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HfO2-based dielectrics are promising for nanoscale ferroelectric applications, and the most favorable material within the family is Zr-substituted hafnia, i.e., Hf1−xZrxO2 (HZO). The extent of Zr substitution can be great, and x is commonly set to 0.5. However, the bandgap of ZrO2 is lower than HfO2, thus it is uncertain how the Zr content should influence the electronic band structure of HZO. A reduced bandgap is detrimental to the cycling endurance as charge injection and dielectric breakdown would become easier. Another issue is regarding the comparison on the bandgaps between HfO2/ZrO2 superlattices and HZO solid-state solutions. In this work, we systematically investigated the electronic structures of HfO2, ZrO2, and HZO using self-energy corrected density functional theory. In particular, the conduction band minimum of Pca21-HfO2 is found to lie at an ordinary k-point on the Brillouin zone border, not related to any interlines between high-symmetry k-points. Moreover, the rule of HZO bandgap variation with respect to x has been extracted. The physical mechanisms for the exponential reduction regime and linear decay regime have been revealed. The bandgaps of HfO2/ZrO2 ferroelectric superlattices are investigated in a systematic manner, and the reason why the superlattice could possess a bandgap lower than that of ZrO2 is revealed through comprehensive analysis. [ABSTRACT FROM AUTHOR]

An unparalleled copper(I)-catalyzed synthesis of 1,3,4-oxadiazoles from tertiary amines in one step has been described. The one-pot reactions involving (N-isocyanimine)triphenylphosphorane, tertiary amines, and carboxylic acids resulted in the formation of 1,3,4-oxadiazoles in moderate to good yields through a consecutive oxidative Ugi/aza-Wittig reaction, enabling the direct functionalization of sp3 C-H bonds adjacent to the nitrogen atom. This method offered several notable advantages, including ligands-free, exceptional productivity and a high functional group tolerance. The preliminary biological evaluation demonstrated that compound 4f inhibited hepatoma cells efficiently, suggesting potentially broad applications of the approach for synthesis and medicinal chemistry. [ABSTRACT FROM AUTHOR]

Statistical tests for biomarker identification and classification methods for patient grouping are two important topics in adaptive designs of clinical trials related to genomic studies. In this article, we evaluate four test methods for biomarker identification in the first stage of an adaptive design: a model-based identification method, the popular two-sided t-test, the nonparametric Wilcoxon Rank-Sum test (two-sided), and the Regularized Generalized Linear Models. For patients grouping in the second stage, we examine classification methods such as Random Forest, Elastic-net Regularized Generalized Linear Models, Support Vector Machine (SVM), Gradient Boosting Machine (GBM), and Extreme Gradient Boosting (XGBoost). Simulation studies are carried out to assess the performance of the different methods. The best identification methods are chosen based on the well-known F 1 score, while the best classification techniques are selected based on the area under a receiver operating characteristic curve (AUC). The chosen methods are then applied to the Adaptive Signature Design (ASD) with a real data set from breast cancer patients for the purpose of evaluating the performance of ASD in different situations. [ABSTRACT FROM AUTHOR]

The adjustable conductance of a two‐terminal memristor in a crossbar array can facilitate vector‐matrix multiplication in one step, making the memristor a promising synapse for efficiently implementing neuromorphic computing. To achieve controllable and gradual switching of multi‐level conductance, important for neuromorphic computing, a theoretical design of a superlattice‐like (SLL) structure switching layer for the multi‐level memristor is proposed and validated, refining the growth of conductive filaments (CFs) and preventing CFs from the abrupt formation and rupture. Ti/(HfOx/AlOy)SLL/TiN memristors are shown with transmission electron microscopy , X‐ray photoelectron spectroscopy , and ab initio calculation findings corroborate the SLL structure of HfOx/AlOy film. The optimized SLL memristor achieves outstanding conductance modulation performance with linearly synaptic weight update (nonlinear factor α = 1.06), and the convolutional neural network based on the SLL memristive synapse improves the handwritten digit recognition accuracy to 94.95%. Meanwhile, this improved synaptic device has a fast operating speed (30 ns), a long data retention time (≥ 104 s at 85 ℃), scalability, and CMOS process compatibility. Finally, its physical nature is explored and the CF evolution process is characterized using nudged elastic band calculations and the conduction mechanism fitting. In this work, as an example the HfOx/AlOy SLL memristor provides a design viewpoint and optimization strategy for neuromorphic computing. [ABSTRACT FROM AUTHOR]

Tumor vascular endothelial cells play a pivotal in the tumor microenvironment, influencing the proliferation, invasion, and metastasis of tumor progression. The present study investigated a novel method for inducing the transformation of breast cancer stem cells into endothelial cells, providing a cellular model investigating anti-angiogenic mechanisms in vitro. The breast cancer cell line MCF-7 was used, and the expression of CD133 was initially detected using flow cytometry. CD133+ breast cancer cells were purified using immunomagnetic bead sorting technology, yielding an MCF-7CD133+ subpopulation. The proliferation ability of these cells was assessed using an MTT assay, while their microsphere formation ability was evaluated using a microsphere formation assay. Post-transformation in an optimized endothelial cell culture medium, expression of endothelial cell markers CD31 and CD105 were detected using flow cytometry. Endothelial cell tube formation assays and DiI-labeled acetylated low-density lipoprotein (DiI-Ac-LDL) assays were employed to analyze the endothelial cell function of the MCF-7CD133+ cells. MDM2/CEN12 gene amplification was detected through fluorescence in situ hybridization (FISH). The MCF-7 breast cancer cell line exhibited 1.7±0.3% trace cells expressing the stem cell surface marker CD133. After anti-CD133 immunomagnetic bead sorting, MCF-7CD133+ and MCF-7CD133- subpopulation cells were obtained, with CD133 expression rates of 85.6±2.8 and 0.18±0.08%, respectively. MTT assay results demonstrated that, after 7 days, the proliferation rate of MCF-7CD133+ cells was significantly higher compared with MCF-7CD133- cells. MCF-7CD133+ subpopulation cells displayed strong stem cell characteristics, growing in suspension in serum-free media and forming tumor cell spheres. In contrast, MCF-7CD133- cells failed to form microspheres. After culturing cells in endothelial cell differentiation and maintenance media, the percentage of MCF-7CD133+ cells before and after endothelial cell culture was 0.3±0.16 and 81.4±8.37% for CD31+ cells and 0.2±0.08 and 83.8±7.24% for CD105+ cells, respectively. Vascular-like structure formation and Ac-LDL phagocytosis with red fluorescence in the tube formation assays confirmed endothelial cell function in the MCF-7CD133+ cells. FISH was used to verify MDM2/CEN12 gene amplification in the induced MCF-7CD133+ cells, indicating tumor cell characteristics. The modified endothelial cell transformation medium effectively induced differentiated tumor stem cells to express vascular endothelial cell markers and exhibit endothelial functions, ideal for in vitro anti-angiogenesis research. [ABSTRACT FROM AUTHOR]

Background: Helicobacter pylori (Hp) eradication has been used for many years. Yet, the impact of this eradication on the normal gastric microflora is not well understood. In this study, we explored the effect of eradication on the stomach microbial community and its recovery after successful Hp eradication. Methods: Among the 89 included patients, 23, 17, 40, and 9 were included in the Hp-negative, Hp-positive, successful eradication, and failed eradication groups, respectively. Four subgroups were further determined according to disease status (Hp-negative chronic gastritis [N-CG], Hp-negative atrophic gastritis [N-AG], successful-eradication chronic gastritis [SE-CG], and atrophic gastritis with successful eradication [SE-AG]). During the endoscopic examination, one piece of gastric mucosa tissue was obtained from the lesser curvature side of the gastric antrum and gastric corpus, respectively. In addition, 16S rDNA gene sequencing was used to analyze the gastric mucosal microbiome. Results: In the Hp-negative group, the gastric microbiota was dominated by five phyla: Firmicutes, Proteobacteria, Actinobacteria, Bacteroidetes, and Fusobacteria. After successfully eradicating Hp, the bacterial flora in the stomach recovered to a considerable extent. In the failed eradication group, the flora was similar to the flora in Hp-positive subjects based on the alpha and beta diversities. Among the groups, Curvibacter and Acinetobacter were enriched in the presence of Hp (i.e., failed eradication and Hp-positive groups), suggesting that these two genera could be used as biomarkers in the symbiotic flora in the presence of Hp. SE-CG was characterized by an increase in Firmicutes taxa and a decrease in Proteobacteria taxa compared with N-CG. SE-AG was characterized by a decrease in Firmicutes relative to N-AG. Finally, no differences were found in the pairwise comparisons of nitrate and nitrite reductase functions of the microflora among the four subgroups. Conclusions: After Hp infection, the diversity and relative abundance of gastric microflora were significantly decreased. Yet, gastric microbiota could be partially restored to the Hp-negative status after eradication. Still, this effect was incomplete and might contribute to the long-term risks. [ABSTRACT FROM AUTHOR]

This study presents new zircon U–Pb ages, Sr–Nd–Hf isotopic data, and whole‐rock geochemical data obtained from the Early Cretaceous volcanic rocks from the north‐western Great Xing'an Range, Northeast China, to constrain the late Mesozoic magmatism and geodynamic setting of this region, which is located in the eastern segment of the Central Asian Orogenic Belt (CAOB). Zircon U–Pb age determinations show that the studied samples formed at 124–114 Ma with an Early Cretaceous magmatic event produced voluminous felsic and minor mafic volcanic rocks. The mafic rocks are dominantly basalt and basaltic andesite, with relatively low SiO2 contents (49.88–56.64 wt.%). These rocks are enriched in Th, U, large‐ion lithophile elements (LILE; e.g., Rb, Ba, and K) and light rare‐earth elements (REEs), and depleted in high‐field‐strength elements (HFSE; e.g., Nb, Ta, and Ti) and heavy REEs (Yb and Lu). The rocks have εNd(t) values of 0.44–0.75 and initial 87Sr/86Sr ratio of 0.70499–0.70548. These results indicate that the mafic rocks were derived from the partial melting of enriched lithospheric mantle that had been previously metasomatized by subduction‐related fluids and experienced variable amounts of fractional crystallization and moderate crustal contamination. In contrast to the mafic rocks, the felsic rocks are dominantly peraluminous trachytes, rhyolites, and dacites with high SiO2 contents and low MgO contents. These felsic rocks display enriched and variable concentrations of LILEs and REEs, show negative Eu anomalies, and have εHf(t) values of +2.6 to +8.3 with TDM2 ages of 1,014–655 Ma, indicating they were derived from partial melting of juvenile crustal materials. These Early Cretaceous igneous rock assemblages record a post‐collisional lithospheric extensional setting resulting from the closure of the Mongol–Okhotsk Ocean, consistent with the results of previous studies on the contemporaneous tectono‐magmatic activities in NE China. [ABSTRACT FROM AUTHOR]

The exact composition and structure of conductive filaments in hafnia-based memristors are still not fully understood, but recent theoretical investigations reveal that hexagonal HfOx phases close to the h.c.p. Hf structure are probable filament candidates. In this work we list h.c.p. Hf, Hf6O, Hf3O and Hf2O as possible phases for the filament in hafnia memristors. Their differences in lattice parameters, electronic structures and O charge states are studied in details. Migration of O ions for both in-plane and out-of-plane directions in these phases is investigated using first-principles calculations. Both single-phase supercells and filament-in-dielectric models are used for migration barrier calculations, while the latter is proven to be more accurate for the c-direction. The migration of O ions is fastest in metal Hf, while slowest in Hf2O. The existence of O interstitials in Hf tends to hinder the transport of O. [ABSTRACT FROM AUTHOR]

Structural connections among the hubs of the revised Papez circuit remain to be elucidated in the human brain. As the original Papez circuit failed to explain functional imaging findings, a more detailed investigation is needed to delineate connections among the circuit’s key hubs. Here we acquired diffusion spectrum imaging (DSI) from eight normal subjects and used data from the Human Connectome Project (HCP) to elucidate connections among hubs in the retrosplenial gyrus, hippocampus, mammillary bodies, and anterior thalamic nuclei. Our results show that the ventral hippocampal commissure (VHC) was visualized in all eight individual DSI datasets, as well as in the DSI and HCP group datasets, but a strictly defined VHC was only visualized in one individual dataset. Thalamic fibers were observed to connect with both the posterior cingulate cortex (PCC) and retrosplenial cortex (RSC). The RSC was mainly responsible for direct hippocampal connections, while the PCC was not. This indicates that the RSC and PCC represent separate functional hubs in humans, as also shown by previous primate axonal tracing studies and functional magnetic resonance imaging observations. [ABSTRACT FROM AUTHOR]

Antibiotics are emerging pollutants in aquatic ecosystems and there is much recent interest in their removal from water systems. However, the development of efficient sorbents for handling this problem remains a challenge. Herein, we report biomimetic hydrophilic, hollow polydopamine (PDA)-based composites of Fe3O4@PDA that were synthesized by a facile oxidation polymerization route. In order to assess the feasibility of Fe3O4@PDA hollow spheres as a potential sorbent for antibiotic removal, a series of adsorption experiments were conducted using tetracycline (TC) as the model antibiotic molecule. In contrast to the non-hollow counterpart of PS@Fe3O4@PDA, the designed Fe3O4@PDA hollow spheres exhibited much enhanced adsorption in removing TC at pH values from 2 to 10. The adsorption of TC onto Fe3O4@PDA hollow spheres fit a pseudo-second-order kinetics model, and the maximum adsorption capacity was 151.7 mg g−1 calculated from a Langmuir isotherm model at pH = 8. After adsorption, the Fe3O4@PDA hollow spheres could be quickly recovered from the TC solution due to the room-temperature paramagnetic property of Fe3O4 nanoparticles that were pre-loaded into the interior surface of hollow PDA shells. The combination of excellent adsorption capacity, good reusability and high stability, together with a mild preparation procedure enables these types of hollow composites to have potential applications in specific fields. [ABSTRACT FROM AUTHOR]

By periodically inserting the higher migration barrier of oxygen vacancy (VO) in Al SB 2 sb O SB 3 sb atomic layer into HfO SB x sb , it gracefully controls the VO migration and the formation and rupture of conductive filaments. B Superlattice-Like Memristive Synapse b In article number 2201446, Xingsheng Wang and co-workers propose a HfO SB x sb /AlO SB y sb superlattice-like memristor and achieve controllable multi-level conductance switching in the electric synapse for neuromorphic computing. [Extracted from the article]

A molecular hybridization approach is a powerful tool in the design of new molecules with improved affinity and efficacy. In this context, a series of diarylpyrimidine–quinolone hybrids were synthesized and evaluated against both wt HIV-1 and mutant viral strains. The most active hybrid 5a displayed an EC 50 value of 0.28 ± 0.07 μM against HIV-1 III B . A couple of enzyme-based assays clearly pinpoint a RT-targeted mechanism of action. Docking studies revealed that these hybrids could be well located in the NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid moiety in the molecules. [ABSTRACT FROM AUTHOR]

A consortium comprised of an engineered Escherichia coli DH5α and a natural pentachlorophenol (PCP) degrader, Sphingobium chlorophenolicum ATCC 39723, was assembled for degradation of hexachlorobenzene (HCB), a persistent organic pollutant. The engineered E. coli strain, harbouring a gene cassette ( camA camB camC) that encodes the F87W/Y96F/L244A/V247L mutant of cytochrome P-450cam (CYP101), oxidised HCB to PCP. The resulting PCP was then further completely degraded by ATCC 39723. The results showed that almost 40 % of 4 μM HCB was degraded by the consortium at a rate of 0.033 nmol/mg (dry weight)/h over 24 h, accompanied by transient accumulation and immediate consumption of the intermediate PCP, detected by gas chromatography. In contrast, in the consortium comprised of Pseudomonas putida PaW340 harbouring camA camB camC and ATCC 39723, PCP accumulated in PaW340 cells but could not be further degraded, which may be due to a permeability barrier of Pseudomonas PaW340 for PCP transportation. The strategy of bacterial co-culture may provide an alternative approach for the bioremediation of HCB contamination. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics. At present, there are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin is the most widely used prescription drug in the world and improves glycemic control in diabetes patients. There is some evidence that metformin enhances the efficacy of cancer treatment. The aim of this study was to test the hypothesis that metformin protects against chemotherapy-induced neuropathic pain and sensory deficits. Mice were treated with cisplatin together with metformin or saline. Cisplatin induced increased sensitivity to mechanical stimulation (mechanical allodynia) as measured using the von Frey test. Co-administration of metformin almost completely prevented the cisplatin-induced mechanical allodynia. Co-administration of metformin also prevented paclitaxel-induced mechanical allodynia. The capacity of the mice to detect an adhesive patch on their hind paw was used as a novel indicator of chemotherapy-induced sensory deficits. Co-administration of metformin prevented the cisplatin-induced increase in latency to detect the adhesive patch indicating that metformin prevents sensory deficits as well. Moreover, metformin prevented the reduction in density of intra-epidermal nerve fibers (IENFs) in the paw that develops as a result of cisplatin treatment. We conclude that metformin protects against pain and loss of tactile function in a mouse model of CIPN. The finding that metformin reduces loss of peripheral nerve endings indicates that mechanism underlying the beneficial effects of metformin includes a neuroprotective activity. Because metformin is widely used for treatment of type II diabetes, has a broad safety profile, and is currently being tested as an adjuvant drug in cancer treatment, clinical translation of these findings could be rapidly achieved. [ABSTRACT FROM AUTHOR]

Studies investigating the association of milk consumption with bladder cancer risk have reported inconsistent findings. We conducted a meta-analysis of published cohort and case-control studies to pool the risk estimates of the association between milk intake and bladder cancer. We quantified associations with bladder cancer using meta-analysis of odds ratio (OR) associated with the highest vs. the lowest category of milk intake using fixed- or random-effect models depending on the heterogeneity of effects among studies. Nineteen cohort and case-control studies were eligible for inclusion. High milk intake was significantly associated with decreased risk of bladder cancer (OR, 0.84; 95% CI, 0.71–0.97) when comparing the highest with the lowest category of milk intake. The inverse association was stronger in Asia (OR, 0.60; 95% CI, 0.40–0.81) than North America (OR, 0.89; 95% CI, 0.76–1.03), and no association was observed in Europe (OR, 1.05; 95% CI, 0.85–1.26). This relationship also varied significantly by specific dairy products. Our results suggest that milk may be related to the reduction of bladder cancer risk. Further studies need to clarify the biological mechanisms. [ABSTRACT FROM PUBLISHER]

Abstract: In prior studies, Eph/ephrin system was demonstrated to be involved in inflammatory and neuropathic pain modulation. The present study was to investigate whether the spinal Eph/ephrin signaling was involved in modulation of spinal inflammatory cytokines in bone cancer pain (BCP) of rats. BCP was induced by intra-tibial inoculation of Walker 256 mammary gland carcinoma cells. The expressions of EphB1/ephrinB1 in spinal cord (SC) and dorsal root ganglia (DRG) were determined. At 16 days post inoculation, the pain relieving effect and the mRNA levels of inflammatory cytokines were detected after intrathecal administration of EphB1-Fc (blocker of EphB1 receptor, 10μg). The results showed that the EphB1/ephrinB1 expression was significantly increased in SC, but ephrinB1 was decreased in DRG after Walker 256 inoculation. The mechanical allodynia induced by bone cancer was significantly alleviated by intrathecal administration of EphB1-Fc. Furthermore, the RT-PCR analysis showed that the mRNA levels of IL-1β, IL-6 and TNF-α were significantly increased at 16 days post Walker 256 inoculation and were significantly suppressed by intrathecal administration of EphB1-Fc in SC. We concluded that Eph/ephrin might be involved in the maintenance of mechanical allodynia, via modulating the expression of spinal inflammatory cytokines, in the present rat model of BCP. This study suggested that Eph/ephrin signaling would be a potential target for the treatment of BCP. [Copyright &y& Elsevier]

Abstract: Kisspeptin/GPR54 system plays a crucial role in the control of puberty onset and reproductive function. In the present study, we gave the first report that kisspeptin and GPR54 were expressed in the small- to large-sized neurons, and co-localized with Bandeiraea simplicifolia isolectin B4 (IB4), calcitonin-gene-related peptide (CGRP) and neurofilament 200 (NF200) in the L4/5 dorsal root ganglion (DRG) of naïve rats, detected by the double immunofluorescent staining. Interestingly, a marked elevation in the levels of KiSS-1 and GPR54 mRNA as well as protein was observed in the spinal dorsal horn and DRG 4 and 14 days following intra-articular injection of complete Freund''s adjuvant (CFA), indicating a possible involvement of the kisspeptin/GPR54 system in chronic inflammatory pain. [Copyright &y& Elsevier]

Abstract: Electroacupuncture (EA) can effectively control the exaggerated pain in humans with inflammatory disease and animals with experimental inflammatory pain. However, there have been few investigations on the effect of co-administration of EA and analgesics and the underlying synergistic mechanism. Using behavioral test, RT-PCR analysis, enzyme immunoassay (EIA) and enzyme-linked immunosorbent assay (ELISA), the present study demonstrated that (1) Unilateral intra-articular injection of complete Freund''s adjuvant (CFA) produced a constant hyperalgesia and an up-regulation of the prostaglandin E2 (PGE2) level as well as the tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels in the spinal cord; (2) Celecoxib, a selective inhibitor of cyclooxygenase-2 (COX-2), at a dose of 2, 10, and 20mg/kg (twice daily, p.o.), presented a dose-dependent anti-hyperalgesic effect; (3) Repeated EA stimulation of ipsilateral ‘Huan-Tiao’ (GB30) and ‘Yang-Ling-Quan’ (GB34) acupoints significantly suppressed CFA-induced hyperalgesia, and markedly inhibited the CFA-induced increase of the level of PGE2 as well as IL-1β, IL-6, and TNF-α in the spinal cord; (4) EA combined with low dose of celecoxib (2mg/kg, twice daily, p.o.) greatly enhanced the anti-hyperalgesic effects of EA, with a synergistic reversing effect on CFA-induced up-regulation of spinal PGE2, but not on the IL-1β, IL-6, or TNF-α. These data indicated that repeated EA combined with low dose of celecoxib produced synergistic anti-hyperalgesic effect in the CFA-induced monoarthritic rats, which could be made possible by regulating the activity of spinal COX, hence the spinal PGE2 level. Thus, this combination may provide an effective strategy for pain management. [Copyright &y& Elsevier]

Abstract: This study described a modified rat model of bone cancer pain. Syngeneic Walker 256 mammary gland carcinoma cells were injected into the tibia medullary cavity via intercondylar eminence. Series of tests were carried out including bone radiology, bone histology, ambulatory pain, thermal hyperalgesia, mechanical allodynia, weight bearing ability, and electrophysiological recording from primary afferent fibers. The rats inoculated with carcinoma cells showed significant ambulatory pain, mechanical allodynia, and reduction in weight bearing, as well as increased incidence of spontaneous activity in Aβ fibers in affected limb, whereas PBS (vehicle) or heat-killed cells (sham) injected rats showed no significant difference in comparison to normal rats. The pain hypersensitive behaviors were aggravated with time and destruction of bone. Interestingly, mechanical allodynia was also observed in the contralateral limb, indicating the involvement of ‘mirror image’ pain in bone cancer pain. In summary, the present study provided a useful and easily established rat model of bone cancer pain which will contribute to further study of the mechanisms underlying cancer pain. [Copyright &y& Elsevier]

Background: Evidence suggests that type 2 diabetes (T2D) is an independent risk factor for Alzheimer's disease (AD), sharing similar pathophysiological traits like impaired insulin signaling. Objective: To test the association between plasma insulin and cerebrospinal fluid (CSF) AD pathology. Methods: A total of 304 participants were included in the Alzheimer's Disease Neuroimaging Initiative, assessing plasma insulin and CSF AD pathology. We explored the cross-sectional and longitudinal associations between plasma insulin and AD pathology and compared their associations across different AD clinical and pathological stages. Results: In the non-demented group, amyloid-β (Aβ)+ participants (e.g., as reflected by CSF Aβ42) exhibited significantly lower plasma insulin levels compared to non-demented Aβ–participants (p < 0.001). This reduction in plasma insulin was more evident in the A+T+ group (as shown by CSF Aβ42 and pTau181 levels) when compared to the A–T– group within the non-dementia group (p = 0.002). Additionally, higher plasma insulin levels were consistently associated with more normal CSF Aβ42 levels (p < 0.001) across all participants. This association was particularly significant in the Aβ–group (p = 0.002) and among non-demented individuals (p < 0.001). Notably, baseline plasma insulin was significantly correlated with longitudinal changes in CSF Aβ42 (p = 0.006), whereas baseline CSF Aβ42 did not show a similar correlation with changes in plasma insulin over time. Conclusions: These findings suggest an association between plasma insulin and early Aβ pathology in the early stages of AD, indicating that plasma insulin may be a potential predictor of changes in early Aβ pathology. [ABSTRACT FROM AUTHOR]

To evaluate the long-term efficacy, prognostic factors, and safety of posteroventral globus pallidus internus deep brain stimulation (DBS) in patients with refractory Tourette syndrome (RTS). This retrospective study recruited 61 patients with RTS who underwent posteroventral globus pallidus internus (GPi) DBS from January 2010 to December 2020 at the Chinese People's Liberation Army General Hospital. The Yale Global Tic Severity Scale (YGTSS), Yale-Brown Obsessive-Compulsive Scale (YBOCS), Beck Depression Inventory (BDI), Gilles de la Tourette Syndrome Quality-of-Life Scale (GTS-QOL) were used to evaluate the preoperative and postoperative clinical condition in all patients. Prognostic factors and adverse events following surgery were analyzed. Patient follow up was conducted for an average of 73.33 ± 28.44 months. The final postoperative YGTSS (32.39 ± 22.34 vs 76.61 ± 17.07), YBOCS (11.26 ± 5.57 vs 18.31 ± 8.55), BDI (14.36 ± 8.16 vs 24.79 ± 11.03) and GTS-QOL (39.69 ± 18.29 vs 78.08 ± 14.52) scores at the end of the follow-up period were significantly lower than those before the surgery (p < 0.05). While age and the duration of follow-up were closely related to prognosis, the disease duration and gender were not. No serious adverse events were observed and only one patient exhibited symptomatic deterioration. Posteroventral-GPI DBS provides long-term effectiveness, acceptable safety and can improve the quality of life in RTS patients. Moreover, DBS is more successful among younger patients and with longer treatment duration. [ABSTRACT FROM AUTHOR]

Background: Nutrients involved in one-carbon metabolism may play a key role in pancreatic carcinogenesis. The aim of this study was to examine the association between pancreatic cancer risk and intake or blood levels of vitamins B6, B12 and methionine via meta-analysis.Methods: A systematic search was performed in PubMed, Web of Knowledge and Chinese National Knowledge Infrastructure (CNKI) up to April 2020 to identify relevant studies. Risk estimates and their 95% confidence intervals (CIs) were retrieved from the studies and combined by a random-effect model.Results: A total of 18 studies were included in this meta-analysis on the association of vitamin B6, B12 and methionine with pancreatic cancer risk. The combined risk estimate (95% CI) of pancreatic cancer for the highest vs lowest category of vitamin B6 intake and blood pyridoxal 5'-phosphate (PLP, active form of vitamin B6) levels was 0.63 (0.48-0.79) and 0.65 (0.52-0.79), respectively. The results indicated a non-linear dose-response relationship between vitamin B6 intake and pancreatic risk. Linear dose-response relationship was found, and the risk of pancreatic cancer decreased by 9% for every 10 nmol/L increment in blood PLP levels. No significant association were found between pancreatic cancer risk and vitamin B12 intake, blood vitamin B12 levels, methionine intake and blood methionine levels.Conclusion: Our study suggests that high intake of vitamin B6 and high concentration of blood PLP levels may be protective against the development of pancreatic cancer. Further research are warranted to confirm the results. [ABSTRACT FROM AUTHOR]

The fast development of high-accuracy neuromorphic computing requires stable analog memristors. While filamentary memory switching is very common in binary oxides, their resistive switching usually involves abrupt changes due to the rupture or reformation of metallic filaments. In this work, we designed a memristor consisting of dual-layer HfOy/HfOx, with different concentrations of oxygen vacancies (y > x). During the electroforming process, both the migration of existing oxygen vacancies in HfOx and the generation of new oxygen vacancies in HfOy occur simultaneously, leaving a semiconducting part close to the HfOy/HfOx interface. The resulting filament is not metallic as a whole, as revealed by first principles calculations. Such a device demonstrates excellent switching uniformity as well as highly gradual resistance change, ideal for neuromorphic computing. Through fine tuning of the filament structure, the device achieves low variation, high speed, gradual SET and RESET processes, and hundreds of stable multi-level state behaviors. The long-term synaptic plasticity was further achieved, showing good linearity and large analog switching window (ΔG as high as 487.5 μS). This works affords a route toward a gradual resistance change in oxide-based memristors. [ABSTRACT FROM AUTHOR]

Objective: The purpose of the present study was to evaluate the effectiveness of probiotics on type II diabetes mellitus (T2DM).Methods: We performed a comprehensive search on PubMed, Web of Science, China National Knowledge Infrastructure, Chinese Scientific Journal Databases, Wan Fang database and China biology medicine disc for relevant studies published before June 2019. Glycated hemoglobin A1c (HbA1c), homeostasis model assessment of insulin resistance (HOMA-IR) and fasting blood glucose (FBG) were used as indicators for T2DM. Inverse-variance weighted mean difference (WMD) with 95% confidence interval (CI) was calculated for the mean HbA1c, FBG and HOMA-IR changes from baseline.Results: 15 randomized controlled trials (RCT) with a total of 902 participants were included into the meta-analysis. Considering the clinical heterogeneity caused by variation of dosage and duration of probiotic treatment, random-effects model was used to estimate the pooled WMD. Significantly greater reduction in HbA1c% (WMD = - 0.24, 95% CI [- 0.44, - 0.04], p = 0.02), FBG (WMD = - 0.44 mmol/L, 95% CI [- 0.74, - 0.15], p = 0.003) and HOMA-IR (WMD = - 1.07, 95% CI [- 1.58, - 0.56], p < 0.00001) were observed in probiotics treated group. Further sensitivity analysis verified the reliability and stability of our results.Conclusion: The results of our meta-analysis indicated that probiotics treatment may reduce HbA1c, FBG and insulin resistance level in T2DM patients. More clinical data and research into the mechanism of probiotics are needed to clarify the role of probiotics in T2DM. [ABSTRACT FROM AUTHOR]

The central Great Xing'an Range contains widespread exposures of Mesozoic igneous rocks, yet the origin of its Late Mesozoic volcanic rocks has long been controversial. They are composed of andesite, trachyte, trachyandesite, trachydacite, rhyolite, and minor basaltic andesite. The intermediate rocks are enriched in large ion lithophiles and light rare earth elements (LILEs and LREEs) and are depleted in high field strength elements (HFSEs) such as Nb, Ta, and Ti, with positive εHf(t) values (+6.2 to +13.4) and Hf single-stage model ages (TDM1 = 556–227 Ma). This indicates that they were derived from the partial melting of a mantle wedge that was modified by previously subducted slab-derived fluids was likely introduced with limited crustal contamination. The felsic rocks show positive εHf(t) values (+4.3 to +10.2) and Hf two-stage model ages (TDM2 = 910–544 Ma), with more enrichment of LILEs and LREEs and more depletion of HFSEs and negative Eu anomalies. This indicates that felsic rocks were mainly derived from partial melting of Neoproterozoic accreted quartz-amphibolite facies mafic crust. We summarise the geochronological and Hf-Nd isotope data for Mesozoic igneous rocks within the central Great Xing'an Range (CGXR), the northern Xing'an block (NXB), and the Erguna block (EB), with the aim of constraining the geochronological framework for Mesozoic volcanism and comparing the growth of continental crust. The evolution of Late Mesozoic magmatism in the three areas reached its climax ~125 Ma ago. Our data, together with regional isotope evidence, suggest that crustal accretion of the CGXR occurred during the Neoproterozoic–Phanerozoic. However, that of the EB occurred during the Meso- to Neoproterozoic. The EB exhibits more lateral and vertical heterogeneities and ancient continental crust than the CGXR and NXB in the northern magma source region. [ABSTRACT FROM AUTHOR]

In this paper, we report on LA‐ICP‐MS zircon U–Pb dates of 14 Mesozoic volcanic rocks from the central Great Xing'an Range (CGXR). These data are integrated with the temporal and spatial distribution of local magmatism‐related Mesozoic mineralization, in an effort to develop an understanding of the geodynamic evolution of the region. Periodic magmatic events in the GXR date from ~1,703 through ~145 Ma. Mesozoic volcanism in the CGXR can be subdivided into three episodes: Triassic (250–205 Ma), Early–Middle Jurassic (182–165 Ma), and Late Jurassic–Early Cretaceous (155–115 Ma). A revision of the previously defined volcanic sequence is offered using a combination of our zircon U–Pb ages and published Mesozoic geological and geophysical evidence from northeast China. We propose that (a) Early–Middle Triassic volcanism in the CGXR resulted from subduction of the Paleo‐Asian oceanic plate; (b) Late Triassic volcanism was related to subduction of the Mongol–Okhotsk oceanic plate (especially near the Erguna Block) and subsequent extension after the closure of the Paleo‐Asian Ocean; (c) Early–Middle Jurassic volcanism was mainly controlled by the southward subduction of the Mongol–Okhotsk oceanic plate; (d) Late Jurassic–initial Early Cretaceous magmatism was initiated by closure of the Mongol–Okhotsk Ocean; and (e) late Early Cretaceous volcanism was induced following the final closure of the Mongol–Okhotsk Ocean and rollback of the Paleo‐Pacific oceanic plate. [ABSTRACT FROM AUTHOR]

Clinical usage of opioids in pain relief is dampened by analgesic tolerance after chronic exposure, which is related to opioid-associated neuroinflammation. In the current study, which is based on a chronic morphine tolerance rat model and sustained morphine treatment on primary neuron culture, it was observed that Akt phosphorylation, cleaved-Caspase-1-dependent NALP1 inflammasome activation and IL-1β maturation in spinal cord neurons were significantly enhanced by morphine. Moreover, treatment with LY294002, a specific inhibitor of PI3k/Akt signaling, significantly reduced Caspase-1 cleavage, NALP1 inflammasome activation and attenuated morphine tolerance. Tail-flick tests demonstrated that pharmacological inhibition on Caspase-1 activation or antagonizing IL-1β dramatically blocked the development of morphine tolerance. The administration of an exogenous analogue of lipoxin, Aspirin-triggered Lipoxin (ATL), caused a decline in Caspase-1 cleavage, inflammasome activation and mature IL-1β production and thus attenuated the development of morphine tolerance by inhibiting upstream Akt phosphorylation. Additionally, treatment with DAMGO, a selective μ-opioid receptor peptide, significantly induced Akt phosphorylation, Caspase-1 cleavage and anti-nociception tolerance, all of which were attenuated by ATL treatment. Taken together, the present study revealed the involvement of spinal NALP1 inflammasome activation in the development of morphine tolerance and the role of the μ-receptor/PI3k–Akt signaling/NALP1 inflammasome cascade in this process. By inhibiting this signaling cascade, ATL blocked the development of morphine tolerance. [ABSTRACT FROM AUTHOR]

Based on molecular simulation, the etravirine–VRX-480773 hybrids previously disclosed by our group were optimized to yield novel pyrimidine sulfonylacetanilides 8 with improved activity against a panel of seven clinically relevant single and double mutant strains of HIV-1. The improvement in potency in this in vitro model of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits the reverse transcriptase (RT), and represents a remarkable step forward in the development of anti-HIV drugs. [ABSTRACT FROM AUTHOR]

The improvement of microstructure and mechanical properties of Ti alloys is of great significance for their industrial application. In this study, a developed multi-step hot deformation process was employed to regulate the grain boundaries (GBs), hetero-phase boundaries (PBs) and dislocation structure for dual-phase titanium alloy. The effects of accumulative thermal deformation ratios from 33% to 75% (2–8 cycles) on the microstructure and mechanical properties have been investigated. It is found that the sintered sample shows a typical Widmanstätten structure without obvious pores and micro-cracks. However, with the increase of the deformation ratio, for the hexagonal close packed (HCP) Ti, the crystal orientations of { 01 1 ‾ 0 } and { 1 ‾ 2 1 ‾ 0 } were gradually transformed into {0001}, with the change of high-angle grain boundaries (HAGBs) to low-angle grain boundaries (LAGBs). The density of stored geometrically necessary dislocations (GNDs) density raised dramatically from 1.95 × 1014 m−2 to 6.5 × 1014 m−2, and various types of dislocations have been characterized. For the β phase, in the thermal deformation process, high density α-precipitates with an average thickness below 20 nm had formed with Burgers relationship of {110} BCC //{0001} HCP and < 1 ‾ 11 > BCC //< 2 1 ‾ 1 ‾ 0 > HCP. Finally, the yield strength of the dual-phase titanium alloy increased dramatically from 881 MPa to 1178 MPa, and the ductility can still maintain at above 8.5%. The enhanced strength was mainly contributed by the increase of geometrically necessary boundaries (GNBs) and nano-lamellae boundaries (NLBs). Therefore, this strategy of combining hetero-phase boundaries (PBs) and dislocation engineering could open up new avenues to designing strong and ductile titanium matrix materials. [ABSTRACT FROM AUTHOR]

Abstract: Cumulative evidences suggest that electroacupuncture (EA) can modulate immune function, but the mechanism needs further study. In the present study, the contribution of EA on toll-like receptors 2 and 4 (TLR2/TLR4) and pro-inflammatory cytokine expression after surgical trauma stress were investigated. The mRNA level of both TLR2/4 and pro-inflammatory cytokine was measured by quantitative real-time PCR. ELISA and Western blot assay were chosen for TLR2/TLR4 protein expression and pro-inflammatory cytokine production, respectively. The results showed that surgical trauma stress increased TLR2 mRNA and TLR2/4 proteins in the spleen and augmented pro-inflammatory cytokines (e.g. IL-1β) mRNA and protein expression in the spleen and plasma. These effects could be deteriorated by adrenalectomy (ADX). EA at “Zusanli” acupoint significantly inhibited surgical trauma-induced TLR2 mRNA and TLR2/4 protein expression in spleen and pro-inflammatory cytokine expression in the spleen and plasma. ADX, however, could not block the effect of EA. These results suggested that surgical trauma stress primes the innate immune system for enhanced TLR2 expression and pro-inflammatory cytokine production. EA inhibits TLR2/4 and pro-inflammatory cytokines to produce an anti-inflammatory effect in a surgical trauma stress model, without adrenal gland involvement. [Copyright &y& Elsevier]

Large oil tanks are often vulnerable to weak bearing capacity and uneven settlement of foundations, which gives rise to potential losses of both lives and property. Although the pile foundation is commonly used for large oil tanks, its high costs make it less applicable in many cases. Recently, improved ground has been adopted as a tank foundation because it is highly cost-effective. In this study, typical composite grounds improved by dynamic compaction, dynamic replacement and cement fly-ash gravel piles were adopted to work as the foundation for ten large, heavy oil tanks under various geological conditions in red soil areas in China. The results relating to improvement of the composite ground were studied comparatively in detail using in situ tests, including the dynamic penetration test, plate-load test and water injection test. Field studies show that the bearing capacity of the composite ground after treatment is over 260 kPa within the improvement depth, meeting the design requirement for the long-term service of the ten oil tanks. The field test and relevant findings indicate a promising future for composite ground in relation to large, heavy oil tanks. [ABSTRACT FROM AUTHOR]

Silicic volcanic rocks are the main components of the upper crust. Understanding their genesis can help us better understand the processes of crustal growth, reconstruction, and crust–mantle interactions. In this study, we examine silicic volcanic rocks from Suolun in the Great Xing'an Range, China. These silicic volcanic rocks are of Cretaceous age (140–123 Ma), with 68–76 wt% SiO2, and the majority are of the high‐K (calc‐alkaline) series. εHf(t) ranges between +1.7 and +9.9, mostly around 7. The Early Cretaceous silicic volcanic rocks from Suolun are cold‐wet‐oxidised, highly differentiated I‐type volcanic rocks, and plagioclase and K‐feldspar are the main fractionation phases. TTiZ shows that silicic magma undergoes a reheating process in the magma chamber, which causes the early rheological lock‐up magma to reactivate and thus drives it to further differentiation. This process is probably driven by the injection of high temperature magma at depth. The wet upwelling of the Mongol‐Okhotsk Oceanic plate in the deep resulted in large‐scale magmatism in the area. These results provide a possible explanation for the formation of highly differentiated magmatic rocks and further confirm the evolutionary link between volcanic rocks and plutonic systems. [ABSTRACT FROM AUTHOR]

BACKGROUND Jiuqu are vital saccharifying and fermenting agents for Chinese fermented foods. Natural ventilation during Jiuqu fermentation causes changes in temperature, oxygen and moisture content, resulting in mass and heat gradients from the outer to inner areas of Jiuqu blocks. In the present study, microbiota stratification in Jiuqu was investigated by single molecule real‐time sequencing and culture isolation. The contributors of Bacillus to amylase activity of Jiuqu and the dynamics of their biomass during Jiuqu fermentation were also analyzed. RESULTS: The dominant orders, genera and species between the inner and outer layers of Huangjiu qu (HJQ) were similar, although they displayed greater variance in two layers of Baijiu qu (BJQ). Bacillus possessed the highest diversity (including 27 species) in Jiuqu. Bacillus licheniformis, Bacillus altitudinis, Bacillus subtilis, Bacillus amyloliquefaciens and Bacillus megaterium were most prevalent in HJQ, whereas B. licheniformis, B. amyloliquefaciens and Bacillus cereus were dominant in BJQ. Isolates of B. amyloliquefaciens, B. subtilis and B. cereus exhibited high activities of amylase and glucoamylase. Quantification of Bacillus members possessing genes of α‐amylase revealed that B. cereus and B. licheniformis were the most dominant microbes to secret α‐amylase in Jiuqu and their biomass were increasing during Jiuqu fermentation. CONCLUSION: The present study demonstrates the microbial distribution in different layers of Jiuqu and clarifies the Bacillus species processing the activity of α‐amylase. These results will help industries control the quality of Jiuqu by rationally selecting starters and optimizing their microbiota. © 2020 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Trigeminal neuralgia (TN) is debilitating and is usually accompanied by mood disorders. The lateral habenula (LHb) is considered to be involved in the modulation of pain and mood disorders, and the present study aimed to determine if and how the LHb participates in the development of pain and anxiety in TN. To address this issue, a mouse model of partial transection of the infraorbital nerve (pT-ION) was established. pT-ION induced stable and long-lasting primary and secondary orofacial allodynia and anxiety-like behaviors that correlated with the increased excitability of LHb neurons. Adeno-associated virus (AAV)-mediated expression of hM4D(Gi) in glutamatergic neurons of the unilateral LHb followed by clozapine-N-oxide application relieved pT-ION-induced anxiety-like behaviors but not allodynia. Immunofluorescence validated the successful infection of AAV in the LHb, and microarray analysis showed changes in gene expression in the LHb of mice showing allodynia and anxiety-like behaviors after pT-ION. Among these differentially expressed genes was Tacr3, the downregulation of which was validated by RT-qPCR. Rescuing the downregulation of Tacr3 by AAV-mediated Tacr3 overexpression in the unilateral LHb significantly reversed pT-ION-induced anxiety-like behaviors but not allodynia. Whole-cell patch clamp recording showed that Tacr3 overexpression suppressed nerve injury-induced hyperexcitation of LHb neurons, and western blotting showed that the pT-ION-induced upregulation of p-CaMKII was reversed by AAV-mediated Tacr3 overexpression or chemicogenetic inhibition of glutamatergic neurons in the LHb. Moreover, not only anxiety-like behaviors, but also allodynia after pT-ION were significantly alleviated by chemicogenetic inhibition of bilateral LHb neurons or by bilateral Tacr3 overexpression in the LHb. In conclusion, Tacr3 in the LHb plays a protective role in treating trigeminal nerve injury-induced allodynia and anxiety-like behaviors by suppressing the hyperexcitability of LHb neurons. These findings provide a rationale for suppressing unilateral or bilateral LHb activity by targeting Tacr3 in treating the anxiety and pain associated with TN. [ABSTRACT FROM AUTHOR]

Background: Cancer pain is a pervasive clinical symptom impairing life quality. Vascular endothelial growth factor A has been well studied in tumor angiogenesis and is recognized as a therapeutic target for anti-cancer treatment. This study tested the hypothesis that vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 contribute to bone cancer pain regulation associated with spinal central sensitization.Methods: This study was performed on female rats using a metastatic breast cancer bone pain model. Nociceptive behaviors were evaluated by mechanical allodynia, thermal hyperalgesia, spontaneous pain, and CatWalk gait analysis. Expression levels were measured by real-time quantitative polymerase chain reaction, western blot, and immunofluorescence analysis. Excitatory synaptic transmission was detected by whole-cell patch-clamp recordings. The primary outcome was the effect of pharmacologic intervention of spinal vascular endothelial growth factor A/vascular endothelial growth factor receptor 2-signaling on bone cancer pain behaviors.Results: The mRNA and protein expression of vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 were upregulated in tumor-bearing rats. Spinal blocking vascular endothelial growth factor A or vascular endothelial growth factor receptor 2 significantly attenuated tumor-induced mechanical allodynia (mean ± SD: vascular endothelial growth factor A, 7.6 ± 2.6 g vs. 5.3 ± 3.3 g; vascular endothelial growth factor receptor 2, 7.8 ± 3.0 g vs. 5.2 ± 3.4 g; n = 6; P < 0.0001) and thermal hyperalgesia (mean ± SD: vascular endothelial growth factor A, 9.0 ± 2.4 s vs. 7.4 ± 2.7 s; vascular endothelial growth factor receptor 2, 9.3 ± 2.5 s vs. 7.5 ± 3.1 s; n = 6; P < 0.0001), as well as spontaneous pain and abnormal gaits. Exogenous vascular endothelial growth factor A enhanced excitatory synaptic transmission in a vascular endothelial growth factor receptor 2-dependent manner, and spinal injection of exogenous vascular endothelial growth factor A was sufficient to cause pain hypersensitivity via vascular endothelial growth factor receptor 2-mediated activation of protein kinase C and Src family kinase in naïve rats. Moreover, spinal blocking vascular endothelial growth factor A/vascular endothelial growth factor receptor 2 pathways suppressed protein kinase C-mediated N-methyl-D-aspartate receptor activation and Src family kinase-mediated proinflammatory cytokine production.Conclusions: Vascular endothelial growth factor A/vascular endothelial growth factor receptor 2 contributes to central sensitization and bone cancer pain via activation of neuronal protein kinase C and microglial Src family kinase pathways in the spinal cord. [ABSTRACT FROM AUTHOR]

Following publication of the original article [1], the authors reported an error in one of the author names. In this Correction the incorrect and correct author names are listed. [ABSTRACT FROM AUTHOR]

The Tayuan plutons located at the boundary of the Erguna and Xing'an blocks expose a coexisting mafic-felsic association that is made of monzogranite and gabbro-monzodiorite as well as subordinate quartz monzonite. LA-ICP-MS U-Pb zircon dating revealed a synchronous emplacement of the monzogranite (314-317 Ma), gabbro (308-315 Ma), and quartz monzonite (310 ± 3 Ma). The majority of these intrusions are characterized by an enrichment in light rare earth elements relative to heavy rare earth elements and a depletion of high strength field elements (e.g. Nb, Ta, Ti). Zircons from the gabbro and monzogranite have εHf(t) values of 1.1-9.6 and −3.0-3.3, respectively. Geochemical data show that the gabbro-monzodiorite may have been generated by the melting of a fluid-metasomatized lithospheric mantle, while the monzogranite may have been formed by a partial melting of the Mesoproterozoic crust. The quartz monzonite has similar whole-rock geochemical and Hf isotopic compositions to those of the gabbros and could have been produced from the same mantle source as that from which the gabbros were extracted. The Tayuan plutonic rocks have high contents of K2O and total alkalis and show a northwestward polarity like that of the continental margin plutonic rocks along the Hegenshan-Heihe suture zone. Combined with data from published studies, our data indicate that the Tayuan intrusive rocks were generated by the northwestward subduction of the Hegenshan-Heihe Oceanic plate. [ABSTRACT FROM AUTHOR]

This paper presents major element, trace element, and new zircon Hf isotopic data for the Early Mesozoic intrusive rocks in the south Hunchun, Yanbian area, Northeast China. These data are used to constrain the petrogenesis of these intrusive rocks and their implications for the Phanerozoic continental growth of the Central Asian Orogenic Belt (CAOB). Combining geology, geochronology, and whole-rock geochemistry, we identify three distinct episodes of magmatism as Early-Middle Triassic (249-237 Ma), Late Triassic (224-206 Ma), and Early Jurassic (200-187 Ma). The Early-Middle Triassic (249-237 Ma) adakitic tonalite and granodiorite were produced by the partial melting of subducted oceanic slabs, and the melts were contaminated by mantle peridotite during their ascent, whereas the coeval non-adakitic diorite and monzogranite were most likely derived from partial melting of crustal material. The remarkably high zircon Hf isotopic signature (εHf(t) = + 9.4 - +18.9), the enrichment in large-ion lithophile element and light rare earth elements, and the depletion in high field strength element suggest that these 224 Ma gabbros were derived from the partial melting of depleted mantle modified by subduction-related fluids. The 212 Ma monzogranite was most likely derived from juvenile material mixed with old crustal material as evidenced by their high SiO2, low MgO, and low Cr concentrations and variable εHf(t) values (-4.6 to +10.0). Except for the 197 Ma tonalites with affinity to the high silica adakites, the overall geochemical evolution of Early Jurassic (200-187 Ma) rocks was consistent with fractional crystallization from quartz diorite, granodiorite, and monzogranite to syenogranite. Both the Early Jurassic syn-subduction lateral continental growth by accretion of arc complexes and the Late Triassic post-collisional vertical continental growth by accretion of mantle-derived material played an important role in the Phanerozoic continental growth of the CAOB. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse side effect of many antineoplastic agents. Patients treated with chemotherapy often report pain and paresthesias in a “glove-and-stocking” distribution. Diverse mechanisms contribute to the development and maintenance of CIPN. However, the role of spinal microglia in CIPN is not completely understood. In this study, cisplatin-treated mice displayed persistent mechanical allodynia, sensory deficits and decreased density of intraepidermal nerve fibers (IENFs). In the spinal cord, activation of microglia, but not astrocyte, was persistently observed until week five after the first cisplatin injection. Additionally, mRNA levels of inflammation related molecules including IL-1β, IL-6, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS) and CD16, were increased after cisplatin treatment. Intraperitoneal (i.p.) or intrathecal (i.t.) injection with minocycline both alleviated cisplatin-induced mechanical allodynia and sensory deficits, and prevented IENFs loss. Furthermore, cisplatin enhanced triggering receptor expressed on myeloid cells 2 (TREM2) /DNAX-activating protein of 12 kDa (DAP12) signaling in the spinal cord microglia. The blockage of TREM2 by i.t. injecting anti-TREM2 neutralizing antibody significantly attenuated cisplatin-induced mechanical allodynia, sensory deficits and IENFs loss. Meanwhile, anti-TREM2 neutralizing antibody prominently suppressed the spinal IL-6, TNF-α, iNOS and CD16 mRNA level, but it dramatically up-regulated the anti-inflammatory cytokines IL-4 and IL-10. The data demonstrated that cisplatin triggered persistent activation of spinal cord microglia through strengthening TREM2/DAP12 signaling, which further resulted in CIPN. Functional blockage of TREM2 or inhibition of microglia both benefited for cisplatin-induced peripheral neuropathy. Microglial TREM2/DAP12 may serve as a potential target for CIPN intervention. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is a sleep-related breathing disorder characterized by intermittent and recurrent upper airway collapse during sleep that leads to chronic intermittent hypoxia (CIH). The genioglossus (GG) is the largest dilator muscle, which controls the upper airway and plays an important role in OSA pathology. Elucidating its genetic alterations may help identify potential targets for OSA. However, the genetic aspects of the GG in CIH mice remain unclear. Here, we have conducted an RNA sequencing (RNA-Seq) analysis to assess the differentially expressed genes (DEGs) in the GG between CIH mice and normoxia (NOR) mice. A total of 637 DEGs were identified to be dysregulated in CIH mice compared with control mice. Bioinformatics analysis showed that the DEGs were related to various physiological processes, such as the endogenous stimulus responses, cellular component organization and metabolic processes. Extracellular matrix (ECM)–receptor interaction was the top KEGG pathway in the environmental information processing category with high significance and large fold changes. From the gene weight distributions of collagen (Col)-related biological processes (BPs), we found several significant DEGs, such as Col1a1, Col1a2, Mmp2, Col3a1, Col5a1, Fmod, and Col5a2. A PPI network showed that Col1a1 was linked to ECM–receptor interactions, responses to reactive oxygen species (ROS) and Col-related BPs. It was verified in vivo and in vitro that hypoxia can induce excess ROS and reduce Col expression levels. Moreover, we found NAC can effectively scavenge ROS and restore collagen synthesis. These findings contribute to a better understanding of the mechanisms linking OSA and upper airway muscle injury and may help identify potential therapeutic targets. • 637 DEGs were identified in mouse genioglossus of chronic intermittent hypoxia model. • ECM–receptor interactions was highly enriched with transcriptional changes in collagen synthesis. • A PPI network showed that Col1a1 was linked to ECM–receptor interactions, responses to ROS and Col-related BPs. [ABSTRACT FROM AUTHOR]

Pseudomonas plecoglossicida NyZ12 (CCTCC AB 2015057), a Gram-negative bacterium isolated from soil, has the ability to degrade cyclohexylamine. The complete genome sequence of this strain (6,233,254 bp of chromosome length) is presented, with information about the genes of characteristic enzymes responsible for cyclohexylamine oxidation to cyclohexanone and the integrated gene cluster for the metabolic pathway of cyclohexanone oxidation to adipate. [ABSTRACT FROM AUTHOR]

The Gram-negative strain of Pseudomonas plecoglossicida NyZ12 isolated from soil has the ability to degrade cyclohexylamine (CHAM). The genes encoding CHAM degradation by gram-negative bacteria, however, have not been reported previously. In this study, ORFs predicted to encode CHAM degradation by NyZ12 were identified by bioinformatics analysis. Differential expression of the proposed ORFs was analyzed via RNA-seq and quantitative reverse transcription-PCR (qRT-PCR), using RNA extracted from NyZ12 cultured with or without CHAM addition. One CHAM-inducible ORF, RK21_02867 predicted to encode a cyclohexanone monooxygenase (ChnB) was disrupted, as were five ORFs, RK21_00425, RK21_02631, RK21_04207, RK21_04637 and RK21_05539, that had weak homology to the only known cyclohexylamine oxidase (CHAO encoded by chaA ) found in Brevibacterium oxydans IH-35A. We also found that a tandem array of five ORFs (RK21_02866-02870) shared homology with those in an operon responsible for oxidation of cyclohexanone to adipic acid, although the ORFs in strain NyZ12 were arranged in a different order with previously found in cyclohexane, cyclohexanol or cyclohexanone degradation strains. The ORFs in this cluster were all up-regulated when CHAM was supplied as the sole carbon source. When one of these five genes, RK21_02867 encoding cyclohexanone (CHnone) monooxygenase, was knocked out, NyZ12 could not grow on CHAM, but it accumulated equimolar amounts of CHnone. Our results show that strain NyZ12 metabolized CHAM directly to CHnone which was then further metabolized to adipate. Despite clearly identifying genes encoding the steps for metabolism of CHAM metabolites, not every one of the putative chaAs was differentially expressed in the presence of CHAM and deletion of each one individually did not completely eliminate the capacity of NyZ12 to degrade CHAM, though it did reduce its growth in several instances. Our results suggest that there is genetic redundancy encoding the initial step in the oxidation of CHAM to CHnone in NyZ12 and that its CHAOs differ considerably from the ChaA, originally described in Brevibacterium oxydans IH-35A. [ABSTRACT FROM AUTHOR]

Background and Objectives: The association between fiber intake and pancreatic cancer risk is conflicting and poorly explored. The aim of study was to investigate the association between dietary fiber intake and the risk of pancreatic cancer by conducting a meta-analysis of epidemiological studies.Methods and Study Design: Systematic search of PubMed and Embase databases up to April 2015 were conducted to identify relevant studies. Adjusted odds ratios (ORs) were combined using random-effects models to assess the risk of pancreatic cancer when comparing extreme categories of fiber intake. Dose-response meta-analysis was performed for studies reporting categorical risk estimates for at least 3 exposure levels.Results: One cohort and thirteen case-control studies were identified. The overall analysis revealed a strong inverse association between risk of pancreatic cancer and high fiber intake (OR 0.52; 95% CI 0.44-0.61). No publication bias was detected by Egger's or Begg's test. The dose-response analyses showed that the summary OR for an increment of 10 g daily intake of fiber was 0.88 (0.84 to 0.92).Conclusion: A high intake of dietary fiber was associated with a reduced risk of pancreatic cancer. Further well-designed prospective studies are warranted to confirm the inverse association and to identify the dietary fiber types involved. [ABSTRACT FROM AUTHOR]

Cancer-induced bone pain (CIBP) is a severe type of chronic pain. It is imperative to explore safe and effective analgesic drugs for CIBP treatment. Baicalein (BE), isolated from the traditional Chinese herbal medicine Scutellaria baicalensis Georgi (or Huang Qin), has been demonstrated to have anti-inflammatory and neuroprotective effects. In this study, we examined the effect of BE on CIBP and the mechanism of this effect. Intrathecal and oral administration of BE at different doses could alleviate the mechanical allodynia in CIBP rats. Intrathecal 100 μg BE could inhibit the production of IL-6 and TNF-α in the spinal cord of CIBP rats. Moreover, intrathecal 100 μg BE could effectively inhibit the activation of p-p38 and p-JNK MAPK signals in CIBP rats. The analgesic effect of BE may be associated with the inhibition of the expression of the inflammatory cytokines IL-6 and TNF-α and through the activation of p-p38 and p-JNK MAPK signals in the spinal cord. These findings suggest that BE is a promising novel analgesic agent for CIBP. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence indicates that nerve damage-initiated neuroinflammation and immune responses, which are evidenced by the up-regulation of proinflammatory cytokines, contribute to the development of neuropathic pain. This study investigated the role of spinal interleukin (IL)-33 and its receptor ST2 in spared nerve injury (SNI)-induced neuropathic pain. Methods: The von Frey test and acetone test were performed to evaluate neuropathic pain behaviors (n = 8 to 12), and Western blot (n = 4 to 6), immunohistochemistry, real-time polymerase chain reaction (n = 5), and Bio-Plex (n = 5) assays were performed to understand the molecular mechanisms. Results: Intrathecal administration of ST2-neutralizing antibody or ST2 gene knockout (ST2) significantly attenuated the SNI-induced mechanical and cold allodynia. On the 7th day after SNI, the expression of spinal IL-33 and ST2 was increased by 255.8 ± 27.3% and 266.4 ± 83.5% (mean ± SD), respectively. Mechanistic studies showed that the increased expression of the spinal N-methyl-D-aspartate (NMDA) receptor subunit 1 after SNI was reduced by ST2 antibody administration or ST2. The induction of nociceptive behaviors in naive mice due to recombinant IL-33 was reversed by the noncompetitive NMDA antagonist MK-801. ST2 antibody administration or ST2 markedly inhibited the increased activation of the astroglial janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) cascade and the neuronal calcium-calmodulin-dependent kinase II (CaMKII)-cyclic adenosine monophosphate response element-binding protein (CREB) cascade after SNI. Moreover, intrathecal pretreatment with the CaMKII inhibitor KN-93 or the JAK2-STAT3 cascade inhibitor AG490 attenuated recombinant IL-33-induced nociceptive behaviors and NMDA subunit 1 up-regulation in naive mice. Conclusion: Spinal IL-33/ST2 signaling contributes to neuropathic pain by activating the astroglial JAK2-STAT3 cascade and the neuronal CaMKII-CREB cascade. [ABSTRACT FROM AUTHOR]

A novel series of etravirine–VRX-480773 hybrids were designed using structure-guided molecular hybridization strategy and fusing the pharmacophore templates of etravirine and VRX-480773. The anti-HIV-1 activity and cytotoxicity was evaluated in MT-4 cell cultures. The most active hybrid compound in this series, N -(2-chlorophenyl)-2-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)thio)acetamide 3d (EC 50 = 0.24 , SI >1225), was more potent than delavirdine (EC 50 = 0.66 μM, SI >67) in the anti-HIV-1 in vitro cellular assay. Studies of structure-activity relationships established a correlation between anti-HIV activity and the substitution pattern of the acetanilide group. [ABSTRACT FROM AUTHOR]

A novel series of piperidin-4-yl-aminopyrimidine derivatives were designed fusing the pharmacophore templates of etravirine–VRX-480773 hybrids our group previously described and piperidine-linked aminopyrimidines. Most compounds displayed significantly improved activity against wild-type HIV-1 with EC 50 values in single-digit nanomolar concentrations compared to etravirine–VRX-480773 hybrids. Selected compounds were also evaluated for activity against reverse transcriptase, and had lower IC 50 values than that of nevirapine. The improved potency observed in this in vitro model of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits reverse transcriptase, and represents a remarkable step forward in the development of AIDS therapeutics. [ABSTRACT FROM AUTHOR]

Chronic pain frequently co-occurs with major depressive disorder but the mechanisms are poorly understood. We investigated the contribution of indoleamine 2,3-dioxygenase-1 (IDO1), a rate-limiting enzyme in the conversion of tryptophan to neurotoxic metabolites, to this comorbidity using the spared nerve injury (SNI) model of neuropathic pain in mice. SNI resulted in unilateral mechanical allodynia, reduced social interaction, and increased immobility in the forced swim test without changes in locomotor activity. These findings indicate SNI-induced pain and comorbid depression-like behavior. These behavioral responses were accompanied by increases in plasma kynurenine/tryptophan ratios and increased expression of Ido1 and Il1b mRNA in the liver. Interestingly, SNI did not induce detectable changes in spinal cord or brain Ido1 mRNA levels. SNI was associated with spinal cord inflammatory activity as evidenced by increased Il1b mRNA expression. The SNI-induced increase of liver Ido1 and Il1b mRNA was abrogated by intrathecal administration of the IL-1 inhibitor IL-1RA. Intrathecal IL-1RA also inhibited both mechanical allodynia and depression-like behavior. We also show that Ido1 is required for the development of depression-like behavior because Ido1 −/− mice do not develop increased immobility in the forced swim test or decreased social exploration in response to SNI. Mechanical allodynia was similar in WT and Ido1 −/− mice. In conclusion, our findings show for the first time that neuropathic pain is associated with an increase of Ido1 in liver, but not brain, downstream of spinal cord IL-1β signaling and that Ido1 mediates comorbid depression. Moreover, comorbidity of neuropathic pain and depression are only partially mediated by a common mechanism because mechanical hyperalgesia develops independently of Ido1 . [ABSTRACT FROM AUTHOR]