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Abstract Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer. In the development and progression of LUAD, epigenetic aberration plays a crucial role. However, the function of RNA N6-methyladenosine (m6A) modifications in the LUAD progression is unknown. The m6A regulator modification patterns in 955 LUAD samples were analyzed comprehensively. Patterns were systematically correlated with the tumor microenvironment (TME) cell-infiltration characteristics. Using principal component analysis algorithms, the m6Ascore was generated to quantify m6A modification patterns in individual tumors. Then, their values for predicting prognoses and therapeutic response in LUAD patients were assessed. Three distinct m6A modification patterns in LUAD were identified. Among them, the prognosis of m6Acluster C was the best, while the prognosis of m6Acluster A was the worst. Interestingly, the characterization of TME cell infiltration and biological behavior differed among the three patterns. To evaluate m6A modification patterns within individual tumors, an m6Ascore signature was constructed. The results showed that the high m6Ascore group was associated with a better prognosis; tumor somatic mutations and tumor microenvironment differed significantly between the high- and low- m6Ascore groups. Furthermore, in the cohort with anti-CTLA-4 treatment alone, patients with a high m6Ascore had higher ICI scores, which indicated significant therapeutic advantage and clinical benefits.

Bone-resorbing osteoclasts are essential for skeletal remodelling, and the hyperactive formation and function of osteoclasts are common in bone metabolic diseases, especially postmenopausal osteoporosis. Therefore, regulating the osteoclast differentiation is a major therapeutic target in osteoporosis treatment. Icariin has shown potential osteoprotective effects. However, existing studies have reported limited bioavailability of icariin, and the material basis of icariin for anti-osteoporosis is attributed to its metabolites in the body. Here, we compared the effects of icariin and its metabolites (icariside I, baohuoside I, and icaritin) on osteoclastogenesis by high-content screening followed by TRAP staining and identified baohuoside I (BS) with an optimal effect. Then, we evaluated the effects of BS on osteoclast differentiation and bone resorptive activity in both in vivo and in vitro experiments. In an in vitro study, BS inhibited osteoclast formation and bone resorption function in a dose-dependent manner, and the elevated osteoclastic-related genes induced by RANKL, such as NFATc1, cathepsin K, RANK, and TRAP, were also attenuated following BS treatment. In an in vivo study, OVX-induced bone loss could be prevented by BS through interrupting the osteoclast formation and activity in mice. Furthermore, mechanistic investigation demonstrated that BS inhibited osteoclast differentiation by ameliorating the activation of the MAPK and NF-kB pathways and reducing the expression of uPAR. Our study demonstrated that baohuoside I could inhibit osteoclast differentiation and protect bone loss following ovariectomy.

Background: Whether bridging treatment combining intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) is superior to direct EVT alone for emergent large vessel occlusion (LVO) in the anterior circulation is unknown. A systematic review and a meta-analysis were performed to investigate and assess the effect and safety of bridging treatment vs. direct EVT in patients with LVO in the anterior circulation.Methods: PubMed, EMBASE, and the Cochrane library were searched to assess the effect and safety of bridging treatment and direct EVT in LVO. Functional independence, mortality, asymptomatic and symptomatic intracranial hemorrhage (aICH and sICH, respectively), and successful recanalization were evaluated. The risk ratio and the 95% CI were analyzed.Results: Among the eight studies included, there was no significant difference in the long-term functional independence (OR = 1.008, 95% CI = 0.845–1.204, P = 0.926), mortality (OR = 1.060, 95% CI = 0.840–1.336, P = 0.624), recanalization rate (OR = 1.015, 95% CI = 0.793–1.300, P = 0.905), and the incidence of sICH (OR = 1.320, 95% CI = 0.931–1.870, P = 0.119) between bridging therapy and direct EVT. After adjusting for confounding factors, bridging therapy showed a lower recanalization rate (effect size or ES = −0.377, 95% CI = −0.684 to −0.070, P = 0.016), but there was no significant difference in the long-term functional independence (ES = 0.057, 95% CI = −0.177 to 0.291, P = 0.634), mortality (ES = 0.693, 95% CI = −0.133 to 1.519, P = 0.100), and incidence of sICH (ES = −0.051, 95% CI = −0.687 to 0.585, P = 0.875) compared with direct EVT. Meanwhile, in the subgroup analysis of RCT, no significant difference was found in the long-term functional independence (OR = 0.927, 95% CI = 0.727–1.182, P = 0.539), recanalization rate (OR = 1.331, 95% CI = 0.948–1.867, P = 0.099), mortality (OR = 1.072, 95% CI = 0.776–1.481, P = 0.673), and sICH incidence (OR = 1.383, 95% CI = 0.806–2.374, P = 0.977) between patients receiving bridging therapy and those receiving direct DVT.Conclusion: For stroke patients with acute anterior circulation occlusion and who are eligible for intravenous thrombolysis, there is no significant difference in the clinical effect between direct EVT and bridging therapy, which needs to be verified by more randomized controlled trials.

Parkinson’s disease (PD) is the most common movement disorder in the world, affecting 1–2 per 1,000 of the population. The main pathological changes of PD are damage of dopaminergic neurons in substantia nigra of the central nervous system and formation of Lewy bodies. These pathological changes also occur in the intestinal tract and are strongly associated with changes in intestinal flora. By reviewing the research progress in PD and its association with intestinal flora in recent years, this review expounded the mechanism of action between intestinal flora and PD as well as the transmission mode of α - synuclein in neurons. In clinical studies, β diversity of intestinal flora in PD patients was found to change significantly, with Lactobacillusaceae and Verrucomicrobiaceae being significantly increased and Lachnospiraceae and Prevotellaceae being significantly decreased. In addition, a longer PD course was associated with fewer bacteria and probiotics producing short chain fatty acids, but more pathogenic bacteria. Moreover, the motor symptoms of PD patients may be related to Enterobacteriaceae and bacteria. Most importantly, catechol-O-methyltransferase inhibitors and anticholinergic drugs could change the intestinal flora of PD patients and increase the harmful flora, whereas other anti-PD drugs such as levodopa, dopamine agonist, monoamine oxidase inhibitors, and amantadine did not have these effects. Probiotics, prebiotics, and synbiotics treatment had some potential values in improving the constipation of PD patients, promoting the growth of probiotics, and improving the level of intestinal inflammation. At present, there were only a few case studies and small sample studies which have found certain clinical efficacy of fecal microbiome transplants. Further studies are necessary to elaborate the relationship of PD with microbes.

Adipose-derived stem cells have been shown to promote peripheral nerve regeneration through the paracrine secretion of neurotrophic factors. However, it is unclear whether these cells can promote myogenic differentiation in muscular dystrophy. Adipose-derived stem cells (6 × 10 6 ) were injected into the gastrocnemius muscle of mdx mice at various sites. Dystrophin expression was found in the muscle fibers. Phosphorylation levels of Akt, mammalian target of rapamycin (mTOR), eIF-4E binding protein 1 and S6 kinase 1 were increased, and the Akt/mTOR pathway was activated. Simultaneously, myogenin levels were increased, whereas cleaved caspase 3 and vimentin levels were decreased. Necrosis and fibrosis were reduced in the muscle fibers. These findings suggest that adipose-derived stem cells promote the regeneration and survival of muscle cells by inhibiting apoptosis and fibrosis, thereby alleviating muscle damage in muscular dystrophy.

Objective The clinical manifestation and electron transfer flavoprotein dehydrogenase (ETFDH) gene mutation of riboflavin-responsive lipid storage myopathy were analyzed for early diagnosis and treatment.mutation of riboflavin-responsive lipid storage myopathy were analyzed for early diagnosis and treatment. Methods Clinical material, ETFDH gene mutation and the motor function before and after vitamin B2 treatment in 3 patients from 2 predigrees were collected from August 2012 to March 2013 in our hospital. Results Case 1 was 16-year-old female. The chief complaint was difficulty of breathing and expectorating for over 3 years. Clinical symptoms included progressive respiratory muscle and proximal limb muscle weakness and worsen by fever, cardiac involvement, myopathic electromyography (EMG) changes and deposition of lipid droplets in muscle fiber by oil red O staining. Case 2 and Case 3 were brothers, the chief complaint of whom was fatigue after exercise for more than 1 year and 1 month, respectively. Clinical symptoms included significantly weakness of lower limbs and neck muscles after exercise and myopathic EMG changes. All 3 patients from two predigrees presented ETFDH gene mutation [c.250G > A (Ala84Thr) homozygous mutations and c.250G > A (Ala84Thr) and c.524G > A (Arg175His) compound heterozygous mutations, respectively]. They all had a dramatic response to vitamin B2 treatment with muscle strength and motor function recovering to normal. The symptoms of Case 1 were completely disappeared with vitamin B2 treatment for over 10 months, including respiratory muscle and proximal limb muscle weakness, and the motor function of her limbs returned to normal, characterized by completing over 10 squat-stand in 1 min. Case 2 could walk and run as ordinary people, raise his head without difficulty and play basketball about 2 h without fatigue after vitamin B2 treatment for over 2 months. Case 3 could participate in any kind of strenuous exercise without fatigue after vitamin B2 treatment for over 2 months. Conclusions Riboflavin-responsive lipid storage myopathy is mainly characterized by proximal limb and trunk muscle weakness and intolerance of movement, however, rare cases with first symptom of respiratory muscle weakness should also be concerned. In addition, it is a treatable genetic disease. The patients could be cured or significantly improved with vitamin B2 monotherapy. So vitamin B2 exploratory treatment should be given when the patients are suspected of riboflavin-responsive lipid storage myopathy. doi: 10.3969/j.issn.1672-6731.2014.06.004

In the title compound, {[Pb(sbc)(bpy)]·2H2O}n [bpy is 2,2′-bipyridine (C10H8N2) and sbc is the 2-sulfonatobenzoate dianion (C7H4O5S)], the PbII ion is bonded to four O atoms including carboxylate and sulfonate from three sbc dianions, and two N atoms from a chelating 2,2′-bipyridine ligand. The sbc ligand acts as a μ3-bridging ligand by one O atom of the sulfonate group and the two O atoms of the carboxylate. Of these two last O atoms, one builds up a dinuclear framework arranged around an inversion center whereas the second one links each dinuclear unit, forming a chain extending along the b axis. These polymeric chains are linked through O—H...O hydrogen bonds involving the water molecules, forming a layer parallel to (10overline{2}).

The development of connected and automated vehicle (CAV) techniques brings an upcoming revolution to traffic management. The control of CAVs in potential conflict areas such as on-ramps and intersections will be complex to traffic management when considering their deployment. There is still a lack of a general framework for dispatching CAVs in these bottlenecks, which is expected to ensure safety, traffic efficiency, and energy consumption in real time. This study aimed to fill the technique gap, and a comprehensive cooperative intelligent driving framework is put forward to study the problem, which can be used in both on-ramp and intersection scenarios. Based on a multi-objective evolutionary algorithm, CAVs are denoted as a sequence to be searched in solution space, while a multitask learning neural network with adaptive loss function is implemented for optimization target feedback to surrogate the simulation test procedure. The simulation results show that the proposed framework can get satisfying performance with low time and energy consumption. It can reduce time consumption by up to 16.51% for the on-ramp scenario and 9.8% for the intersection scenario, while reducing energy consumption by up to 16.39% and 11.39% for the two scenarios. Meanwhile, an analysis of computation time is carried out, illuminating the flexibility and controllability of the new strategy., Author(s): Xia Jiang [1]; Jian Zhang (corresponding author) [1,2]; Qing-yang Li [1]; Tian-yi Chen [3] 1. Introduction Connected and automated vehicles are considered to play an important role in improving [...]

In this paper, we used CALYPSO program which is conjuncted with DFT to investigate Li doped small-sized neutral Bn clusters. From ground-state and low energy structures, the properties and geometric significance of Li-doped boron clusters are greatly affected. Except for LiB9, which adds a B atom on preceding LiB8 boron wheel, the ground-state clusters of LiBn are formed by replacing the terminal boron atom of the Bn+1 clusters in the same size with a Li atom or by adding a Li atom to the Bn clusters. The transition point from 2 to 3D configuration of LiBn clusters appears at n = 5. The stability of LiBn clusters was analyzed by calculating the average binding energy, Gibbs free energy, first-order differential energy, second-order differential energy, HOMO–LUMO gap (the energy gap between the highest occupied and lowest unoccupied molecular orbital) and charge transfer. The results show that the LiB11 cluster with excellent symmetry and planar structure is the relative most stable structure. Molecular orbital and chemical bonding analysis indicated that the main reason for the stability of the LiB11 cluster is mainly due to the strong s-p bonding of B–B. [ABSTRACT FROM AUTHOR]

In this work, particle swarm optimization (CALYPSO) is combined with density functional theory (DFT) to perform a comprehensive structure search for the Bn0/−Rb2 (n = 1–12) clusters. The ground-state structures of the Bn0/−Rb2 (n = 1–12) clusters were determined based on the total energy of the obtained structures. It was also found that when the number of B atoms was low, the doped cluster geometry mainly behaved as planar or planar-like. The addition of doped Rb atoms distorts the boron clusters, with the doping position around the main body of boron. The stability analysis shows that the B8Rb2 cluster with a double pyramidal structure and a symmetry of D7h has excellent stability in the studied system. The energy gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital is 6.14 eV. Bonding analysis is performed using molecular orbitals and density of states, and the results show that strong communications between the two Rb atoms and the B-atom bulk dominate their significant stability, where mainly the p atom orbital of the Rb atoms interacts with the s and p atom orbitals of the B atoms. Furthermore, the bond level density and naturally adapted orbital analysis revealed that the formation of effective π-type naturally adapted orbitals between the doped Rb atoms and the B atoms, with a higher delocalization index, is one of the reasons for the higher cluster stability. [ABSTRACT FROM AUTHOR]

Tracing coupled ocean closure and intra-continental orogenic processes using tectonomagmatic thermal events is important for performing plate reconstructions. In this study, we collected geochronological data obtained from Jurassic–Early Cretaceous volcanic sequences in the Great Xing apos; an Range (GXR) and compared and merged the data to obtain a better understanding of the timing of volcanism in the GXR. Jurassic–Early Cretaceous volcanism, which is mainly represented by the Tamulangou, Manketouebo, and Manitu formations, are ubiquitous in the GXR and do not contain a magmatic hiatus. Thus, 'diachronous' volcanism did not occur in the GXR. The volcanic sequences in these formations are also slightly ambiguous and therefore cannot be used to determine the timing of volcanism. However, absolute ages and rock assemblages can provide better constraints on this timing. Combined with data from Jurassic–Early Cretaceous tectonomagmatic thermal events in Mongolia, Siberia, and NE China, we re-evaluated the influences of the Jurassic–Early Cretaceous closure of the Mongol–Okhotsk Ocean (MOO), as well as the subduction and rollback of the Izanagi Plate, at different times in the GXR. The GXR likely underwent flat-slab subduction during the Late Jurassic–early Cretaceous as the MOO closed in an irregular 'scissor-like' fashion (i.e. not in a progressive west to east manner). Large-scale lithospheric delamination likely led to a large pulse of magmatism and mineralisation in the GXR during the late Early Cretaceous. [ABSTRACT FROM AUTHOR]

Projects about magnesium-based doped of transition metal have constantly attracted much attention in cluster science, while the research of Co, Fe, Ni doped Mid-Sized Mg16 clusters has not been reported. Here, the geometric construction and electronic properties of neutral and negative Mg16X (X = Co, Fe, Ni) clusters were researched by unbiased CALYPSO structure search codes and subsequent DFT calculations at the B3PW91 level. The results show that Fe and Co atoms are more likely to replace the central bits of the caged Mg170/− cluster, but the excellent and stable configuration of the Mg170/− cluster is perfectly maintained. Simultaneously, the doping of Co and Fe can cause the cluster to produce the corresponding magnetic moment. The caged Mg16Co− clusters with a central Co atom have good binding energy, local charge transfer and HOMO–LUMO gap according to stability analysis, which indicates that Mg16Co− clusters has better relative stability. In addition, it is found that there is an intense interaction between Mg-3s, p and Co-3d AO (molecular orbitals) through the analysis of molecular orbitals and adaptive natural density partitioning (AdNDP), which may be the main reason for the high stability of Mg16Co− clusters. [ABSTRACT FROM AUTHOR]