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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 [...]

For problems caused by installation of overhead manned equipment at upper part of district rise and driving modes of motor and gear box, a scheme was proposed, namely adopting overhead manned equipment driven by hydraulic pressure and installing the equipment at lower part of district rise, and models of driving devices including hydraulic motor, hydraulic oil pump and driving motor and ultima overhead manned equipment were determined by analyzing and calculating technique parameters of overhead manned equipment. The application showed the selected overhead manned equipment driven by hydraulic pressure can realize functions of continuously variable transmission, soft starting and soft stopping with no interference signal and harmonic and low fault ratio, and the mode of installing the equipment at lower part of district rise is convenient for maintain and improves security of personnel transportation.

A setting calculation method of microcomputer protection for mine-used main transformer was introduced with an example of a main transformer of a large-scale coal mine. Firstly, the short-circuit current was accurately calculated by normalized value method and verified by MVA method, then setting values of differential protection and standby protection were calculated separately. The practical running result showed that the setting method can cut off fault point sensitively, reliably, quickly and choicely.