters (∼28°S) almost year-round but were most abundant in the southern latitudes in the austral summer and autumn. Abundance, presence and residency were all highest around the latitudes that sharks were tagged, indicating a bias to tagging location, and at estuary mouths and mid-shelf (20–60 m water depth) habitats. Bull sharks were present when sea surface temperature (SST) was 20–26°C, with peak abundance at 24°C, and low chlorophyll a (chl a). There was a higher abundance of sharks in months when SST was higher than the long-term average. Residency duration was longest when SST was <22°C or >24°C, and in areas of low SST slope (<3°C) and chl a slope. Although no sex bias in residency time was detected, sharks <200 cm TL had the longest residency times. These results provide the power to predict when and where bull shark abundance may be higher, which can help management authorities deploy mitigation strategies for bull shark interactions along eastern Australia.

Similar to the recent COVID-19 pandemic, influenza A virus poses a constant threat to the global community. For the treatment of flu disease, both antivirals and vaccines are available with vaccines the most effective and safest approach. In order to overcome limitations in egg-based vaccine manufacturing, cell culture–based processes have been established. While this production method avoids egg-associated risks in face of pandemics, process intensification using animal suspension cells in high cell density perfusion cultures should allow to further increase manufacturing capacities worldwide. In this work, we demonstrate the development of a perfusion process using Madin-Darby canine kidney (MDCK) suspension cells for influenza A (H1N1) virus production from scale-down shake flask cultivations to laboratory scale stirred tank bioreactors. Shake flask cultivations using semi-perfusion mode enabled high-yield virus harvests (4.25 log10(HAU/100 μL)) from MDCK cells grown up to 41 × 106 cells/mL. Scale-up to bioreactors with an alternating tangential flow (ATF) perfusion system required optimization of pH control and implementation of a temperature shift during the infection phase. Use of a capacitance probe for on-line perfusion control allowed to minimize medium consumption. This contributed to a better process control and a more economical performance while maintaining a maximum virus titer of 4.37 log10(HAU/100 μL) and an infectious virus titer of 1.83 × 1010 virions/mL. Overall, this study clearly demonstrates recent advances in cell culture–based perfusion processes for next-generation high-yield influenza vaccine manufacturing for pandemic preparedness.Key points• First MDCK suspension cell–based perfusion process for IAV produciton was established.• “Cell density effect” was overcome and process was intensified by reduction of medium use and automated process control.• The process achieved cell density over 40 × 106cells/mL and virus yield over 4.37 log10(HAU/100 μL).

Accident tolerant fuel (ATF) cladding is a new type of nuclear fuel cladding designed to improve the safety and performance of nuclear reactors. In this paper, the kinetics and degradation mechanisms during high-temperature oxidation in steam of the three most promising ATF cladding materials, i.e., chromium-coated zirconium alloys, FeCrAl alloys, and silicon carbide-based composites, are described. Each system has its own degradation mechanisms leading to different maximum survival temperatures. After providing general information and data to understand the oxidation and degradation processes, illustrative examples obtained at the Karlsruhe Institute of Technology are given for each type of cladding. The maximum temperatures at which the barrier effect of the cladding can be maintained for a reasonable period of time during nuclear accident scenarios are 1200–1300 °C for Cr-coated Zr alloys, 1400 °C for FeCrAl alloys, and 1700 °C for SiC-based composite claddings.

Music spatialisation is one of the means to enrich the performance effect, and the use of digital technology to construct a virtual music space greatly improves the accessibility and availability of the orchestra’s performance. This paper explores the path of virtual music space construction and enhances experience, and proposes a sound field replay technique. A ball microphone array is used to measure the raw ATF, and a sparse decomposition algorithm is used to reduce the number of measurement microphones. The target sound field can be reproduced accurately by solving the loudspeaker excitation signal. Experimental analysis reveals that in the [250,550] Hz interval, the method in this paper has obvious advantages compared with the traditional method, and the mean scores of listeners’ subjective evaluations of physiological immersion, psychological immersion, and emotional immersion are all greater than 4, which indicates that the constructed virtual music space has a better immersive experience, which is conducive to achieving a better performance of small chamber orchestra.

Background Recent studies have reported that microRNAs (miRNAs) often function as negative post-transcriptional regulators with altered expression levels found in colorectal cancer (CRC). There have been few studies on miRNAs that regulate the oncogenic alterations in CRC. Here, we aim to explore the anti-cancer miRNA and the potential mechanisms by which miRNAs modulate CRC progression. Methods We performed an integrated analysis of CRC miRNA expression datasets in The Cancer Genome Atlas (TCGA). The miRNA with the lowest expression, miR-760, was validated in an independent validation sample cohort of 76 CRC tissues. Functional assays, such as CCK-8 assay, colony formation assay, and CFSE staining, were used to determine the oncogenic role of miR-760 in human CRC progression. Furthermore, western blotting and dual-luciferase reporter assay were used to determine the mechanism by which miR-760 promotes proliferation of CRC cells. Xenograft nude mouse models were used to determine the role of miR-760 in CRC tumorigenicity in vivo. Immunohistochemical assays were conducted to study the relationship between miR-760 expression and basic leucine zipper transcriptional factor ATF-like 3 (BATF3) expression in human CRC samples. Results miR-760 was markedly downregulated in CRC tissues, and low miR-760 expression was associated with poor prognosis among CRC patients. Upregulation of miR-760 suppressed CRC cell proliferation, whereas downregulation of miR-760 promoted CRC proliferation in vitro. Additionally, we identified BATF3 as a direct target of miR-760, and that the essential biological function of miR-760 during CRC progression both in vitro and in vivo is to suppress the expression of BATF3 and downstream cyclinD1 via AP-1 transcription factor. Finally, we showed a significant correlation between miR-760 and BATF3 expression in CRC tissues. Conclusions miR-760 inhibited CRC growth by downregulating BATF3/AP-1/ cyclinD1 signaling.