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Lymphangioleiomyomatosis (LAM) is a rare systemic neoplastic disease that exclusively happens in women. Studies focusing on LAM and tuberous sclerosis complex (TSC) have made great progress in understanding the pathogenesis and searching for treatment. The inactive mutation of TSC1 or TSC2 is found in patients with LAM to activate the crucial mammalian target of rapamycin (mTOR) signaling pathway and result in enhanced cell proliferation and migration. However, it does not explain every step of tumorigenesis in LAM. Because cessation of rapamycin would break the stabilization of lung function or improved quality of life and lead to disease recurrent, continued studies on the pathogenesis of LAM are necessary to identify novel targets and new treatment. Researchers have found several aberrant regulations that affect the mTOR pathway such as its upstream or downstream molecules and compensatory pathways in LAM. Some therapeutic targets have been under study in clinical trials. New methods like genome-wide association studies have located a novel gene related to LAM. Herein, we review the current knowledge regarding pathogenesis and treatment of LAM and summarize novel targets of therapeutic potential recently.

A novel fabrication method of uniform porous structures on the glass surface is proposed. The hydrofluoric acid fog formed by air-jet atomization etches the glass surface to fabricate nanoporous structure (NPS) on glass surface. This NPS shows the enhanced average light transmittance of approximately 92.9% and the superhydrophilic property with a contact angle less than 1° which presents an excellent anti-fog property. Passivated by fluorosilane, the NPS shows nearly the superhydrophobic property with a contact angle of 141.2°. This fabrication method has shown promising application prospects due to its simplicity, low cost and efficiency, which can be easily applied to large-scale industrial production.

SPS1-related proline/alanine-rich kinase (SPAK) plays important roles in regulating the function of numerous ion channels and transporters. With-no-lysine (WNK) kinase phosphorylates SPAK kinase to active the SPAK signaling pathway. Our previous studies indicated that WNK kinases regulate the activity of the large-conductance Ca2+-activated K+ (BK) channel and its protein expression via the ERK1/2 signaling pathway. It remains largely unknown whether SPAK kinase directly modulates the BK protein expression in kidney. In this study, we investigated the effect of SPAK on renal BK protein expression in both HEK293 cells and mouse kidney. In HEK293 cells, siRNA-mediated knockdown of SPAK expression significantly reduced BK protein expression and increased ERK1/2 phosphorylation, whereas overexpression of SPAK significantly enhanced BK expression and decreased ERK1/2 phosphorylation in a dose-dependent manner. Knockdown of ERK1/2 prevented SPAK siRNA-mediated inhibition of BK expression. Similarly, pretreatment of HEK293 cells with either the lysosomal inhibitor bafilomycin A1 or the proteasomal inhibitor MG132 reversed the inhibitory effects of SPAK knockdown on BK expression. We also found that there is no BK channel activity in PCs of CCD in SPAK KO mice using the isolated split-open tubule single-cell patching. In addition, we found that BK protein abundance in the kidney of SPAK knockout mice was significantly decreased and ERK1/2 phosphorylation was significantly enhanced. A high-potassium diet significantly increased BK protein abundance and SPAK phosphorylation levels, while reducing ERK1/2 phosphorylation levels. These findings suggest that SPAK enhances BK protein expression by reducing ERK1/2 signaling-mediated lysosomal and proteasomal degradations of the BK channel.

With the extensive application of radiotherapy in various cancers, its side effects in tissues adjacent to cancers are garnering much attention. Intestines are sensitive to irradiation due to its rapid proliferation, and irradiation-induced enteric inflammation is common in patients with pelvic peritoneal tumors. Sirt1, class III protein deacetylase, could lead to transcriptional repression of various inflammation-associated genes, and our previous study has proved its relationship with interleukin (IL)-1β. Here we show that resveratrol, the activator of Sirt1, could alleviate the bowel inflammation induced by irradiation and the expression of Sirt1 is consistent with the inflammation level. We further identified in vivo that Sirt1 repress the expression of IL-1β by the repression of NLR Family, Pyrin Domain Containing protein 3 (NLRP3) expression. In conclusion, this study confirms resveratrol acts against radiation-induced inflammatory bowel disease via NLRP-3 inflammasome repression in mice and supports Sirt1 as a potential biomarker and therapy target in intestinal radiation protection.

Summary: Robot-assisted distal pancreatectomy (RADP) has been developed with the aim of improving surgical quality and overcoming the limitations of laparoscopic distal pancreatectomy (LDP) and open distal pancreatectomy (ODP) for pancreatic resections. A systematic search was performed in the PubMed, EMBASE, Cochrane Library, Web of Science, and China Biology Medicine databases up to December 2016 for studies that compared the surgical outcomes of RADP vs. LDP or ODP for pancreatic resections. The weighted mean differences, odds ratios and 95% confidence intervals were calculated, and the data were combined using the random-effects model. The GRADE system was used to interpret the primary outcomes of this meta-analysis. A total of seventeen non-randomized observational clinical studies involving 2133 patients satisfied the eligibility criteria. Compared with LDP, RADP was associated with a longer operative time (P = 0.018), a shorter hospital length of stay (P = 0.030), and a higher rate of spleen preservation (P = 0.022). Moreover, RADP was associated with a shorter hospital LOS (P = 0.014) and a lower total complication rate (P = 0.034) than ODP. We found no statistically significant differences between the techniques in the mean estimated blood loss, severe complication rate, incidence of total pancreatic fistulas or incidence of severe pancreatic fistulas. The overall quality of evidence was poor for all outcomes. This meta-analysis indicates that RADP may be safe and comparable in terms of surgical results to LDP and ODP. Further RCTs are needed to confirm the outcomes of this meta-analysis. Keywords: Distal pancreatectomy, Robotics, Laparoscopy, Meta-analysis

Organic matter application was one of the suitable ways to improve soil nitrogen availability in saline soils. In this study, two soils of different levels of total soluble salts, 2.45 g kg−1 (LS) and 4.03 g kg−1 (HS), were used in a pot experiment with eight treatments: bio-organic fertilizer (prepared with cow dung) and farmyard manure (fowl manure) each at three dosages (3350, 6700, and 13,400 kg ha−1), chemical fertilizer control (DAP: 1675 kg ha−1), no fertilizer blank. At the same time, an indoor nitrogen mineralization incubation experiment with the same treatments without alfalfa planting was carried out. We aimed to explore the effects of the types and application amounts of organic fertilizers on soil nitrogen mineralization in saline soils and to improve its quality and finally realize its sustainable utilization. The main conclusions are as follows: the biomass of alfalfa treated with medium dose of organic fertilizer was higher than that of alfalfa treated with low or high dose of organic fertilizer. Compared with farmyard manure, bio-organic manure was more effective in increasing the biomass of alfalfa. The nitrogen uptake of alfalfa in high-dose treatment was significantly higher than that in low-dose treatment. The effects of the fertilizer treatments on soil nitrogen availability were in the increasing order of: medium dose, high or low dose of fertilizer treatment, single chemical fertilizer, and fertilizer free treatments by principal component analysis. For possible potential application, medium dosage of bio-organic fertilizer was recommended to apply in the region with saline fluvo-aquic soil.

ABSTRACTAs one of many nonstructural proteins of porcine reproductive and respiratory syndrome virus (PRRSV), nonstructural protein 12 (Nsp12) has received relatively little attention, and its role in virus replication, if any, is essentially unknown. By the application of reverse genetic manipulation of an infectious PRRSV clone, the current study is the first to demonstrate that Nsp12 is a key component of PRRSV replication. In addition, the biochemical properties of Nsp12 were evaluated, revealing that Nsp12 forms dimers when exposed to oxidative conditions. Furthermore, we systemically analyzed the function of Nsp12 in PRRSV RNA synthesis using a strand-specific PCR method. To our surprise, Nsp12 was not found to be involved in minus-strand genomic RNA (-gRNA) synthesis; importantly, our results indicate that Nsp12 is involved in the synthesis of both plus- and minus-strand subgenomic mRNAs (+sgmRNA and -sgmRNA). Finally, we found that the combination of cysteine 35 and cysteine 79 in Nsp12 is required for sgmRNA synthesis. To our knowledge, we are the first to report the biological role of Nsp12 in the PRRSV lifecycle, and we conclude that Nsp12 is involved in the synthesis of both + sgRNA and -sgRNA.

AimThe pathogenesis of non-alcoholic fatty liver disease is currently unclear, however, lipid accumulation leading to endoplasmic reticulum stress appears to be pivotal in the process. At present, FOXO1 is known to be involved in NAFLD progression. The relationship between necroptosis and non-alcoholic steatohepatitis has been of great research interest more recently. However, whether FOXO1 regulates ER stress and necroptosis in mice fed with a high fat diet is not clear. Therefore, in this study we analyzed the relationship between non-alcoholic steatohepatitis, ER stress, and necroptosis.Main MethodsMale C57BL/6J mice were fed with an HFD for 14 weeks to induce non-alcoholic steatohepatitis. ER stress and activation of necroptosis in AML12 cells were evaluated after inhibition of FOXO1 in AML12 cells. In addition, mice were fed with AS1842856 for 14 weeks. Liver function and lipid accumulation were measured, and further, ER stress and necroptosis were evaluated by Western Blot and Transmission Electron Microscopy.Key FindingsMice fed with a high fat diet showed high levels of FOXO1, accompanying activation of endoplasmic reticulum stress and necroptosis. Further, sustained PA stimulation caused ER stress and necroptosis in AML12 cells. At the same time, protein levels of FOXO1 increased significantly. Inhibition of FOXO1 with AS1842856 alleviated ER stress and necroptosis. Additionally, treatment of mice with a FOXO1 inhibitor ameliorated liver function after they were fed with a high fat diet, displaying better liver condition and lighter necroptosis.SignificanceInhibition of FOXO1 attenuates ER stress and necroptosis in a mouse model of non-alcoholic steatohepatitis.

Despite many efforts and diverse approaches, developing an effective herpesvirus vaccine remains a great challenge. Traditional inactivated and live-attenuated vaccines always raise efficacy or safety concerns. This study used Pseudorabies virus (PRV), a swine herpes virus, as a model. We attempted to develop a live but replication-incompetent PRV by genetic code expansion (GCE) technology. Premature termination codon (PTC) harboring PRV was successfully rescued in the presence of orthogonal system MbpylRS/tRNAPyl pair and unnatural amino acids (UAA). However, UAA incorporating efficacy seemed extremely low in our engineered PRV PTC virus. Furthermore, we failed to establish a stable transgenic cell line containing orthogonal translation machinery for PTC virus replication, and we demonstrated that orthogonal tRNAPyl is a key limiting factor. This study is the first to demonstrate that orthogonal translation system-mediated amber codon suppression strategy could precisely control PRV-PTC engineered virus replication. To our knowledge, this is the first reported PTC herpesvirus generated by GCE technology. Our work provides a proof-of-concept for generating UAAs-controlled PRV-PTC virus, which can be used as a safe and effective vaccine.

Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, the authors perform discovery GWAS for BP in East Asians and meta-analysis in East Asians and Europeans and report ancestry-specific BP SNPs and selection signals.

AIM: To analyze the association of extracellular matrix metalloprotease 9(MMP-9)single nucleotide polymorphism(SNP)with genetic susceptibility of primary angle-closure glaucoma(PACG)in a Han Chinese population. METHODS: Totally 200 PACG patients(PACG group)and 200 healthy people(normal control group)were collected in our hospital from January 2014 to December 2016. Peripheral venous blood was collected and extracted for genomic DNA, the polymerase chain reaction-restriction fragment length polymorphism technique(PCR-RFLP)was applied to detect the alleles and genotypes of rs2250889, rs2274755 and rs2664538 sites in MMP-9 gene. The frequency distribution of alleles and genotypes in the two groups were calculated by chi-square test, and its association with genetic susceptibility of PACG was analyzed. RESULTS: There were no statistical differences in age, gender, body mass index, diastolic blood pressure and systolic blood pressure in the two groups(P>0.05). The genotype frequencies of rs2250889, rs2274755 and rs2664538 sites in MMP-9 gene were in line with Hardy-Weinberg equilibrium. The genotype and allele frequency distribution of rs2250889 and rs2664538 sites were significantly different between the PACG group and the normal control group(PP>0.05). The subjects whose rs2250889 site carrying the CC genotype was susceptible to PACG. Similarly, the rs2664538 site carrying the GG genotype was susceptible to PACG. CONCLUSION: The rs2250889 and rs2664538 polymorphisms of MMM-9 are correlated with the risk of PACG in a Han Chinese population, while the rs2274755 polymorphism is not related to genetic susceptibility of PACG.

Atomically thin transition metal dichalcogenides are an ideal platform to investigate the underlying physics of strongly bound excitons in low dimensions. Here, the authors demonstrate the formation of a bosonic condensate driven by excitons in two-dimensional MoSe2 strongly coupled to light in a solid-state resonator.

Abstract Background Talaromyces marneffei (T. marneffei) is a thermal dimorphic pathogenic fungus that often causes fatal opportunistic infections in human immunodeficiency virus (HIV)-infected patients. Although T. marneffei-infected cases have been increasingly reported among non-HIV-infected patients in recent years, no cases of T. marneffei infection have been reported in pulmonary sarcoidosis patients. In this case, we describe a T. marneffei infection in an HIV-negative patient diagnosed with pulmonary sarcoidosis. Case presentation A 41-year-old Chinese man who had pre-existing pulmonary sarcoidosis presented with daily hyperpyrexia and cough. Following a fungal culture from bronchoalveolar lavage (BAL), the patient was diagnosed with T. marneffei infection. A high-resolution computed tomography (HRCT) chest scan revealed bilateral lung diffuse miliary nodules, multiple patchy exudative shadows in the bilateral superior lobes and right inferior lobes, air bronchogram in the consolidation of the right superior lobe, multiple hilar and mediastinal lymphadenopathies and local pleural thickening. After 3 mos of antifungal therapy, the patient’s pulmonary symptoms rapidly disappeared, and the physical condition improved markedly. A subsequent CT re-examination demonstrated that foci were absorbed remarkably after treatment. The patient is receiving follow-up therapy and assessment for a cure. Conclusion This case suggested that clinicians should pay more attention to non-HIV-related lung infections in patients with pulmonary sarcoidosis. Early diagnosis and treatment with antifungal therapy can improve the prognosis of T. marneffei infection.

Abstract Porcine reproductive and respiratory syndrome virus (PRRSV) is an important globally distributed and highly contagious pathogen that has restricted cell tropism in vivo and in vitro. In the present study, we found that annexin A2 (ANXA2) is upregulated expressed in porcine alveolar macrophages infected with PRRSV. Additionally, PRRSV replication was significantly suppressed after reducing ANXA2 expression in Marc-145 cells using siRNA. Bioinformatics analysis indicated that ANXA2 may be relevant to vimentin, a cellular cytoskeleton component that is thought to be involved in the infectivity and replication of PRRSV. Co-immunoprecipitation assays and confocal analysis confirmed that ANXA2 interacts with vimentin, with further experiments indicating that the B domain (109–174 aa) of ANXA2 contributes to this interaction. Importantly, neither ANXA2 nor vimentin alone could bind to PRRSV and only in the presence of ANXA2 could vimentin interact with the N protein of PRRSV. No binding to the GP2, GP3, GP5, nor M proteins of PRRSV was observed. In conclusion, ANXA2 can interact with vimentin and enhance PRRSV growth. This contributes to the regulation of PRRSV replication in infected cells and may have implications for the future antiviral strategies.

Alloys of two-dimensional materials normally occur when two components crystallize in the same phase. Here, the authors observe an anomalous phase instability, accompanied by a band bowing effect, in GaSe1-x Te x alloys on GaAs(111).

Abstract Microgrid as an important part of smart grid comprises distributed generators (DGs), adjustable loads, energy storage systems (ESSs) and control units. It can be operated either connected with the external system or islanded with the support of ESSs. While the daily output of DGs strongly depends on the temporal distribution of natural resources such as wind and solar, unregulated electric vehicle (EV) charging demand will deteriorate the unbalance between the daily load curve and generation curve. In this paper, a statistic model is presented to describe daily EV charging/discharging behaviors considering the randomness of the initial state of charge (SOC) of EV batteries. The optimization problem is proposed to obtain the economic operation for the microgrid based on this model. In day-ahead scheduling, with the estimated power generation and load demand, the optimal charging/discharging scheduling of EVs during 24 h is achieved by serial quadratic programming. With the optimal charging/discharging scheduling of EVs, the daily load curve can better track the generation curve. The network loss in grid-connected operation mode and required ESS capacity in islanded operation mode are both decreased.

Abstract Forced oscillations (FOs), or low-frequency oscillations (LFOs) caused by periodic, continuous, small power disturbances, threaten the security and stability of power systems. Flexible AC transmission system (FACTS) devices can effectively mitigate LFOs via stability control. We propose a novel method that mitigates FOs by shifting the resonant frequency. Based on the features of the linearized swing equation of a generator, a resonant frequency shift can be achieved by controlling the synchronous torque coefficient using a unified power flow controller (UPFC). Because of the resonance mechanism, the steady-state response of an FO can be effectively mitigated when the resonant frequency changes from the original one, which was close to the disturbance frequency. The principle is that a change in resonant frequency affects the resonance condition. Simulations are conducted in a single-machine infinite-bus (SMIB) system, and the simulation results verify that the method is straightforward to implement and can significantly mitigate FOs. The controller robustness when the resonant frequency is not accurately estimated is also analyzed in the simulations.

The static problem of a layered isotropic elastic body is a very useful research subject in relation to the analysis and design of foundation works. Due to the complexity of the problem, there is no analytical solution to the problem so far. This study provides an efficient analytical approach to accurately calculate the displacement and stress fields of the soil. The constraints of bedrock on soil, different soil layer thickness and the shear stress of the foundation on soil were all taken into account in the analysis. In this study, each layer is regarded as an isotropic elastomer with infinite width, and the layers are in complete contact. By using conformal mapping, each layer is mapped to a unit circle, and the two complex potential functions are expanded into Taylor series with unknown coefficients. These unknown coefficients are obtained by satisfying boundary conditions and continuity conditions. The boundary and continuity conditions were verified in this paper. As a validation step, we compared the analytical results for the settlement with the results of the ANSYS numerical simulations and found good agreement. Parametric analyses were also carried out to investigate the influence of different distribution forms of base pressure on surface settlement, and the effects of layered properties on the surface settlement and stress field.

Background: Despite the various anticancer activities of tocopherols, little is known about tocopherols associated with lung cancer risk among low-income African Americans (AA) and European Americans (EA) who are disproportionately affected by the disease. Methods: We conducted a nested case-control study that included 209 incident lung cancer cases and 406 matched controls within the Southern Community Cohort Study. Using biospecimens collected at cohort enrollment, plasma levels of α-, β/γ-, δ-, and total-tocopherols were measured by high-performance liquid chromatography with photodiode array detection. Conditional logistic regression was used to estimate ORs and 95% confidence intervals (CI) for lung cancer risk after adjusting for potential confounders. Stratified analyses were also conducted. Results: Plasma levels of total-tocopherols were inversely associated with lung cancer risk overall [OR (95% CI) for the highest vs. lowest tertile = 0.51 (0.30-0.90)]. The inverse association remained significant among EAs [0.20 (0.06-0.65)], men [0.43 (0.21-0.90)], current smokers [0.49 (0.26-0.93)], and cases diagnosed within 2 years of blood draw [0.36 (0.15-0.86)], though we did not find a significant risk reduction among AAs [0.75 (0.39-1.45)]. Notably, we found significant interactions between α-tocopherol and race after controlling the FDR to correct for multiple comparisons (Pinteraction = 0.02). Conclusions: Our results indicate that plasma total-tocopherols are inversely associated with lung cancer risk, but the association may differ across specific isomeric forms of tocopherols, race, or other individuals' characteristics. Further large-scale studies are warranted to confirm our findings. Impact: Recommendations on tocopherols for lung cancer prevention should take isomers, race, and smoking behaviors into consideration.. [ABSTRACT FROM AUTHOR]