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Abstract: Our previous study has revealed that malonyl-ginsenosides from Panax ginseng (PG-MGR) play a crucial role in the treatment of T2DM. However, its potential mechanism was still unclear. In this study, we investigated the anti-diabetic mechanisms of action of PG-MGR in high fat diet-fed (HFD) and streptozotocin-induced diabetic mice and determined the main constituents of PG-MGR responsible for its anti-diabetic effects. Our results showed that 16 malonyl ginsenosides were identified in PG-MGR by HPLC-ESI-MS/MS. PG-MGR treatment significantly reduced fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels and improved insulin resistance and glucose tolerance. Simultaneously, PG-MGR treatment improved liver injury by decreasing aspartate aminotransferase (AST) and alanine aminotransferase (ALT) expression. Furthermore, Western blot analysis demonstrated that the protein expression levels of p-PI3K/PI3K, p-AKT/AKT, p-AMPK/AMPK, p-ACC/ACC and GLUT4 in liver and skeletal muscle were significantly up-regulated after PG-MGR treatment, and the protein expression levels of p-IRS-1/IRS-1, Fas and SREBP-1c were significantly reduced. These findings revealed that PG-MGR has the potential to improve glucose and lipid metabolism and insulin resistance by activating the IRS-1/PI3K/AKT and AMPK signal pathways.

Drug resistance is often developed during clinical chemotherapy of ovarian cancers. The ubiquitin‐like protein interferon‐stimulated gene 15 (ISG15) is possibly dependent on tumour context to promote or suppress progression of various tumours. The ubiquitin‐like protein interferon‐stimulated gene 15 (ISG15) was decreased in cisplatin‐resistant ovarian cancer cells. The current study identified that both ectopic wild type and nonISGylatable mutant ISG15 expression inhibited CSC‐like phenotypes of cisplatin‐resistant ovarian cancer cells. Moreover, ectopic ISG15 expression suppressed tumour formation in nude mice. In addition, ISG15 downregulation promoted CSC‐like features of cisplatin‐sensitive ovarian cancer cells. Furthermore, low ISG15 expression was associated with poor prognosis in patients with ovarian cancer. Transcriptional repressor Krüppel‐like factor 12 (KLF12) downregulated ISG15 in cisplatin‐resistant cells. Our data indicated that downregulating ISG15 expression, via weakening effect of KLF12, might be considered as new therapeutic strategy to inhibit CSC phenotypes in the treatment of cisplatin‐resistant ovarian cancer.

A new species of fern, Pteris pseudoamoena (Pteridaceae), was identified and characterized. It is currently found in Guangxi Province, China, and Vietnam. Pteris pseudoamoena shares similar morphological characters with P. amoena and P. mcclurei, but can be distinguished by spores with echinate-tuberculate and auriculate ornamentation, straw-colored stipes, rachises and costae, and mostly free, occasionally interlinked veins. In addition, molecular evidence indicated that the new species is sister to a clade consisting of P. amoena, P. nakasimae and P. mcclurei.

Ji-sheng Wang,1,2,* Xue-feng Gong,3,4,* Jun-long Feng,1,2,* Hai-song Li,2 Xiao Li,5 Sheng Deng,1,2 Pei-zhong Ren,3,4 Jia-mei Wang,3,4 Ming-sheng Lv,3,4 Rui-feng Jin,3,4 Qiu-yi Chen,3,4 Bin Wang,2 Hong-sheng Cui4 1First Clinical Medical College, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2Andrology Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, People’s Republic of China; 3The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 4Pneumology Department, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 5Department of Andrology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450046, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bin WangAndrology Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, People’s Republic of ChinaEmail dayiwangbln@sina.comHong-sheng CuiPneumology Department, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of ChinaEmail Hshcui@sina.comBackground: Jiawei Shengjiang Powder (JWSJP) is a classical Chinese medicinal formula, which has been widely applied in the treatment of asthma and complications for many years due to its curative effect.Aim: To verify the effect of JWSJP in improving abnormal sperm motility caused by asthma and to explore its potential mechanism.Materials and Methods: The active compounds of JWSJP were obtained from high performance liquid chromatography tandem mass spectrometry and the Traditional Chinese Medicine System Pharmacology. The key active components and targets of JWSJP were predicted based on network pharmacological analysis and bioinformatics research. Rats were randomly divided into normal, model and treatment groups. The rat model of allergic asthma was induced by intraperitoneal injection of ovalbumin solution. The experiment judged improvement of semen quality by evaluating sperm motility, and detected the expression of related proteins in testicular tissue of Sprague-Dawley rats by RT-qPCR and Western blot methods. Hematoxylin and eosin (HE) staining was used to observe the changes in testicular tissue structure in rats.Results: Through the analysis of network pharmacology and bioinformatics, it was found that beta-sitosterol, quercetin, gallic acid, pelargonidin and kaempferol were the key active components of Jiawei Shengjiang Powder. Tumor necrosis factor (TNF), interleukin-6 (IL-6) and insulin (INS) genes are crucial targets of JWSJP in the treatment of spermatogenic dysfunction caused by acute asthma. After 8 weeks of intervention, compared with the model group, the treatment group had significantly improved sperm motility (P < 0.05). There were significant differences in TNF, IL6, and INS proteins in the treatment group, and the HE staining of testicular tissue structure in the treatment group was significantly improved.Conclusion: JWSJP can improve the abnormal sperm motility induced by asthma, and its mechanism may be related to the expression of related proteins and mRNA of TNF, IL6, and INS.Keywords: Jiawei Shengjiang Powder, asthmatic attack, asthenospermia, network pharmacology

Papillary thyroid cancer (PTC) is the most common endocrine tumor with an increasing incidence, has a strong propensity for neck lymph node metastasis. Limited treatment options are available for patients with advanced or recurrent metastatic disease, resulting in a poor prognosis. Tripartite motif protein 29 (TRIM29) is dysregulated in various cancer and functions as oncogene or tumor suppressor in discrete cancers. In this study, we found that both TRIM29 and fibronectin 1 (FN1) were upregulated with positive correlation in PTC tissues. Neither overexpression nor downregulation of TRIM29 altered the proliferation of PTC cells significantly. Overexpression of TRIM29 significantly promotes, while knockdown of TRIM29 significantly decreases migration and invasion by regulating FN1 expression in PTC cells. In terms of mechanism, we found that TRIM29 altered the stability of FN1 mRNA via regulation of miR-873-5p expression. The current study also demonstrated that long non-coding RNA (LncRNA) CYTOR suppressed maturation of miR-873-5p via interaction with premiR-873, and TRIM29 decreased miR-873-5p via upregulation of CYTOR. This study suggests that involvement of TRIM29 in migration and invasion in PTC cells may reveal potential metastatic mechanism of PTC and represent a novel therapeutic target and strategy.

Multifunctional nanoparticles hold great potential for clinical and medical research. Herein, Ag2Te QDs were applied as multifunctional contrast agents for the second near-infrared region (NIR-II) ...

High-strength flexible net barriers have achieved a certain effect in mountainous debris flow prevention, but research on the mechanism of structural stress and deformation is still developing. This study first presents an analytical model based on the quasi-static mechanical equilibrium to evaluate the geometric nonlinearity and the load performance of the structure and then conducts a flume experiment to reveal the load mechanism of the structure. Then, a full-scale simulation is performed to investigate the deformation and failure of the flexible net barrier impacted by the debris flow via PFC3D software. The results show that the deformation of the flexible net barrier occurs not only in the direction of flow but also in other directions to make the structure force balanced under debris flow impact. The load impacting on the barrier is far less than the total impact force exerted by debris flow. The flexible barrier has an obvious effect to block a coarse debris flow, and the blocking capacity is related to the volume of debris flow and the slope gradient of the flume. The displacement patterns of loaded cable in the experiment and the simulation are different, but the cable under non-debris flow impact is only dragged by the mesh rope showing a regular parabolic shape, and the tension inside the flexible mesh is far less than that of the transverse cable. In addition, the model shows the failure characteristics of flexible barrier under large-scale debris flow, which plays a guiding role in practical engineering design of the structure.

Solid tumour frequently undergoes metabolic stress during tumour development because of inadequate blood supply and the high nutrient expenditure. p53 is activated by glucose limitation and maintains cell survival via triggering metabolic checkpoint. However, the exact downstream contributors are not completely identified. BAG3 is a cochaperone with multiple cellular functions and is implicated in metabolic reprogramming of pancreatic cancer cells. The current study demonstrated that glucose limitation transcriptionally suppressed BAG3 expression in a p53‐dependent manner. Importantly, hinderance of its down‐regulation compromised cellular adaptation to metabolic stress triggered by glucose insufficiency, supporting that BAG3 might be one of p53 downstream contributors for cellular adaptation to metabolic stress. Our data showed that ectopic BAG3 expression suppressed p53 accumulation via direct interaction under metabolic stress. Thereby, the current study highlights the significance of p53‐mediated BAG3 suppression in cellular adaptation to metabolic stress via facilitating p53 accumulation.

Ovarian cancer (OC) is a common gynecological malignant tumor that seriously endangers the health of women worldwide. Tripartite motif containing 29 (TRIM29) is a TRIM family member that is frequently overexpressed in OC. However, the specific role of TRIM29 in OC remains obscure. To investigate the underlying molecular mechanism, a global proteomics analysis identified SET binding protein 1 (SETBP1) as a crucial target of TRIM29. Subsequently, the SETBP1/SET/Protein phosphatase 2 (PP2A) axis was confirmed to be required for the recovery of cancer stem cell (CSC)-like phenotype suppressed by TRIM29 knockdown. Mechanistically, TRIM29 facilitated SETBP1 transcriptional activation via the VEZF1 transcription factor. More importantly, TRIM29 promoted VEZF1 mRNA translation by recruiting RNA binding protein BICC1 to its 3'UTR. The clinical significance was established by the association of TRIM29 and SETBP1 expression with clinicopathological features in OC samples. The SETBP1/SET/PP2A axis driven by TRIM29 via transcription factor VEZF1 is at least one of the primary mechanisms underlying TRIM29 maintenance of the CSC-like characteristics in OC.

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The pathogenesis of papillary thyroid cancer (PTC), the most common type of thyroid cancer, is not yet fully understood. This limits the therapeutic options for approximately 7% of invasive PTC patients. The critical role of AUF1 in the progression of thyroid cancer was first reported in 2009, however, its molecular mechanism remained unclear. Our study used CRISPR/Cas 9 system to knockdown AUF1 in IHH4 and TPC1 cells. We noticed that the expression of TRIM58 and ZBTB2 were increased in the AUF1 knockdown IHH4 and TPC1 cells. When TRIM58 and ZBTB2 were inhibited by small hairpin RNAs (shRNAs) against TRIM58 (shTRIM58) and ZBTB2 (shZBTB2), respectively, the proliferation, migration, and invasion ability of the AUF1-knockdown IHH4 and TPC1 cells were increased. In addition, two ZBTB2 binding sites (-719~-709 and -677~-668) on TRIM58 promoter and two AUF1 binding sites (1250-1256 and 1258-1265) on ZBTB2 3’-UTR were identified. These results suggested that AUF1 affecting thyroid cancer cells via regulating the expression of ZBTB2 and TRIM58.

Glucose limitation activates p53, which functions as an adaptive response to maintain cell survival. However, p53 is frequently deleted or mutated in a variety of tumors, while most cancer cells can acclimatize themselves to metabolically unfavorable surrounding, indicating that alternative mechanisms other than p53 transactivation underly adaptive response of cancer cells with p53 deletion or mutation to metabolically hostile environment. Sestrin 2 (SESN2) is a p53 downstream target, which plays a protective role against various stressful stimuli, such as genotoxic, energetic, and oxidative stress. In the current study, we demonstrated that SESN2 transcript was stabilized by glucose limitation at the posttranscriptional level irrespective of p53 status. Importantly, SESN2 also protected cells from metabolic stress triggered by glucose limitation in a p53-independent manner. Our data indicated that stabilization of SESN2 transcript might be an alternative adaptive response to metabolic stress other than p53 activation. Thereby, the current study highlights the significance of stabilization of SESN2 transcript in adaptation of cells with p53 deletion or mutation to metabolic stress.

BAG3 is constitutively expressed in multiple types of cancer cells and its high expression is associated with tumour progression and poor prognosis of PDAC. However, little is known about the role of BAG3 in the regulation of stromal microenvironment of PDAC. The current study demonstrated that beside PDAC tumour cells, BAG3 was also expressed in some activated stroma cells in PDAC tissue, as well as in activated PSCs. In addition, the current study demonstrated that BAG3 expression in PSCs was involved in maintenance of PSCs activation and promotion of PDACs invasion via releasing multiple cytokines. The current study demonstrated that BAG3‐positive PSCs promoted invasion of PDACs via IL‐8, MCP1, TGF‐β2 and IGFBP2 in a paracrine manner. Furthermore, BAG3 sustained PSCs activation through IL‐6, TGF‐β2 and IGFBP2 in an autocrine manner. Thereby, the current study provides a new insight into the involvement of BAG3 in remodelling of stromal microenvironment favourable for malignant progression of PDAC, indicating that BAG3 might serve as a potential target for anti‐fibrosis of PDAC.

Lysine acetylation is critical in regulating important biological processes in many organisms, yet little is known about acetylome evolution and its contribution to phenotypic diversity. Here, we compare the acetylomes of baker’s yeast and the three deadliest human fungal pathogens, Cryptococcus neoformans, Candida albicans, and Aspergillus fumigatus. Using mass spectrometry enriched for acetylated peptides together with public data from Saccharomyces cerevisiae, we show that fungal acetylomes are characterized by dramatic evolutionary dynamics and limited conservation in core biological processes. Notably, the levels of protein acetylation in pathogenic fungi correlate with their pathogenicity. Using gene knockouts and pathogenicity assays in mice, we identify deacetylases with critical roles in virulence and protein translation elongation. Finally, through mutational analysis of deactylation motifs we find evidence of positive selection at specific acetylation motifs in fungal pathogens. These results shed new light on the pathogenicity regulation mechanisms underlying the evolution of fungal acetylomes., Yanjian Li and Hailong Li, et al. report interspecific comparisons of the acetylomes of yeast and three human fungal pathogens. Through evolutionary analysis and experimental validation, they show that pathogen-specific aceylation motifs and deacetylase genes are required for normal virulence in an animal infection model.

Bcl-2 associated athanogene 3 (BAG3) is an important molecule that maintains oncogenic features of cancer cells via diverse mechanisms. One of the important functions assigned to BAG3 is implicated in selective macroautophagy/autophagy, which attracts much attention recently. However, the mechanism underlying regulation of autophagy by BAG3 has not been well defined. Here, we describe that BAG3 enhances autophagy via promotion of glutamine consumption and glutaminolysis. Glutaminolysis initiates with deamination of glutamine by glutaminase (GLS), by which yields glutamate and ammonia in mitochondria. The current study demonstrates that BAG3 stabilizes GLS via prohibition its interaction with SIRT5, thereby hindering its desuccinylation at Lys158 and Lys164 sites. As an underlying molecular mechanism, we demonstrate that BAG3 interacts with GLS and decreases SIRT5 expression. The current study also demonstrates that occupation by succinyl at Lys158 and Lys164 sites prohibits its Lys48-linked ubiquitination, thereby preventing its subsequent proteasomal degradation. Collectively, the current study demonstrates that BAG3 enhances autophagy via stabilizing GLS and promoting glutaminolysis. For the first time, this study reports that succinylation competes with ubiquitination to regulate proteasomal GLS degradation.

The GH4169 superalloy with different content of δ-Ni3Nb phase was welded by tungsten inert gas welding. A detailed study of microstructure and hardness of heat-affected zone (HAZ) was performed in both as-welded and aged state. The results show that the precipitation of δ phase, especially the intergranular δ phase, can lead to the enrichment of Nb and Mo elements, which promote the formation of γ/Laves eutectic constituent at grain boundaries in HAZ. In as-welded state, the hardness decreases first and then increases (exhibiting a “V” shape) with distance away from fusion line in HAZ, which is governed by grain size. After aging treatment, however, the γ″ phase plays a key role in hardness and leads to the “Λ” shape profiles of hardness in HAZ.

Ovarian cancer is the most lethal gynecologic malignant cancer, frequently due to its late diagnosis and high recurrence. Cancer stem cells (CSCs) from different malignancies including ovarian cancer have been linked to chemotherapy resistance and poor prognosis. Therefore, identifying the molecular mechanisms mediating therapy resistance is urgent to finding novel targets for therapy-resistant tumors. Aberrant O-glycosylation ascribed to subtle alteration of GALNT family members during malignant transformation facilitate metastasis in various cancers. The current study demonstrated that BAG3 was upregulated in platin-resistant ovarian cancer tissues and cells, and high BAG3 predicted dismal disease-free survival of patients with ovarian cancer. In addition, the current study showed that BAG3 facilitated CSC-like properties of ovarian cancer cells via regulation of GALTN10. In a term of mechanism, BAG3 epigenetically regulated GALNT10 transactivation via histone H3 lysine 4 (H3K4) presenter WDR5. We demonstrated that WDR5 increased H3K4 trimethylation (H3K4me3) modification at the promoter regions of GALNT10, facilitating recruitment of transcription factor ZBTB2 to the GALNT10 promoter. Collectively, our study uncovers an epigenetic upregulation of GALNT10 by BAG3 via WDR5 to facilitate CSCs of platin-resistant ovarian cancers, providing additional information for further identification of attractive targets with therapeutic significance in platin-resistant ovarian cancer.

HYOU1 is upregulated in many kinds of cancer cells, and its high expression is associated with tumour invasiveness and poor prognosis. However, the role of HYOU1 in papillary thyroid cancer (PTC) development and progression remains to be elucidated. Here, we reported that HYOU1 was highly expressed in human PTC and associated with poor prognosis. HYOU1 silencing suppressed the proliferation, migration and invasion of PTC cells. Mechanistic analyses showed that HYOU1 silencing promoted oxidative phosphorylation while inhibited aerobic glycolysis via downregulating LDHB at the posttranscriptional level. We further confirmed that the 3'UTR of LDHB mRNA is the indirect target of HYOU1 silencing and HYOU1 silencing increased miR‐375‐3p levels. While LDHB overexpression significantly suppressed the inhibitory effects of HYOU1 silencing on aerobic glycolysis, proliferation, migration and invasion in PTC cells. Taken together, our findings suggest that HYOU1 promotes glycolysis and malignant progression in PTC cells via upregulating LDHB expression, providing a potential target for developing novel anticancer agents.

Background: Individual cognitive stimulation therapy (ICST) can benefit cognition and quality of life for people with dementia, but the evidence for nurses-led individual cognitive stimulation interventions is limited.Objectives: The current study aimed to develop the process of planning and implementing ICST, and evaluate the effect of ICST on cognitive function and therapeutic effect in patients with mild Alzheimer’s disease (AD). Methods: It was a randomized controlled trial lasting for a half year. 38 patients with mild AD were recruited. The control group was given the “Individual Cognitive Stimulation Therapy Manual for AD” to deliver the sessions at home. The intervention group was given 90 minutes ‘cognitive stimulation sessions, completed up to three times weekly over 24 weeks. The outcomes were measured at baseline and 24weeks by the scales widely used in AD evaluation (MMSE, MoCA and ADL).Results: There were statistical significance between the two groups, especially the scores of memory, delayed memory in MMSE and scores of memory, delayed memory, immediate memory, attention in MoCA were significantly improved in the intervention group compared with control group. ICST show positive effects that may help preserve memory in mild AD.Conclusions: The ICST can improve the memory and attention cognitive domains in patients with mild AD. And the feedback from patient and caregiver in ICST was favorable.

Background: Ovarian cancer is the most frequent cause of death among gynecologic malignancies due to the absence of an early effective diagnostic approach. Although the majority of patients typically respond well to the first line of chemotherapy based on platinum compounds and taxanes, recurrence and chemoresistance limits its clinical utility. Remarkably, cancer stem cells (CSC) tend to form minimal residual disease after chemotherapy and exhibit recurrent potential. The ability of cancer cells to reprogram their metabolism has recently been related with resistance to chemotherapies.Methods: BAG5 expression was studied in 16 cisplatin-sensitive and 8 cisplatin-resistant ovarian cancer tissues by Western blot. BAG5-induced cell proliferation, migration and invasion were investigated by CCK-8 assay, colony formation assay, wound healing and Transwell assay. To investigate whether BAG5 is implicated in metabolism regulation, mitochondrial function was monitored by real-time measurement of changes in the oxygen consumption rate (OCR) and glycolysis was also determined by measuring the extracellular acidification rate (ECAR). Immunohistochemical staining measured correlations between BAG5 and Bcl6, Rictor in most ovarian serous adenocarcinoma tissues.Results: The current study found BAG5 expression was decreased in cisplatin-resistant ovarian cancer cells and clinical tissues. Our data demonstrated that BAG5 knockdown was implicated in metabolic reprogramming and maintenance of cancer stem cell (CSC)-like features of cisplatin-resistant ovarian cancer cells via regulation of Rictor and subsequent mTORC2 signaling pathway. In addition, the current study demonstrated that Bcl6 upregulation was responsible for repression of BAG5 transactivation via recruitment on the BAG5 promoter in cisplatin-resistant ovarian cancer. The current study also demonstrated reverse correlations between BAG5 and Bcl6, BAG5 and Rictor in ovarian serous adenocarcinoma tissues. Conclusions: Collectively, the current study identified the implication of Bcl6/BAG5/Rictor-mTORC2 signaling pathway in metabolic reprograming and maintenance of CSC-like features including cisplatin-resistance in cisplatin-resistant ovarian cancer cells. Therefore, further studies on the mechanism underlying regulation of metabolic reprogramming and CSC-like characteristics of cisplatin-resistant ovarian cancer cells may contribute to the establishment of novel therapeutic strategy for cisplatin-resistance.

Cancer cells frequently exhibit aerobic glycolysis, known as the Warburg effect. An et al. identify a novel RNA regulatory activity of BAG3, a protein implicated in various cancers. BAG3 enhances posttranscriptionally the expression of Hexokinase 2, the first enzyme involved in glycolysis, and it reprograms glucose metabolism by pancreatic cancer cells., Aerobic glycolysis, a phenomenon known historically as the Warburg effect, is one of the hallmarks of cancer cells. In this study, we characterized the role of BAG3 in aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) and its molecular mechanisms. Our data show that aberrant expression of BAG3 significantly contributes to the reprogramming of glucose metabolism in PDAC cells. Mechanistically, BAG3 increased Hexokinase 2 (HK2) expression, the first key enzyme involved in glycolysis, at the posttranscriptional level. BAG3 interacted with HK2 mRNA, and the degree of BAG3 expression altered recruitment of the RNA-binding proteins Roquin and IMP3 to the HK2 mRNA. BAG3 knockdown destabilized HK2 mRNA via promotion of Roquin recruitment, whereas BAG3 overexpression stabilized HK2 mRNA via promotion of IMP3 recruitment. Collectively, our results show that BAG3 promotes reprogramming of glucose metabolism via interaction with HK2 mRNA in PDAC cells, suggesting that BAG3 may be a potential target in the aerobic glycolysis pathway for developing novel anticancer agents.

Iron–sulfur clusters (ISC) are indispensable cofactors for essential enzymes in various cellular processes. In the model yeast Saccharomyces cerevisiae, the precursor of ISCs is exported from mitochondria via a mitochondrial ABC transporter Atm1 and used for cytosolic and nuclear ISC protein assembly. Although iron homeostasis has been implicated in the virulence of the human fungal pathogen Cryptococcus neoformans, the key components of the ISC biosynthesis pathway need to be fully elucidated. In the current study, a homolog of S. cerevisiae Atm1 was identified in C. neoformans, and its function was characterized. We constructed C. neoformans mutants lacking ATM1 and found that deletion of ATM1 affected mitochondrial functions. Furthermore, we observed diminished activity of the cytosolic ISC-containing protein Leu1 and the heme-containing protein catalase in the atm1 mutant. These results suggested that Atm1 is required for the biosynthesis of ISCs in the cytoplasm as well as heme metabolism in C. neoformans. In addition, the atm1 mutants were avirulent in a murine model of cryptococcosis. Overall, our results demonstrated that Atm1 plays a critical role in iron metabolism and virulence for C. neoformans.

Ovarian cancer is the most frequent cause of gynecologic malignancies associated death. Primary or acquired cisplatin resistance is frequently occurred during ovarian cancer therapy. Cancer stem cells (CSC) tend to form minimal residual disease after chemotherapy and are implicated in relapse. The ability of cancer cells to reprogram their metabolism has recently been related with maintenance of CSC and resistance to chemotherapies. The current study found that BAG5 expression was decreased in cisplatin-resistant ovarian cancer cells and clinical tissues. Our data demonstrated that BAG5 knockdown was implicated in metabolic reprogramming and maintenance of cancer stem cell (CSC)-like features of ovarian cancer cells via regulation of Rictor and subsequent mTORC2 signaling pathway. In addition, the current study demonstrated that Bcl6 upregulation was responsible for repression of BAG5 transactivation via recruitment on the BAG5 promoter in cisplatin-resistant ovarian cancer. The current study also demonstrated reverse correlations between BAG5 and Bcl6, BAG5 and Rictor in ovarian serous adenocarcinoma tissues. Collectively, the current study identified the implication of Bcl6/BAG5/Rictor-mTORC2 signaling pathway in metabolic reprograming and maintenance of CSC-like features in cisplatin-resistant ovarian cancer cells. Therefore, further studies on the mechanism underlying regulation of metabolic reprogramming and CSC-like characteristics of cisplatin-resistant ovarian cancer cells may contribute to the establishment of novel therapeutic strategy for cisplatin-resistance.

This work presents a highly miniaturized, ultra-low-frequency, multi-stable and tri-hybrid portable energy harvester to harness structural and biomechanical vibration energy efficiently. This energy harvester is developed by using a novel multi-stability-based frequency up-converted approach, in which two new configurations of magneto-multi-stable oscillators are closely integrated. Hence, the displacement stroke of low-frequency vibration and the mechanical energy transfer process can almost completely overlap, and consequently magnify the power output and power density under low-frequency broadband vibration sources. By hybridizing two impact-driven piezoelectric generators, an array-type electromagnetic generator, a sliding-mode triboelectric nanogenerator and a contact-separation triboelectric nanogenerator in a highly compact design arrangement, more electric power can be generated from a single mechanical motion, which can successfully enhance the output performance. A fabricated prototype of the present design is tested using shaker excitations and body-induced motions. Under the shaker test, the prototype works well at a wide bandwidth of 1–11 Hz under 1 g (=9.8 m s−2) and generates a maximum output power of 85.9 mW across the optimum resistance loads, corresponding to the normalized power density of 3.70 mW cm - 3 g - 2 at 3 Hz under 1 g. During the human activity motions (i.e., walking, slow running, and handshaking), the prototype also shows good performance under different wearable positions of the human body and can power up 20 thermohygrometers and 296 commercial light-emitting diodes continuously. The present energy harvester is a promising application to enable as a sustainable power source for wearable/portable electronics and wireless monitoring systems.

The effects of dissolved gas and cold work on the electrochemical behaviors of Type 304 stainless steel were investigated in simulated pressurized water reactor primary water environment by potentiodynamic polarization and electrochemical impedance spectroscopy. Results reveal that both dissolved gas and cold work have a significant influence on anodic passivation properties and corrosion resistance of the oxide film. In Ar deaerated water and oxygenated water environments, the corrosion potential of stainless steel and Pt is controlled by the dissolved oxygen concentration, and the corrosion resistance of the inner barrier layer is much higher. However, in H2 deaerated water, the corrosion potential is depressed by the H2/H2O redox potential and the inner oxide film formed in H2 deaerated water is less stable. In addition, the passive region of polarization curves on 304 stainless steel in oxygenated and Ar deaerated water is controlled by metal dissolution instead of water oxidation, and the passive cur...

A horizontal permeable retaining structure (i.e., a sloping roof grill barrier) is an efficient way to separate water from sediment. However, the effect of the structural parameters and lateral deposit area on separation efficiency has not been investigated. Taking Yanmen gully as an example, this paper first expands the lateral deposit area of the retaining structure, and then conducts a series of flume experiments to study the influences of the structural parameters (grid spacing and grid inclination degree) on the separation efficiency. The experimental results indicate that the retention ability of the structure with the optimized lateral deposit area is much higher. The grid spacing is the main factor affecting the grain-size distribution of the debris flow beyond the barrier and should be higher than the d80 value of grain-size distribution of the debris-flow. The retention capacity is directly proportional to the grid inclination degree, while the separation efficiency is inversely proportional to the grid inclination degree. The steeper the grid inclination is, the smaller the displacement of debris flow particles along the barrier surface is. The experimental results are analysed to correlate the barrier length with the structural parameters. This paper serves as a reference for the structural design of horizontal permeable barriers.

Papillary thyroid cancer (PTC), the most common thyroid malignancy, has a strong propensity for neck lymph node metastasis, which will increase the risk of local recurrence and decrease the survival in some high-risk groups. Hence, it is essential to set up a reliable biomarker to predict lymph node metastasis. BAG5 is a unique member of the BAG cochaperone family because it consists of more than one BAG domain, which acts as modulator of chaperone activity. In this study, we found that expression of BAG5 was significantly increased in PTC cells and tissues. Neither overexpression nor downregulation of BAG5 altered the proliferation of PTC cells. On the contrary, overexpression of BAG5 significantly promoted, while knockdown of BAG5 significantly decreased migration and invasion of PTC cells. Along with this, fibronectin 1 (FN1) was significantly increased and decreased in cells that overexpress or downregulate BAG5, respectively. Mechanistically, we found that BAG5 modulated FN1 expression at the translational level and promoted invasion via suppression of miR-144-3p, which targeted the 3' untranslational region (UTR) of FN1 transcript. This study suggests that BAG5 is an important regulator of migration and invasion in PTC cells and may represent a novel therapeutic target for intervening in PTC progression.

Cisplatin-based chemotherapies have long been considered as a standard chemotherapy in ovarian cancer. However, cisplatin resistance restricts beneficial therapy for patients with ovarian cancer. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, that is implicated in the post-translational modification of diverse proteins. In this work, we found that ISG15 was downregulated in cisplatin resistant tissues and cell lines of ovarian cancer. Functional studies demonstrated that overexpression of wild type (WT) ISG15, but not nonISGylatable (Mut) ISG15 increased cell responses to cisplatin in resistant ovarian cancer cells. Furthermore, we found that WT ISG15 decreased ABCC2 expression at the protein level. Importantly, overexpression of ABCC2 blocked sensitizing effect of ISG15 on cisplatin. In addition, we identified that hnRNPA2B1 was recruited to 5'UTR of ABCC2 mRNA and promoted its translation, which was blocked by ISG15. We further demonstrated that hnRNPA2B1 could be ISGylated, and ISGylation blocked its recruitment to ABCC2 mRNA, thereby suppressed translation of ABCC2. Altogether, our data support targeting ISG15 might be a potential therapeutic strategy for patients with cisplatin-resistant ovarian cancer.

BAG3 is a member of the cochaperone BAG family and often highly expressed in various cancers. Recently, evidences show that BAG3 promotes stemness of human cancer cells. IFN-stimulated genes 15 (ISG15) is an ubiquitin-like molecule, which is covalently conjugated with substrates to form ISGylated proteins. Global screening BAG3 interacting partners demonstrated that ISG15 might be a potential binding partner. The current study revealed that BAG3 did not interact with ISG15, but positively regulated ISG15 expression in pancreatic ductal adenocarcinoma cancer (PDAC). It was further found that BAG3 deletion stabilized ISG15 mRNAs, while suppressed its translation via increasing Serine phosphorylation of Ago2 at position 387 (S387). Both BAG3 deletion and ISG15 knockdown suppressed stem cell-like phenotypes of PDAC cells, including clonogenicity, invasiveness and spheroid formation. In addition, ectopic ISG15 expression rescued the suppressive role of BAG3 deletion in cancer stem cell (CSC)-like phenotypes of PDAC cells, and this effect of ISG15 was independent of its ISGylation function. The current study implies that BAG3 and ISG15 may provide a therapeutic advantage for PDAC.

Bcl-2 associated athanogene 3 (BAG3) is highly expressed in pancreatic ductal adenocarcinoma (PDAC), and its high expression appears to be a poor prognostic factor for patients with PDAC. In this study, we show that BAG3 knockdown significantly decreases migration and invasion of PDACs via reduction of interleukine-8 (IL-8) production. BAG3 knockdown regulates IL-8 expression at the posttranscriptional levels via interplay between recruitment of RNA-binding protein HuR and miR-4312. HuR binds to the cis-elements located in the 3′-untranslational region (UTR) of the IL-8 transcript to stabilize it, whereas miR-4312-containing miRNA-induced silencing complex (miRISC) is recruited to the adjacent seed element to destabilize it. The binding of HuR prevents the recruitment of Argonaute (Ago2), overriding miR-4312-mediated translation inhibition of IL-8. BAG3 knockdown decreases cytoplasmic distribution of HuR via increasing its phosphorylation at Ser202, therefore compromising its recruitment while promoting recruitment of miR-4312 containing miRISC to IL-8 transcript. Furthermore, our data indicate that only phosphorylated Ago2 at Ser387 interacts with IL-8 transcript. BAG3 knockdown increases phosphorylation of Ago2 at Ser387, thereby further promoting loading of miR-4312 containing miRISC to IL-8 transcript. Taken together, we propose that BAG3 promotes invasion by stabilizing IL-8 transcript via HuR recruitment, and subsequently suppressing the loading of miR-4312 containing miRISC in PDACs. Our results reveal a novel pathway linking BAG3 expression to enhanced PDAC metastasis, thus making BAG3 a potential target for intervention in pancreatic cancer.

This study involves the design and investigation of a low-frequency, broadband, tri-hybrid energy harvester. The harvester consists of a novel septuple-stable nonlinearity-enhanced mechanical frequency up-conversion mechanism that not only enhances the output performance of the frequency up-conversion via inter-well motions, and also offers a wide and highly efficient operating bandwidth at low acceleration via the combination of resonant inter-well oscillation behavior and non-resonant behavior. The integration of an impact-driven piezoelectric generator, an electromagnetic generator, and a freestanding-mode triboelectric nanogenerator allows more energy to be harvested from a single mechanical motion, which further improves the power density. A prototype is fabricated and demonstrated using an electrodynamic shaker and various human motions. In the electrodynamic shaker test, the prototype exhibits a broad bandwidth of 2–12.5 Hz and generates an output power of 24.17 mW, corresponding to a power density of 700.3 W/m3 across a matching load resistance of 35 kΩ at a frequency of 5 Hz and 1 g acceleration. Under various basic human motions such as handshaking, walking, and slow running, the prototype can generate output powers of 38.5, 24.5, and 27.2 mW, respectively, in horizontal positions and 42.7, 10.2, and 33.1 mW, respectively, in vertical positions. A comparison study is also presented to demonstrate that the tri-hybrid prototype can produce a much higher power density than other devices reported recently. This work makes significant progress toward hybrid-energy harvesting from various human motions and its potential application in powering wearable devices.

To enhance the efficiency of the Multistage depressed collector (MDC) of traveling wave tube amplifiers (TWTs), TiN film was deposited by arc ion plating. The thickness and roughness of the film were respectively measured by scanning electron microscopy (SEM) and atomic force microscopy (AFM). In order to study the effects of the preparation parameters and the process methods of substrates, the orthogonal experimental design method was applied to find out experimental optimum parameters. The analysis of experimental results showed that the film thickness decreased as the bias voltage increased within a certain range. The root mean square (rms) of roughness Rqwas the minimum value for TiN film, when the bias voltage was 150V, the maximum value of the secondary electron emission yield (SEEY) reduced from 1.5 to 1.25 at the optimum parameters.

A flexible riverbed protection called tetrahedron framed permeable weirs (TFPW) is proposed to protect riverbeds in mountainous areas from scouring. Under clear water conditions, a series of laboratory flume experiments were performed to study the effects of TFPW with different layout types on the stability of riverbeds. The objectives of this paper were to advance understanding of the role that TFPW play in the erosion process of river beds and to optimize the TFPW design for reducing velocity, promoting sediment deposition and good structural stability. Data on velocity distribution and variation, equilibrium bathymetry, flow resistance, bed form characteristics and structural stability were collected and analyzed. The results indicate that (1) with good structural stability, all the TFPW with different layout types had significant effects on the stabilization of the riverbed by reducing velocity, raising the water level, increasing the roughness coefficient, protecting the riverbed from degradation and promoting deposition; and (2) the random Double TFPW with large rates of deceleration, large deposition ranges, and good structural stability, and the paved Single TFPW with small rates of deceleration but large deposition ranges and perfect structural stability, were suitable and optimal for riverbed protection in a clear water channel.

Cofilins (CFL), including CFL1 and CFL2, are members of the family of actin-binding proteins in eukaryote. CFL2 is predominantly expressed in mammalian skeletal muscle and heart and is important to muscle fiber formation and muscular regeneration. To study transcriptional regulation of porcine CFL2, a 2.5 kb upstream sequence starting from the major CFL2 transcriptional start site was cloned by genome walking. Twelve DNA fragments of the 5' flank region of the porcine CFL2 gene were further isolated from porcine genomic DNA via PCR and inserted into the luciferase reporter vector pGL4.10 to make 12 CFL2 reporter constructs. All reporter vectors were transfected into C2C12, NIH3T3, or Hela cells and their relative luciferase activity measured after 48 h, respectively. Bioinformatics analysis suggested that there were two TATA-boxes at the -508 bp and -453 bp, as well as a GC-box and a CAAT-box in this sequence. Additional transcription factor binding sites including SP1, AP1, AP2, and GATA-1 sites were also predicted. The transcriptional activity of pGL4.10-1554 (1502 bp to +51 bp) was the strongest, and the promoter's active region was mapped to a region from -1502 bp to -1317 bp. Our data provide a foundation for future studies into transcriptional regulation of CFL2.

Lactose intolerance in northern Europeans is strongly associated with a single-nucleotide polymorphism (SNP) located 14 kb upstream of the human lactase gene: -13,910 C/T. We examined whether SNPs in the 5' flanking region of the pig lactase gene are similar to those in the human gene and whether these polymorphisms play a functional role in regulating pig lactase gene expression. The 5' flanking region of the lactase gene from several different breeds of pigs was cloned and analyzed for gene regulatory activity of a luciferase reporter gene. One SNP was found in the enhancer region (-797 G/A) and two were found in the promoter region (-308G/C and -301 A/G). The promoter C-308,G-301(Pro-CG) strongly promotes the expression of the lactase gene, but the promoter G-308,A-301(Pro-GA) does not. The enhancer A-797(Enh-A) genotype for Pro-GA can significantly enhance promoter activity, but has an inhibitory effect on Pro-CG. The Enhancer G-797(Enh-G) has a significant inhibitory effect on both promoters. In conclusion, the order of effectiveness on the pig lactase gene is Enh-A+Pro-GA>Enh-A/G+Pro-CG>Enh-G+Pro-GA.

Summary Background Acne conglobata is hardly curable and easily leads to scar formation after treatment using traditional methods. Aim To develop a novel way to treat acne conglobata. Methods Seventy-five patients with facial acne conglobata were included in this clinical study and divided into either a treatment group (n = 35) to receive photodynamic therapy (PDT) with topical 5% 5-aminolevulinic acid and red light once every 10 days for a month or a control group (n = 40) to receive a Chinese herbal medicine mask plus red light once per week for the same duration. Patients in both groups were given oral viaminate capsules, doxycycline, zinc gluconate, and topical metronidazole. Efficacy was evaluated with respect to symptom score, cure rate, and response rate up to 2 weeks following the final treatment, and time points for assessment included baseline (D0), the visit before each treatment (D10 and D20 for the treatment group, and D7, D14, and D21 for the control group), and 2 weeks after treatment (D34 for the treatment group and D35 for the control group). Safety was assessed by recording adverse effects. Results Treatment with PDT significantly improved acne lesions and reduced scar formation. The treatment group had a significantly lower symptom score, a higher cure rate, and response rate than the control group. No systemic side effects occurred. Conclusion The treatment of acne conglobata with PDT is associated with a high cure rate, short treatment period, few side effects, and reduced scar formation. To the best of our knowledge, this is the first report on the treatment of acne conglobata with PDT.

Flexible grade control structures (GCSs) are increasingly popular alternative countermeasures consisting of conventional solid structures for protecting riverbeds from erosion. Among this structure typology, tetrahedron framed permeable weirs (TFPW) were proposed to stabilize riverbeds and protect cross-river structures. The bed morphology as well as the interactions among the structures, water flow and bed features have not been systematically analyzed. Therefore, based on the field data collected in the Jianjiang River, a series of physical model experiments were carried out in this study to investigate the river morphology in unstable gravel-bed rivers under five different structural conditions, including no GCSs, solid bed sills and flexible TFPW with three different layout types. Data on bedform features, topography changes and the volume of erosion or deposition were collected and analyzed. The results indicated that dramatic general erosion and bed armoring would occur without any protection. The bed would be protected from upstream erosion with bed sills, but, at the same time, in addition to general erosion and bed armoring downstream of the structures, deep local scour might pose a serious threat to structural safety. TFPW had good protective effects on riverbeds by preventing the bed from erosion and even inducing sediment deposition both upstream and downstream from the structures. Because the flexible structures have advantages in ecology, structural stability and construction, TFPW were suitable and optimal for riverbed stabilization in unstable gravel-bed rivers.