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The microstructure of conventionally solidified and rapidly solidified Ti–46Al–8Nb-2.5V alloys was analyzed with phase transformation geometric models, revealing the phase transformation mechanisms. The β→α→γ phase transformation processes follow Burgers and Blackburn orientation relationships (ORs), respectively, from which the calculated transformation between the β/β0and γ phases follow K–S OR. Whlie, the direct β/β0→γ phase transformation can be directly observed in the microstructure, which follows a variety of ORs, mainly following the K–S OR but also following the N–W or Bain ORs, most of which deviate from the strict ORs. In cases where N–W and Bain ORs are followed, there is a large dislocation spacing between the habit planes of the β/β0and γ phases, resulting in low static energy at the interface and narrow elongated morphology of precipitated phases. Conversely, when following K–S OR for β/β0→ γ phase transformation, interfacial migration energy is relatively lower and grain precipitated phases is larger. The rapidly solidified microstructure of Ti–46Al–8Nb-2.5V alloy consists of the massive α2phase, massive γ phase, and basket-weave β0phase closely resembling those found in β-type titanium alloys. After annealing at service temperature, the rapidly solidified alloy forms a microstructure highly similar to that of conventionally solidified TiAl alloy. Various metastable phases, such as the Ti2Al, L12and Ti1.4Al phases, precipitate in the blocky γ phase, which provides a theoretical basis for studying the phase transformations of TiAl alloys in service.

ABSTRACTAminoglycosides exhibit ototoxicity by damaging mitochondria, which in turn generate reactive oxygen species that induce hair cell death and subsequent hearing loss. It is well known that damaged mitochondria are degraded by mitophagy, an important mitochondrial quality control system that maintains mitochondrial homeostasis and ensures cell survival. However, it is unclear whether dysregulation of mitophagy contributes to aminoglycoside-induced hair cell injury. In the current study, we found that PINK1-PRKN-mediated mitophagy was impaired in neomycin-treated hair cells. Our data suggested that mitochondrial recruitment of PRKN and phagophore recognition of damaged mitochondria during mitophagy were blocked following neomycin treatment. In addition, the degradation of damaged mitochondria by lysosomes was significantly decreased as indicated by the mitophagic flux reporter mt-mKeima. Moreover, we demonstrated that neomycin disrupted mitophagy through transcriptional inhibition of Pink1expression, the key initiator of mitophagy. Moreover, we found that neomycin impaired mitophagy by inducing ATF3 expression. Importantly, treatment with a mitophagy activator could rescue neomycin-treated hair cells by increasing mitophagy, indicating that genetic modulation or drug intervention in mitophagy may have therapeutic potential for aminoglycoside-induced hearing loss.Abbreviations:AAV: adeno-associated virus; ABR: auditory brainstem response; ATF3: activating transcription factor 3; ATOH1/MATH1: atonal bHLH transcription factor 1; BafA1: bafilomycin A1; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; COX4I1/COXIV: cytochrome c oxidase subunit 4I1; CTBP2/RIBEYE: C-terminal binding protein 2; DFP: deferiprone; EGFP: enhanced green fluorescent protein; FOXO3: forkhead box O3; GRIA2/GLUR2: glutamate receptor, ionotropic, AMPA2 (alpha 2); HC: hair cell; HSPD1/HSP60: heat shock protein 1 (chaperonin); IHC: inner hair cell; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MYO7A: myosin VIIA; OPTN: optineurin; OMM: outer mitochondrial membrane; PRKN: parkin RBR E3 ubiquitin protein ligase; PINK1: PTEN induced putative kinase 1; RT-qPCR: real-time quantitative polymerase chain reaction; TOMM20/TOM20: translocase of outer mitochondrial membrane 20; TUNEL: Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling; USP30: ubiquitin specific peptidase 30; XBP1: X-box binding protein 1.

Building an effective resilient supply chain system (RSCS) is critical and necessary to reduce the risk of supply chain disruptions in unexpected scenarios such as COVID-19 pandemic and trade wars. To overcome the impact of insufficient raw material supply on the supply chain in mass disruption scenarios, this study proposes a novel RSCS considering product design changes (PDC). An RSCS domain model is first developed from the perspective of PDC based on a general conceptual framework, i.e., function-context-behavior-principle-state-structure (FCBPSS), which can portray complex systems under unpredictable situations. Specifically, the interaction among the structure, state and behavior of the infrastructure system and substance system is captured, and then a quantitative analysis of the change impact process is presented to evaluate the resilience of both the product and supply chain. Next, a case study is conducted to demonstrate the PDC strategy and to validate the feasibility and effectiveness of the RSCS domain model. The results show that the restructured RSCS based on the proposed strategy and model can remedy the huge losses caused by the unavailability of raw materials.

This study investigates an integrated optimization problem of aircraft assembly scheduling and flexible preventive maintenance (PM) with decision-making (FPM/DM), in which both machine flexibility and worker flexibility are considered. A mixed integer linear programming (MILP) model targeted at minimizing the assembly cycle is first established to formulate the problem. Then, CPLEX is used for solving the exact solution of the MILP model, however, it is time-consuming and difficult to apply to complex scenarios. For the tradeoff between solution quality and computational efficiency, an improved double-layer Q-learning (QL) algorithm with PM decision-making (IDLQL/PM) is further designed. Specifically, upper-layer QL is responsible for learning a proper machine selection heuristic from the given action set to ensure the machine load balance, and lower-layer QL provides a proper action (either an operation or a PM) for the selected machine to reduce unnecessary idle time and PM. Next, some instances are generated to evaluate the performance of IDLQL/PM. In a small-sized instance compared to CPLEX, the average solution gap is 1.8%, while the model solving time is reduced by 481%. As for 16 large-sized instances, IDLQL/PM presents a clear advantage over the well-known genetic algorithm and two other QL-based approaches. In addition, three state-of-the-art maintenance strategies are selected as rivals to validate the effectiveness of FPM/DM. It is observed that the proposed FPM/DM strategy can avoid improper maintenance during aircraft final assembly and ensure higher assembly efficiency.

Gefitinib, a well-known epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for the targeted therapy of lung cancer, induces autophagy in association with drug resistance. However, it remains unclear whether gefitinib treatment can affect the selective form of autophagy (i.e., mitophagy) and be beneficial for the treatment of human diseases with decreased autophagy, such as neurodegenerative diseases. Here, we show that gefitinib treatment promotes PINK1/Parkin-mediated mitophagy in both nonneuronal and neuronal cells, and this effect is independent of EGFR. Moreover, we found that gefitinib treatment increases the recruitment of the autophagy receptor optineurin (OPTN) to damaged mitochondria, which is a downstream signaling event in PINK1/Parkin-mediated mitophagy. In addition, gefitinib treatment significantly alleviated neuronal damage in TBK1-deficient neurons, resulting in impeded mitophagy. In conclusion, our study suggests that gefitinib promotes PINK1/Parkin-mediated mitophagy via OPTN and may be beneficial for the treatment of neurodegenerative diseases that are associated with defective mitophagy.

Cloud healthcare system (CHS) can provide the telemedicine services, which is helpful to cope with the difficulty of patients getting medical service in the traditional medical systems. However, resource scheduling in CHS has to face with a great of challenges since managing the trade-off of efficiency and quality becomes complicated due to the uncertainty of patient choice behavior. Motivated by this, a resource scheduling problem with multi-stations queueing network in CHS is studied in this paper. A Markov decision model with uncertainty is developed to optimize the match process of patients and scarce resources with the objective of minimizing the total medical costs that consist of three conflicting sub-costs, i.e., medical costs, waiting time costs and the penalty costs caused by unmuting choice behavior of patients. For solving the proposed model, a three-stage dynamic scheduling method is designed, in which an improved Q-learning algorithm is employed to achieve the optimal schedule. Numerical experimental results show that this Q-learning-based scheduling algorithm outperforms two traditional scheduling algorithms significantly, as well as the balance of the three conflicting sub-costs is kept and the service efficiency is improved.

Currently, manufacturing enterprises attach great importance to improving processing quality and customer satisfaction. Hybrid flow shops have widespread applications in real-world manufacturing systems such as steel production and chemical industry. In a practical production process, uncertainty commonly arises due to the difficulty of knowing exact information of facilities and jobs beforehand. In order to improve processing quality and customer satisfaction of manufacturing systems in uncertain environments, this article proposes a stochastic multiobjective hybrid flow shop scheduling problem aiming at maximizing processing quality and minimizing total tardiness, where the processing time of jobs obeys a known random distribution. To describe jobs’ processing quality mathematically, a quality-based cost function is presented, and further a chance-constrained programming approach is used to formulate this problem. Then, a multiobjective artificial bee colony algorithm incorporating a stochastic simulation approach is designed by considering its characteristics. Simulation experiments are performed on a set of instances and several state-of-the-art multiobjective optimization algorithms are chosen as peer approaches. Experiment results confirm that the proposed algorithm has an excellent performance in handling this problem.

Reproduction and immune defense are costly functions, and they are expected to tradeoff with each other to drive evolution. The brown planthopper (BPH), Nilaparvata lugensStål (Hemiptera, Delphacidae), is a global superpest that mostly damages rice crops. Yeast-like symbionts (YLS) exist in the abdominal fat body tissue and are tightly associated with the development, growth, and reproduction of BPH. Our previous research demonstrated that mating behavior promotes the release of YLS from the fat body into the hemolymph in the BPH, thereby triggering an immune response. Additionally, the fitness costs related to life-history traits of BPH (such as survival rate) have a strong dependence on the relative abundance of YLS. However, the possible relationship between reproduction and the immune response in BPH has not been identified. In this study, an omics-based approach was used to analyze the transcriptome of fat body tissues in mated and unmated BPH at 72 h post-eclosion, from which two antimicrobial peptide genes, NlDefensin A(NlDfA) and NlDefensin B(NlDfB), were selected since they were highly expressed in mated BPH. Subsequently, the full-length cDNA sequences of the NlDfAand NlDfBgenes were cloned and analyzed. qPCR results showed up-regulation of the NlDfAand NlDfBgenes in mated BPH when compared to unmated BPH. Spatial-temporal expression analysis indicated that the NlDfAand NlDfBgenes were expressed in all tissues and developmental stages, and they were most highly expressed in the fat body at 24 h post-eclosion. Moreover, the symbionts in BPH were significantly inhibited by the in vitroexpression of the NlDfA and NlDfB proteins. Furthermore, RNA interference (RNAi)-mediated suppression of NlDfAand NlDfBdramatically increased the relative abundance of YLS in the fat body, while YLS in the hemolymph decreased significantly. These BPH also displayed some fitness disadvantages in survival, fecundity, hatchability, and possibly the vertical transmission of YLS from hemolymph to egg. Our results indicated that mating could heighten the immunity of BPH by up-regulating the expression of the NlDfAand NlDfBgenes, which protect the host from pathogen challenge during reproduction. However, the reduced content of YLS may act as a fitness disadvantage in dictating the life-history traits of BPH. This work has significant theoretical and practical implications for the precise green control technology that involves crucial gene targeting, as well as for the “endosymbionts for pest control” strategy in insects.

Late leaf spot (LLS) is one of important diseases that causes severe yield losses in peanut. Peanut has various sources of resistance to LLS, and the identification of resistant QTLs and the development of related molecular markers are of great importance for breeding of LLS-resistant peanut. In this study, 173 individual lines of a recombinant inbred line (RIL) population and 48K SNP array for genotyping were used to construct a high-density genetic map with 1475 SNP marker and 20 linkage groups. A total of 11 QTLs were obtained through QTL analysis using the constructed genetic map. Among them, a stable major QTL qLLS.LG02was identified on linkage group 2 in all six environments, with a phenotypic variation explained (PVE) ranging from 15.57 to 31.09%. Additionally, QTL-seq technology was also employed for QTL analysis of LLS resistance. As a result, 14 QTL loci related to LLS resistance were identified using the G prime algorithm. Notably, physical position of qLLS02 and qLLS03are coincided with that of qLLS.LG02and qLLS.LG03respectively. Gene annotation analysis within the 14 QTL intervals by QTL-seq revealed that there were a total of 163 NBS-LRR disease resistance genes, accounting for 22.86% of all R genes in peanut genome and showing a 4.26-fold enrichment with a p-value of 5.19e-57. Within the QTL region qLLS02of the resistant parent Mi-2, there was a 5 Mb structural variation interval (SV) containing 81 NBS-LRR genes. A PCR diagnostic marker was developed, and validation data suggest that this SV might lead to gene deletion or replacement with other genes. This SV has the potential to enhance peanut resistance to late leaf spot disease. This study holds significant implications for improving peanut breeding for LLS resistance through development of associated molecular markers.

Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSC-EVs) have been recognized as a promising cell-free therapy for acute kidney injury (AKI), which avoids safety concerns associated with direct cell engraftment. However, low stability and retention of MSC-EVs have limited their therapeutic efficacy. RGD (Arg-Gly-Asp) peptide binds strongly to integrins, which have been identified on the surface of MSC-EV membranes; yet RGD has not been applied to EV scaffolds to enhance and prolong bioavailability. Here, we developed RGD hydrogels, which we hypothesized could augment MSC-EV efficacy in the treatment of AKI models. In vivotracking of the labeled EVs revealed that RGD hydrogels increased retention and stability of EVs. Integrin gene knockdown experiments confirmed that EV–hydrogel interaction was mediated by RGD–integrin binding. Upon intrarenal injection into mouse AKI models, EV-RGD hydrogels provided superior rescuing effects to renal function, attenuated histopathological damage, decreased tubular injury, and promoted cell proliferation in early phases of AKI. RGD hydrogels also augmented antifibrotic effects of MSC-EVs in chronic stages. Further analysis revealed that the presence of microRNA let-7a-5p in MSC-EVs served as the mechanism contributing to the reduced cell apoptosis and elevated cell autophagy in AKI. In conclusion, RGD hydrogels facilitated MSC-derived let-7a-5p-containing EVs, improving reparative potential against AKI. This study developed an RGD scaffold to increase the EV integrin-mediated loading and in turn improved therapeutic efficacy in renal repair; therefore this strategy shed light on MSC-EV application as a cell-free treatment for potentiated efficiency.

ABSTRACTSignificant evidences indicate that reactive oxygen species (ROS) can induce macroautophagy/autophagy under both physiological and pathological conditions. Although the relationship between ROS and autophagy regulation has been well studied, the basic mechanism by which ROS affects autophagy and the biological role of this regulation are still not fully understood. In the present study we show that multiple MiT-TFE transcription factors including TFEB, TFE3 and MITF, which are master regulators of autophagy and lysosomal biogenesis, can be activated upon direct cysteine oxidation by ROS. Oxidation promotes the nuclear translocation of these MiT-TFE transcription factors by inhibiting the association of them with RRAG GTPases, which in turn leads to enhanced global gene expression level in autophagy-lysosome system. Our study highlights the role of oxidation of MiT-TFE transcription factors in ROS-linked autophagy, and provides novel mechanism that MiT-TFE transcription factors-mediated transcriptional control of autophagy may govern cell homeostasis in response to oxidative stress, a biological process tightly linked to human diseases including neurodegenerative diseases and cancer.AbbreviationsBafi A1: bafilomycin A1; EBSS: Earle’s balanced salt solution; EGFP: enhanced green fluorescent protein; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTORC1: mechanistic target of rapamycin kinase complex 1; ROS: reactive oxygen species; RPS6KB/p70S6K: ribosomal protein S6 kinase B; TFEB: transcription factor EB; WT: wild type.

SiCp/Al composites have excellent comprehensive properties and have been widely used in aerospace, automotive industry and other fields. Due to the huge difference in performance between SiC particles and matrix alloys, traditional fusion welding methods are difficult to meet the join requirements of SiCp/Al composites. Friction stir joining (friction stir welding), as a solid phase joining process, has been proved to be a new technology with fine prospect in joining SiCp/Al composites compared with fusion welding process. Although some progress has been made in recent years, there are still full of challenges. In this paper, the research status of friction stir joining of SiCp/Al composites in recent years is expatiated, including the weldability of SiCp/Al composites, the macrostructure and the microstructure of joints, mechanical properties of joints, and tool wear and monitoring. Furthermore, the existing challenges of friction stir joining of SiCp/Al composites are summarized and the future development directions are prospected.

The Commensal Radio Astronomy Five-hundred-meter Aperture Spherical radio Telescope (FAST) Survey (CRAFTS) utilizes the novel drift-scan commensal survey mode of FAST and can generate billions of pulsar candidate signals. The human experts are not likely to thoroughly examine these signals, and various machine sorting methods are used to aid the classification of the FAST candidates. In this study, we propose a new ensemble classification system for pulsar candidates. This system denotes the further development of the pulsar image-based classification system (PICS), which was used in the Arecibo Telescope pulsar survey, and has been retrained and customized for the FAST drift-scan survey. In this study, we designed a residual network model comprising 15 layers to replace the convolutional neural networks (CNNs) in PICS. The results of this study demonstrate that the new model can sort >96% of real pulsars to belong the top 1% of all candidates and classify >1.6 million candidates per day using a dual-GPU and 24-core computer. This increased speed and efficiency can help to facilitate real-time or quasi-real-time processing of the pulsar-search data stream obtained from CRAFTS. In addition, we have published the labeled FAST data used in this study online, which can aid in the development of new deep learning techniques for performing pulsar searches.

Recently, the ow shop scheduling problem with deteriorating jobs has gained increasing concern from academic communities and industrial areas. The de- teriorating job is that the processing time of the jobs depends on their starting time. Due to the essential complexity of this problem, most studies focus on the two and three stages setting, and there are few studies that have considered a multiple stage setting. In this paper, a multiobjective ow shop deteriorating scheduling problem is considered, where the objectives are to minimize the makespan and the total tardiness, simultaneously. In order to solve it e_ciently, a novel adaptive multipopulation mul- tiobjective genetic algorithm is proposed. In the proposed algorithm, multiple scalar optimization problems of the multiobjective ow shop deteriorating scheduling prob-lem are developed, which will be introduced into the iteration course in multiple stages. An adaptive multipopulation strategy is designed to construct multiple subpopulations to search the optimal solutions of several scalar optimization problems in parallel. In addition, some special strategies, i.e. selection, crossover, mutation and the evolution of external archives are designed to improve the performance of the adaptive multi-population multiobjective genetic algorithm for the investigated multiobjective ow shop deteriorating scheduling problem. Based on a set of test instances on the multiob-jective ow shop deteriorating scheduling problem, simulation experiments are carried out to examine the performance of adaptive multipopulation multiobjective genetic al-gorithm in comparison with several peer multiobjective evolutionary algorithms. The experimental results show that the proposed adaptive multipopulation multiobjective genetic algorithm performs well when solving the multiobjective ow shop deteriorating scheduling problem.

With the widespread popularity of electric vehicles (EVs) in recent years, electric vehicle routing problem (EVRP) has received considerable attention from logistics management field. However, the real-world logistics and transportation system is always time-varying, such as new customer demand arrives dynamically. This dynamic transportation environment poses a great deal of challenges upon the decision-making of EVRP since the mid-route recharging of EVs has to be considered to meet the dynamic arrival of new customer demand due to the limited battery capacity. Therefore, a dynamic EVRP (DEVRP) with mid-route recharging and new demand arrival is investigated in this study. A mathematical model considering both recharging and routing decision-makings is developed, and then an improved memetic algorithm (IMA) with adaptive local search and economical random immigrant strategy is proposed. Four peer algorithms are used to test the performance of the proposed IMA on numerous extended benchmarks. It is observed that IMA can be treated as a more effective solution tool to achieve a better routing plan as well as the improved energy efficiency of EVs.

The recent financial crisis and other major crises have suggested that there are some strong interactions and interdependence between several supply chains and their external environments in various ways. A set of supply chains that are interdependent is called a holistic supply chain network (H-SCN) in this paper. There is a need to focus on building the resilience (in short, the ability of a system to recover from damage or disruption) of an entire H-SCN as it is believed that such a network system is strongly relevant to the recent economic recession that is triggered by financial crises. The objectives of this paper are to provide a classification of different SCNs in literature, leading to the identification of a new type of SCN system, i.e., an H-SCN, and to discuss the state of knowledge on the resilience of SCNs, particularly of an H-SCN. A systematic review approach is applied in this paper. Another contribution of this paper is the provision of a more comprehensive definition and description of resilient systems, including SCN systems. A final contribution of this paper is the proposal of the future directions of research on resilient SCN systems, particularly resilient H-SCN systems.

By gradually adjusting the proportion of tetraphenylethene (TPE) and phosphine oxide (PO), the series of n-type, ambipolar, and p-type aggregation-induced emission (AIE) luminogens (E,Z)-((1,2-diphenylethene-1,2-diyl)bis(4,1-phenylene))bis(diphenylphosphine oxide) (TPEDPO), diphenyl(4-(1,2,2-triphenylvinyl)phenyl)phosphine oxide (TPEPO), phenylbis(4-(1,2,2-triphenylvinyl)phenyl)phosphine oxide (DTPEPO), and tris(4-(1,2,2-triphenylvinyl)phenyl)phosphine oxide (TTPEPO) were developed for the first time. Their optical and electronic properties and AIE characteristics were investigated carefully. Time-resolved spectra indicate that the transient fluorescence decay lifetimes of aggregation-induced blue luminogens change regularly with the aggregation degree in THF/water solution. Particularly, identical electron and hole mobilities (∼2.3 × 10 –4cm2V–1s–1) can be realized when the TPE/PO ratio is 1:1. In electroluminesent (EL) devices, the sky-blue-doped device based on TPEPO was found to exhibit a low turn-on voltage of 2.8 V, a maximum luminance (Lmax) of 8656 cd m–2, a maximum current efficiency (ηC,max) of 9.32 cd A–1, and a maximum power efficiency (ηP,max) of 10.23 lm W–1.

Neurodegenerative diseases are severe disorders characterized by progressive neurodegeneration in specific brain regions. The ubiquitin-proteasome system (UPS) is closely linked to neurodegenerative disease. In most cases, UPS impairment and dysregulation of the UPS components are frequently observed. Moreover, toxin-induced neurodegeneration produces neuronal cell death accompanied by decreased UPS function. These studies suggest an involvement of the UPS in these diseases. In this review, we summarize the changes to UPS components in neurodegenerative diseases and the association between the UPS and disease pathology. Dysfunction of the UPS results in the abnormal accumulation of proteins; thus, the UPS plays a critical role in disease pathogenesis. Drugs targeting specific components of the UPS may provide promising strategies for disease treatment.

Abstract: Recently, multimodal optimization problems (MMOPs) have gained a lot of attention from the evolutionary algorithm (EA) community since many real-world applications are MMOPs and may require EAs to present multiple optimal solutions. In this paper, a memetic algorithm that hybridizes particle swarm optimization (PSO) with a local search (LS) technique, called memetic PSO (MPSO), is proposed for locating multiple global and local optimal solutions in the fitness landscape of MMOPs. Within the framework of the proposed MPSO algorithm, a local PSO model, where the particles adaptively form different species based on their indices in the population to search for different sub-regions in the fitness landscape in parallel, is used for globally rough exploration, and an adaptive LS method, which employs two different LS operators in a cooperative way, is proposed for locally refining exploitation. In addition, a triggered re-initialization scheme, where a species is re-initialized once converged, is introduced into the MPSO algorithm in order to enhance its performance of solving MMOPs. Based on a set of benchmark functions, experiments are carried out to investigate the performance of the MPSO algorithm in comparison with some EAs taken from the literature. The experimental results show the efficiency of the MPSO algorithm for solving MMOPs. [Copyright &y& Elsevier]

In this study, the surface of friction stir surface processing (FSSP)-modified copper alloy was altered by different passes of modification and lower pressure after selecting FSSP process parameters. The results showed that the grain size of the modified copper alloy surface was refined under various processes. In the modified section, the grains changed from fine equiaxed grains to rolling strips from the surface layer to the bottom of copper alloy sheet. FSSP could change the surface metallographic organization but could not change the internal structure of the sheet. The hardness values of samples obtained under various processes were higher than those of base metal, but the hardness of modified boundary region was slightly lower than that of base metal. The tensile strength of samples obtained under various processes was higher than that of base metal. Among them, FSSP was the best after one pass of modification, followed by two passes, and the worst was three passes. Most of the stretches appeared on the advancing side, and only a few appeared on the retreating side. The tensile parts had a honeycomb-type morphology, with a ductile fracture mode.

ABSTRACTIn a recent paper we addressed the mechanism by which defective autophagy contributes to TARDBP/TDP-43-mediated neurodegenerative disorders. We demonstrated that TARDBP regulates MTORC1-TFEB signaling by targeting RPTOR/raptor, a key component and an adaptor protein of MTORC1. Loss of TARDBP decreased the mRNA stability of RPTOR and this regulation in turn enhanced autophagosomal and lysosomal biogenesis in an MTORC1-dependent manner. Meanwhile, loss of TARDBP could also impair autophagosome-lysosome fusion in an MTORC1-independent manner. Importantly, we found that modulation of MTOR activity by treatment with rapamycin and phosphatidic acid had strong effects on the neurodegenerative phenotypes of TBPH (DrosophilaTARDBP)-depleted flies. Taken together, our data reveal that multiple dysfunctions in the autophagic process contribute to TARDBP-linked neurodegeneration and may help to identify potential therapeutic targets in the future.

Establishment of an optimal culture system is crucial for the production of high quality porcine embryos suitable for their use in biotechnology applications, and for biomedical research. The objectives of this study were to determine culture conditions supporting better embryo development, and to elucidate the roles of transcription and translation during early porcine embryogenesis. To accomplish these objectives in Experiment 1, porcine oocytes were in vitro matured and fertilized, and the resultant zygotes were cultured in two different medium, namely PZM3 and NCSU23. Cleavage and development to blastocyst stage were recorded at 48 hours and on day 6 post insemination respectively. In Experiment 2, porcine embryos were cultured in PZM3 supplemented with alpha-amainitin (25μg/ml) or cycloheximide (2μg/ml) between 24 and 84 hpi, respectively. Cleavage and embryonic development were recorded same as above. In experiment 1, no difference was found at the cleavage rate between PZM-3 and NCSU-23, however, PZM3 produced significantly more blastocysts (20% vs. 5.8%, respectively). In experiment 2, only the cycloheximide had a negative effect on the cleavage, while no blastocysts were observed in the treated groups (P>0.05) because the inhibitors caused an arrest in embryonic development at ∼72 hpi. In conclusion, PZM3 medium supports better embryonic development, and that both transcriptional and translational activities become necessary for embryonic development beyond 72 hpi. (platform)