ATP-Independent Initiation during Cap-Independent Translation of m6A-Modified mRNA

The methylation of adenosine in the N⁶ position (m⁶A) is a widely used modification of eukaryotic mRNAs. Its importance for the regulation of mRNA translation was put forward recently, essentially due to the ability of methylated mRNA to be translated in conditions of inhibited cap-dependent translation initiation, e.g., under stress. However, the peculiarities of translation initiation on m⁶A-modified mRNAs are not fully known. In this study, we used toeprinting and translation in a cell-free system to confirm that m⁶A-modified mRNAs can be translated in conditions of suppressed cap-dependent translation. We show for the first time that m⁶A-modified mRNAs display not only decreased elongation, but also a lower efficiency of translation initiation. Additionally, we report relative resistance of m⁶A-mRNA translation initiation in the absence of ATP and inhibited eIF4A activity. Our novel findings indicate that the scanning of m⁶A-modified leader sequences is performed by a noncanonical mechanism.     

Interleukin 6 and Aneurysmal Subarachnoid Hemorrhage. A Narrative Review

Interleukin 6 (IL-6) is a prominent proinflammatory cytokine. Neuroinflammation in general, and IL-6 signaling in particular, appear to play a major role in the pathobiology and pathophysiology of aneurysm formation and aneurysmal subarachnoid hemorrhage (SAH). Most importantly, elevated IL-6 CSF (rather than serum) levels appear to correlate with delayed cerebral ischemia (DCI, “vasospasm”) and secondary (“vasospastic”) infarctions. IL-6 CSF levels may also reflect other forms of injury to the brain following SAH, i.e., early brain damage and septic complications of SAH and aneurysm treatment. This would explain why many researchers have found an association between IL-6 levels and patient outcomes. These findings clearly suggest CSF IL-6 as a candidate biomarker in SAH patients. However, at this point, discrepant findings in variable study settings, as well as timing and other issues, e.g., defining proper clinical endpoints (i.e., secondary clinical deterioration vs. angiographic vasospasm vs. secondary vasospastic infarct) do not allow for its routine use. It is also tempting to speculate about potential therapeutic measures targeting elevated IL-6 CSF levels and neuroinflammation in SAH patients. Corticosteroids and anti-platelet drugs are indeed used in many SAH cases (not necessarily with the intention to interfere with detrimental inflammatory signaling), however, no convincing benefit has been demonstrated yet. The lack of a robust clinical perspective against the background of a relatively large body of data linking IL-6 and neuroinflammation with the pathophysiology of SAH is somewhat disappointing. One underlying reason might be that most relevant studies only report correlative data. The specific molecular pathways behind elevated IL-6 levels in SAH patients and their various interactions still remain to be delineated. We are optimistic that future research in this field will result in a better understanding of the role of neuroinflammation in the pathophysiology of SAH, which in turn, will translate into the identification of suitable biomarkers and even potential therapeutic targets.     

Design,Synthesis, and Biological Evaluation of Novel 6H-Benzo[c]chromen-6-one Derivatives as Potential Phosphodiesterase II Inhibitors

Urolithins (hydroxylated 6H-benzo[c]chromen-6-ones) are the main bioavailable metabolites of ellagic acid (EA), which was shown to be a cognitive enhancer in the treatment of neurodegenerative diseases. As part of this research, a series of alkoxylated 6H-benzo[c]chromen-6-one derivatives were designed and synthesized. Furthermore, their biological activities were evaluated as potential PDE2 inhibitors, and the alkoxylated 6H-benzo[c]chromen-6-one derivative 1f was found to have the optimal inhibitory potential (IC₅₀: 3.67 ± 0.47 μM). It also exhibited comparable activity in comparison to that of BAY 60-7550 in vitro cell level studies.     

Molecular Mechanisms of the Deregulation of Muscle Contraction Induced by the R90P Mutation in Tpm3.12 and the Weakening of This Effect by BDM and W7

Point mutations in the genes encoding the skeletal muscle isoforms of tropomyosin can cause a range of muscle diseases. The amino acid substitution of Arg for Pro residue in the 90th position (R90P) in γ-tropomyosin (Tpm3.12) is associated with congenital fiber type disproportion and muscle weakness. The molecular mechanisms underlying muscle dysfunction in this disease remain unclear. Here, we observed that this mutation causes an abnormally high Ca²⁺-sensitivity of myofilaments in vitro and in muscle fibers. To determine the critical conformational changes that myosin, actin, and tropomyosin undergo during the ATPase cycle and the alterations in these changes caused by R90P replacement in Tpm3.12, we used polarized fluorimetry. It was shown that the R90P mutation inhibits the ability of tropomyosin to shift towards the outer domains of actin, which is accompanied by the almost complete depression of troponin’s ability to switch actin monomers off and to reduce the amount of the myosin heads weakly bound to F-actin at a low Ca²⁺. These changes in the behavior of tropomyosin and the troponin–tropomyosin complex, as well as in the balance of strongly and weakly bound myosin heads in the ATPase cycle may underlie the occurrence of both abnormally high Ca²⁺-sensitivity and muscle weakness. BDM, an inhibitor of myosin ATPase activity, and W7, a troponin C antagonist, restore the ability of tropomyosin for Ca²⁺-dependent movement and the ability of the troponin–tropomyosin complex to switch actin monomers off, demonstrating a weakening of the damaging effect of the R90P mutation on muscle contractility.     

耐腐蚀摩托艇ADC12-0.5La铝合金微观组织及制备

为改善ADC12铝合金的耐腐蚀性能,通过超声熔铸法制备ADC12-0.5La铝合金,并利用光学显微镜、扫描电镜、能谱分析仪、硬度计、浸泡腐蚀试验和电化学工作站研究了T6热处理和稀土La改性对ADC12铝合金的微观组织、硬度和耐腐蚀性能的影响。结果表明,T6态ADC12-0.5La铝合金微观组织明显细化,α-Al尺寸减小,形貌变圆整,共晶Si相和AlFeMnSi相细化为短棒状。相比于ADC12铝合金,T6态ADC12-0.5La铝合金硬度达到117.7HV,提高了26.8%,腐蚀电流密度降低了10.7%,腐蚀电位上升了64.4%,腐蚀速率降低了54.4%,腐蚀表面平坦且光滑,表现为较轻微的晶间腐蚀。T6态ADC12-0.5La铝合金提高了腐蚀电位,Al-La-Cu稀土相阻碍了电子移动,铝合金的耐腐蚀性能得到大幅度提高。     

机械合金化Al—12Ti—6Nb合金的热稳定性

将机械合金化（ＭＡ）Ａｌ－１２Ｔｉ－６Ｎｂ合金在５５０℃下空气中长时间暴露后，用光学显微镜和电子探针对其组织结构变化进行了观察与分析，测定了维氏硬度。结果表明，ＭＡＡｌ－１２Ｔｉ－６Ｎｂ表现出良好的热稳定性，在５５０℃下暴露２００ｈ后，Ａｌ３Ｔｉ中的亚稳的α－Ｔｉ核才全部转变为Ａｌ３Ｔｉ，Ａｌ３Ｔｉ颗粒随之粗化，饼状的Ａｌ３Ｔｉ变成椭球体；Ａｌ３Ｔｉ颗粒的粗化是通过Ｔｉ，Ａｌ原子扩散所控制的α－Ｔ     

Stress relaxation behavior of Ti-6Al-4V alloy

1　INTRODUCTIONTi 6Al 4VisoneofthemostimportantTial loys[1,2 ] .Butthisalloyhasbadformabilityforitshighelasticresilience .Therefore ,hotsizingisimpor tant[36 ] .Asthebaseofhotsizing ,thestudyofstressrelaxationhasimportanttheoreticalvalueandpracticalsignificance .Ontheotherhand ,Ti 6Al 4Visusedasfastenermaterialssometimes .Whenthefastenersworkatthetemperaturehigherthanroomtemperature ,stressrelaxationmayresultsinacci dents .Sohowtopreventthestressrelaxationisveryimportant[7] .Uptonow ,…     

钛合金中亚晶的电子显微镜观察

用透射电子显微镜观察了TC6钛合金在高温退火过程中形成的亚晶(Subgrain)。合金经850℃,920℃退火后炉冷和空冷,在初生α相晶粒内形成亚晶,多为成簇分布的狭长形状,亚晶的数量随退火后冷却速度的增加而减少。亚晶界(Subgrain boundary)是由位错构成的,亚晶的形成是多边化(polygonization)的结果。     

Study On the Tribological Behavior of the Arc-added Glow Discharge Plasma Non-hydrogen Carburization On Titanium Alloy Surfaces

This paper introduces a new titanium alloys surface strengthening treatment by using the arc-added glow discharge plasmas non-hydrogen carburization technique. High purity and high strength graphite is selected as cooling cathode arc source for supplying carbon atoms and particle, which migrate to the titanium alloy(Ti6Al4V) surface and form modified layer. Thus, the hydrogen embrittlement is avoided while the tfibological behavior of the titanium alloy surface is improved in the respects of anti-friction and anti-wear ability.The tribological behavior of the modified layer under dry sliding against SAE52100 steel was evaluated on a ball-on-disc test rig. The results showed that the modified layer obtained a thickness of 30μm at 980℃, 30minutes. The microhardness of the Ti6Al4V alloy surface attained 936 HV, which was much larger than that of the Ti6AI4V alloy. The Ti6AI4V alloy was characterized by adhesion wear and scuffing under dry sliding against the steel, while the surface modified layer experienced much abated adhesion wear and scuffing under the same testing condition. This could be attributed to the carbon dement with different modalities exists in the modified layer.The modified layer showed good friction-reducing and fair anti-wear ability in dry sliding against the steel. Using the SEM,XRD and XPS, the phase structure and morphology of the carburization modified layer was analyzed.