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Non-small cell lung cancer (NSCLC) continues to be one of the major causes of cancer-related deaths worldwide, and brain metastases are the major cause of death in NSCLC patients. With recent advances in understanding the underlying molecular mechanism of NSCLC development and progression, mutations in epidermal growth factor receptor (EGFR) have been recognized as a key predictor of therapeutic sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Using EGFR-TKI alone or in combination with standard treatments such as whole-brain radiotherapy and surgery has been an effective strategy for the management of brain metastasis. Particularly, a newer generation of EGFR-TKIs, including osimertinib and AZD3759, has been developed. These new EGFR-TKIs can cross the blood–brain barrier and potentially treat EGFR-TKI resistance and improve prognosis. In this article, current progress and outcomes of clinical trials on the use of EGFR-TKIs for treating NSCLC patients with brain metastasis will be reviewed.

Abstract Background Jiangtang decoction (JTD) is a China patented drug which contains Euphorbia humifusa Willd, Salvia miltiorrhiza Bunge, Astragalus mongholicus Bunge, Anemarrhena asphodeloides Bunge, and Coptis chinensis Franch. For decades, it has also been used clinically to treat diabetic nephropathy (DN) effectively; however, the associated mechanisms remain unknown. Thus, the present study aimed to examine the protective efficacy of JTD in DN and elucidate the underlying molecular mechanisms. Methods A diabetic model using KK-Ay mice received a daily administration of JTD for 12 weeks. Body weight, blood glucose, triglycerides (TGs), total cholesterol (TC), urea nitrogen (UN), creatinine (Cr), and microalbumin/urine creatinine (MA/UCREA) was measured every 4 weeks. Furthermore, on the day of the sacrifice, blood, urine, and kidneys were collected to assess renal function according to general parameters. Pathological staining was performed to evaluate the protective renal effect of JTD. In addition, the levels of inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin [IL]-6 and intercellular adhesion molecule [ICAM]-1), insulin receptor substrate [IRS]-1, advanced glycation end products [AGEs], and receptor of glycation end products [RAGE] were assessed. Finally, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway and involvement of nuclear factor-κB (NF-κB) was further analyzed. Results After 12 weeks of metformin and JTD administration, the mice exhibited a significant amelioration in glucose and lipid metabolism dysfunction, reduced morphological changes in the renal tissue, decreased urinary albumin excretion, and normalized creatinine clearance. JTD treatment also reduced the accumulation of AGEs and RAGE, up-regulated IRS-1, and increased the phosphorylation of both PI3K (p85) and Akt, indicating that the activation of the PI3K/Akt signaling pathway was involved. Additionally, JTD administration reduced the elevated levels of renal inflammatory mediators and decreased the phosphorylation of NF-κB p65. Conclusions These results demonstrate that JTD might reduce inflammation in DN through the PI3K/Akt and NF-κB signaling pathways.

The van der Waals compound, MnBi_{2}Te_{4}, is the first intrinsic magnetic topological insulator, providing a materials platform for exploring exotic quantum phenomena such as the axion insulator state and the quantum anomalous Hall effect. However, intrinsic structural imperfections lead to bulk conductivity, and the roles of magnetic defects are still unknown. With higher concentrations of the same types of magnetic defects, the isostructural compound MnSb_{2}Te_{4} is a better model system for a systematic investigation of the connections among magnetism, topology, and lattice defects. In this work, the impact of antisite defects on the magnetism and electronic structure is studied in MnSb_{2}Te_{4}. Mn-Sb site mixing leads to complex magnetic structures and tunes the interlayer magnetic coupling between antiferromagnetic and ferromagnetic. The detailed nonstoichiometry and site mixing of MnSb_{2}Te_{4} crystals depend on the growth parameters, which can lead to ≈40% of Mn sites occupied by Sb and ≈15% of Sb sites by Mn in as-grown crystals. Single-crystal neutron diffraction and electron microscopy studies show nearly random distribution of the antisite defects. Band structure calculations suggest that the Mn-Sb site mixing favors a ferromagnetic interlayer coupling, consistent with experimental observation, but is detrimental to the band inversion required for a nontrivial topology. Our results suggest a long-range magnetic order of Mn ions sitting on Bi sites in MnBi_{2}Te_{4}. The effects of site mixing should be considered in all layered heterostructures that consist of alternating magnetic and topological layers, including the entire family of MnTe(Bi_{2}Te_{3})_{n}, its Sb analogs, and their solid solution.

Halenia (Gentianaceae) originated from the mountain regions of East Asia, and diversified in America following long migrations via Beringia. While Halenia elliptica, one species of the genus in China, migrated toward high latitudes in China. Spur length of H. elliptica is highly variable. We examined the relationship between spur length and mating pattern along a latitude gradient. Field experiments were performed in two populations of H. elliptica, and we found that this species could produce seeds via both autonomous selfing and the aid of pollinators, suggesting a mixed mating system. In seven populations of H. elliptica along a latitudinal gradient, we found a trend of decrease in spur length with the increase of latitude. Based on molecular data from 11 microsatellite loci, we found that multilocus outcrossing rate decreased with the increase of latitude while the estimated inbreeding depression increased significantly, indicating that a high degree of inbreeding depression might have prevented evolution toward complete selfing in the high latitude populations with short spur length, and thus maintained mixed mating system of H. elliptica. Our results suggest that the mixed mating system of this species might be helpful in overcoming pollinator scarcity in newly colonized populations toward high latitudes after its origination in the mountain regions of China, and the decrease of spur length in the high latitude populations could result from reduced resource allocation to pollinator associated traits.

Sufficient conditions are established for the permanence in a delayed Nicholson’s blowflies model with feedback control on time scales. Our investigation confirms that the bounded feedback terms do not have any influence on the permanence of this system.

We propose a new algorithm for solving the terminal value problems on a q-difference equations. Through some transformations, the terminal value problems which contain the first- and second-order delta-derivatives have been changed into the corresponding initial value problems; then with the help of the methods developed by Liu and H. Jafari, the numerical solution has been obtained and the error estimate has also been considered for the terminal value problems. Some examples are given to illustrate the accuracy of the numerical methods we proposed. By comparing the exact solution with the numerical solution, we find that the convergence speed of this numerical method is very fast.

“Zhu She Yong Xue Shuan Tong” lyophilized powder (ZSYXST), consists of a series of saponins extracted from Panax notoginseng, which has been widely used in China for the treatment of strokes. In this study, an ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) combined with preparative high performance liquid chromatography (PHPLC) method was developed to rapidly identify both major and minor saponins in ZSYXST. Some high content components were removed through PHPLC in order to increase the sensitivity of the trace saponins. Then, specific characteristic fragment ions in both positive and negative mode were utilized to determine the types of aglycone, saccharide, as well as the saccharide chain linkages. As a result, 94 saponins, including 20 pairs of isomers and ten new compounds, which could represent higher than 98% components in ZSYXST, were identified or tentatively identified in commercial ZSYXST samples.

Rice panicles are composed of many branches with two types of extreme grains, the superior and the inferior. Traditionally, it has been well accepted that earlier flowers result in superior grains and late flowers generate inferior grains. However, these correlations have never been strictly examined in practice. In order to determine the accurate relationship between superior and inferior grains and the flowering order, we localized all the seeds in a panicle in four distinct rice species and systematically documented the rice flowering order, flower locations and the final grain weight for their relationships. Our results demonstrated that the grain weight is more heavily determined by the position of the seeds than by the flowering order. Despite earlier flowering has a positive correlation with the grain weight in general, grains from flowers blooming on the second day after anthesis generally gained the highest weight. This suggests earlier flowers may not result in superior grains. Therefore, we concluded that superior and inferior grains, commonly determined by grain weight, are not fully correlated with the flowering order in rice. Following the order of the grain weight, the superior grains are generally localized at the middle parts of the primary branches, whereas inferior grains were mainly on the last two secondary branches of the lower half part of the panicle. In addition, the weight of inferior grains were affected by spikelet thinning and spraying with exogenous plant growth regulators, indicating that physiological incompetence might be the major reason for the occurrence of the inferior grains.

Soybean seed storage protein is one of the most important plant vegetable proteins, and β subunit is of great significance to enhance soybean protein quality and processing property. F2 segregated population and residual heterozygous lines (RHL) derived from the cross between Yangyandou (low level of β subunit) and Zhonghuang 13 (normal level of β subunit) were used for mapping of β subunit content. Our results showed that β subunit content was controlled by a single dominant locus, qBSC-1 (β subunit content), which was mapped to a region of 11.9 cM on chromosome 20 in F2 population of 85 individuals. This region was narrowed down to 2.5 cM between BARCSOYSSR_20_0997 and BARCSOYSSR_20_0910 in RHL with a larger population size of 246 individuals. There were 48 predicted genes within qBSC-1 region based on the reference genome (Glyma 1.0, Williams 82), including the two copies of β subunit coding gene CG4. An InDel marker developed from a thymine (TT) insertion in one copy of CG4 promoter region in Yangyandou cosegregrated with BARCSOYSSR_20_0975 within qBSC-1 region, suggesting that this InDel marker maybe useful for marker-assisted selection (MAS).

In order to simplify the design of path tracking controller and solve the problem relating to nonlinear dynamic model of autonomous underwater vehicle motion planning, feedback linearization method is first adopted to transform the nonlinear dynamic model into an equivalent pseudo-linear dynamic model in horizontal coordinates. Then considering wave disturbance effect, mixed-sensitivity method of H ∞ robust control is applied to design state-feedback controller for this equivalent dynamic model. Finally, control law of pseudo-linear dynamic model is transformed into state (surge velocity and yaw angular rate) tracking control law of nonlinear dynamic model through inverse coordinate transformation. Simulation indicates that autonomous underwater vehicle path tracking is successfully implemented with this proposed method, and the influence of parameter variation in autonomous underwater vehicle dynamic model on its tracking performance is reduced by H ∞ controller. All the results show that the method proposed in this article is effective and feasible.

Considering the case of autonomous underwater vehicle navigating with low speed near water surface, a new method for designing of roll motion controller is proposed in order to restrain wave disturbance effectively and improve roll stabilizing performance under different sea conditions. Active disturbance rejection fuzzy control is applied, which is based on nonlinear motion model of autonomous underwater vehicle and the principle of zero-speed fin stabilizer. Extended state observer is used for estimation of roll motion state and unknown wave disturbance. Wave moment is counteracted by introducing compensation term into the roll control law which is founded on nonlinear feedback. Fuzzy reasoning is used for parameter adjustment of the controller online. Simulation experiments on roll motion are conducted under different sea conditions, and the results show better robustness improved by active disturbance rejection fuzzy controller of autonomous underwater vehicle navigating near water surface.

OBJECTIVE:This study aimed to examine the association between negative life events (NLEs) and attempted suicide in rural China. METHODS:Six rural counties were selected from disease surveillance points in Shandong province, China. A total of 409 suicide attempters in rural areas between October 1, 2009, and March 31, 2011, and an equal number of matched controls were interviewed. We compared negative life events experienced within 1 month, 1-3 months, 3-6 months, and 6-2 months prior to attempted suicide for cases and prior to interview for controls. We used multivariate logistic regression to examine the association between NLEs and attempted suicide. RESULTS:Suicide attempters experienced more NLEs within the last year prior to suicide attempt than controls prior to interview (83.1% vs. 33.5%). There was a significant dose-response relationship between NLEs experienced within the last year and increased risk of attempted suicide. Timing of NLEs analysis showed that NLEs experienced in the last month and 6-12 months prior to suicide attempt were significantly associated with elevated risk of attempted suicide, even after adjusting for mental disorders and demographic factors. Of NLEs, quarrelling with spouse, quarrelling with other family members, conflicting with friends or neighbors, family financial difficulty, and serious illness were independently related to attempted suicide. CONCLUSION:NLEs are significantly associated with increased risk for attempted suicide in rural China. Stress management and intervention may be important to prevent suicidal behavior in rural China.

We study the existence and global stability of positive periodic solutions of a periodic discrete predator-prey system with delay and Holling type III functional response. By using the continuation theorem of coincidence degree theory and the method of Lyapunov functional, some sufficient conditions are obtained.

The existence of positive periodic solutions for a delayed discrete predator-prey model with Holling-type-III functional response N1(k+1)=N1(k)exp{b1(k)−a1(k)N1(k−[τ1])−α1(k)N1(k)N2(k)/(N12(k)+m2N22(k))}, N2(k+1)=N2(k)exp{−b2(k)+α2(k)N12(k−[τ2])/(N12(k−[τ2])+m2N22(k−[τ2]))} is established by using the coincidence degree theory. We also present sufficient conditions for the globally asymptotical stability of this system when all the delays are zero. Our investigation gives an affirmative exemplum for the claim that the ratio-dependent predator-prey theory is more reasonable than the traditional prey-dependent predator-prey theory.

We report the findings of three-dimensional (3D) transesophageal echocardiography (TEE) in a patient with a parachute mitral valve (MV) accompanied by aortic valve (AV) malformation. The results indicated an enhanced echo in MV anterior leaves, incrassate, and shortened subvalvular chordae tendineae, and posteromedial papillary muscle that had echo reinforcement, calcification, retroposition, and a significant decrease compared with anterolateral papillary muscle. In addition, the anterolateral papillary muscle was huge, with the bilateral papillary muscles fused partly, and the posterior subvalvular chordae tendineae incrassate, shortened, and attached parachute-like to the anterolateral papillary muscle. The MV appeared dome-shaped for the open limit in diastole with an MV area of 1.6 cm. Moreover, the left ventricle increased in size and the bicuspid AV was malformed. Continuous wave Doppler angiograph showed that the flow rate increased to 398 cm/seconds at the AV orifice area. A 3D form of the MV structure was observed from the left ventricle using 3D-TEE inspection. The anterolateral papillary muscle was fused with its posteromedial homologue. The chordae tendineae was attached to the anterolateral papillary with the parachute-like structure, indicating dome movement.

Amyloid-β peptides (Aβ) exist in several forms and are known as key modulators of Alzheimer’s disease (AD). Fibrillary Aβ (fAβ) has been found to disrupt the blood-brain barrier (BBB) by triggering and promoting inflammation. In this study, luteolin, a naturally occurring flavonoid that has shown beneficial properties in the central nervous system, was evaluated as a potential agent to preserve barrier function and inhibit inflammatory responses at the BBB that was injured by fAβ1–40. We established an in vitro BBB model by co-culturing human brain microvascular endothelial cells (hBMECs) and human astrocytes (hAs) under fAβ1–40-damaged conditions and investigated the effect of luteolin by analyzing cellular toxicity, barrier function, cytokine production and inflammation-related intracellular signaling pathways. Our results demonstrated that, in cells injured by fAβ1–40, luteolin increased cell viability of hBMECs and hAs. The cytoprotection of the co-culture against the damage induced by fAβ1–40 was also increased at both the apical and basolateral sides. Luteolin protected the barrier function by preserving transendothelial electrical resistance and relieving aggravated permeability in the human BBB model after being exposed to fAβ1–40. Moreover, in both the apical and basolateral sides of the co-culture, luteolin reduced fAβ1–40-induced inflammatory mediator and cytokine production, including cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), interleukin 1 β (IL-1β), interleukin 6 (IL-6), and interleukin 8 (IL-8), however it did not show sufficient effects on scavenging intracellular reactive oxygen species (ROS) in hBMECs and hAs. The mechanism of BBB protection against fAβ1–40-induced injury may be related to the regulation of inflammatory signal transduction, which involves inhibition of p38 mitogen-activated protein kinase (MAPK) activation, downregulation of phosphorylated inhibitory κB kinase (phosphor-IKK) levels, relief of inhibitory κB α (IκBα) degradation, blockage of nuclear factor κB (NF-κB) p65 nuclear translocation, and reduction of the release of inflammatory cytokines. Moreover, the employment of p38 MAPK and NF-κB inhibitors reversed luteolin-mediated barrier function and cytokine release. Taken together, luteolin may serve as a potential therapeutic agent for BBB protection by inhibiting inflammation following fAβ1–40-induced injury.

Aims. To determine whether multiple daily injections (MDIs) or continuous subcutaneous insulin infusion (CSII) contributes to better glucose control in children with different type 1 diabetes duration. Methods. Subjects were grouped according to early (≤1 year after disease onset; 1A) or late (1–3 years after onset; 2A) MDIs/CSII treatment initiation. Corresponding control groups (1B, 2B) received insulin injections twice daily. Results. HbA1c levels were consistently lower in group 1A than in group 1B (6 months (T2): 7.37% versus 8.21%; 12 months (T3): 7.61% versus 8.41%; 24/36 months (T4/T5): 7.61% versus 8.72%; all P

We give a sufficient and necessary condition for the permanence of a discrete model with Beddington-DeAngelis functional response with the form x(n+1) = x(n)exp{a(n)-b(n)x(n)-c(n)y(n)/(α(n)+β(n)x(n)+γ(n)y(n))},y(n+1)=y(n)exp{-d(n)+f(n)x(n)/(α(n)+β(n)x(n)+γ(n)y(n))}, where a(n),b(n),c(n),d(n),f(n),α(n),β(n), and γ(n) are periodic sequences with the common period ω;b(n) is nonnegative; c(n),d(n),f(n),α(n),β(n), and γ(n) are positive. It is because of the difference between the comparison theorem for discrete system and its corresponding continuous system that an additional condition should be considered. In addition, through some analysis on the limit case of this system, we find that the sequence α(n) has great influence on the permanence.

X-linked hyper-IgM syndrome (XHIGM) is one type of primary immunodeficiency diseases, resulting from defects in the CD40 ligand/CD40 signaling pathways. We retrospectively analyzed the clinical and molecular features of 20 Chinese patients diagnosed and followed up in hospitals affiliated to Shanghai Jiao Tong University School of Medicine from 1999 to 2013. The median onset age of these patients was 8.5 months (range: 20 days–21 months). Half of them had positive family histories, with a shorter diagnosis lag. The most common symptoms were recurrent sinopulmonary infections (18 patients, 90%), neutropenia (14 patients, 70%), oral ulcer (13 patients, 65%), and protracted diarrhea (13 patients, 65%). Six patients had BCGitis. Six patients received hematopoietic stem cell transplantations and four of them had immune reconstructions and clinical remissions. Eighteen unique mutations in CD40L gene were identified in these 20 patients from 19 unrelated families, with 12 novel mutations. We compared with reported mutation results and used bioinformatics software to predict the effects of mutations on the target protein. These mutations reflected the heterogeneity of CD40L gene and expanded our understanding of XHIGM.

BACKGROUND/AIMS: Chronic myocardial infarction (MI) results in the formation of arrhythmogenic substrates, causing lethal ventricular arrhythmia (VA). We aimed to determine whether mesenchymal stem cells (MSCs) carrying a hepatocyte growth factor (HGF) gene modification (HGF-MSCs) decrease the levels of arrhythmogenic substrates and reduce the susceptibility to developing VA compared with unmodified MSCs and PBS in a swine infarction model. METHODS: The left descending anterior artery was balloon-occluded to establish an MI model. Four weeks later, the randomly grouped pigs were administered MSCs, PBS or HGF-MSCs via thoracotomy. After an additional four weeks, dynamic electrocardiography was performed to assess heart rate variability, and programmed electrical stimulation was conducted to evaluate the risk for VA. Then, the pigs were euthanized for morphometric, immunofluorescence and western blot analyses. RESULTS: The HGF-MSC group displayed the highest vessel density and Cx43 expression levels, and the lowest levels of apoptosis, and tyrosine hydroxylase (TH) and growth associated protein 43 (GAP43) expression. Moreover, the HGF-MSC group exhibited a decrease in the number of sympathetic nerve fibers, substantial decreases in the low frequency and the low-/high- frequency ratio and increases in the root mean square of successive differences (rMSSD) and the percentage of successive normal sinus R-R intervals longer than 50 ms (pNN50), compared with the other two groups. Finally, the HGF-MSC group displayed the lowest susceptibility to developing VA. CONCLUSION: HGF-MSCs displayed potent antiarrhythmic effects, reducing the risk for VA.

Injured tendons often heal with scar tissue formation, resulting in uniformly smaller collagen fibrils and poor mechanical properties. The small leucine-rich proteoglycan decorin is well known to regulate fusion of collagen fibrils. Rat patellar tendon cells were transfected with lentiviral-encoded shRNA that specifically targets decorin. Silencing of decorin expression resulted in decreased cell growth. Three types of scaffold-free engineered tendons with different mix ratios of anti-decorin shRNA-treated cells to untreated cells at 1:0 (DCN), 1:1 (MIX), and 0:1 (CON) were utilized for repair of injured patellar tendons. Four weeks after implantation in situ, the MIX group manifested the best results (best coordination of histology, more mature collagen deposition, and larger collagen fibril diameter). Although the DCN group exhibited the largest collagen fibril diameter, this was associated with abnormal shape. Hence, regulation of decorin expression to an appropriate level is crucial for tendon repair with gene therapy.

Average conditions are obtained for the permanence of a discrete bounded system with Holling type II functional response u(n+1)=u(n)exp{a(n)-b(n)u(n)-c(n)v(n)/(u(n)+m(n)v(n))}, v(n+1)=v(n)exp{-d(n)+e(n)u(n)/(u(n)+m(n)v(n))}. The method involves the application of estimates of uniform upper and lower bounds of solutions. When these results are applied to some special delay population models with multiple delays, some new results are obtained and some known results are generalized.

BACKGROUND: Autophagy is an evolutionarily conserved protein degradation pathway. A defect in autophagy may contribute to tumorigenesis. Autophagy inducers could have a potential function in tumor prevention and treatment. METHODOLOGY/PRINCIPAL FINDINGS: Our results showed that Rhabdastrellic acid-A, an isomalabaricane triterpenoid isolated from the sponge Rhabdastrella globostellata, inhibited proliferation of human cancer cell lines Hep3B and A549 and induced caspase-independent cell death in both the cell lines. Further investigation showed that Rhabdastrellic acid-A induced autophagy of cancer cells determined by YFP-LC3 punctation and increased LC3-II. The pretreatment with autophagy inhibitor 3-MA inhibited Rhabdastrellic acid-A-induced cell death. Knockdown of autophagy-related gene Atg5 inhibited Rhabdastrellic acid-A-induced cell death in A549 cells. Also, phospho-Akt and its downstream targets significantly decreased after treatment with Rhabdastrellic acid-A in both cancer cell lines. Transfection of constitutive active Akt plasmid abrogated autophagy and cell death induced by Rhabdastrellic acid-A. CONCLUSIONS/SIGNIFICANCE: These results suggest that Rhabdastrellic acid-A could induce autophagy-associated cell death through blocking Akt pathway in cancer cells. It also provides the evidence that Rhabdastrellic acid-A deserves further investigation as a potential anticancer or cancer preventive agent.

Verifiable criteria are established for the permanence and existence of positive periodic solutions of a delayed discrete predator-prey model with monotonic functional response. It is shown that the conditions that ensure the permanence of this system are similar to those of its corresponding continuous system. And the investigations generalize some well-known results. In particular, a more acceptant method is given to study the bounded discrete systems rather than the comparison theorem.

The permanence of a single-species population discrete model with feedback control is considered. We found that if we use the method of comparison theorem, then the additional condition, to some extent, is necessary. But for the system itself, this condition may not be necessary. Here, we use new methods instead of the comparison theorem to get the permanence of the system in consideration; the additional condition in Chen's paper (2007) is deleted.

Harvesting renewable energy to split water offers an ideal approach to the production of clean hydrogen energy. Among various water electrolysis devices, the proton exchange membrane water electrolyser (PEMWE) with a high current density, quick response operation, and compact design has attracted much attention. The anodic oxygen evolution reaction (OER) in an acidic electrolyte seriously relies on iridiumbased catalysts, but their use is limited owing to their scarcity and high cost. Ruthenium (Ru)-based catalysts have been considered as the most promising candidates to replace Ir in acidic OER, due to their low cost and high activity. Nevertheless, there is still much room to enhance the OER activity and durability of Ru-based catalysts for the practical application in PEMWEs. Herein, we first give a brief introduction of the main configuration and operating factors of PEMWEs. Then we discuss three OER mechanisms and reasons for the degradation of Ru-based catalysts in acid. Afterwards, the performance improvement strategies of Ru-based acidic OER catalysts are emphatically summarized. We further spotlight some typical examples of PEMWEs using Ru-based OER catalysts as anodes. Finally, further challenges and directions in the development of high-performance Ru-based OER catalysts in PEMWEs are offered and speculated. [ABSTRACT FROM AUTHOR]