Cocaine Induces Cytoskeletal Changes in Cardiac Myocytes: Implications for Cardiac Morphology

Cocaine is one of the most widely abused illicit drugs worldwide and has long been recognised as an agent of cardiac dysfunction in numerous cases of drug overdose. Cocaine has previously been shown to up-regulate cytoskeletal rearrangements and morphological changes in numerous tissues; however, previous literature observes such changes primarily in clinical case reports and addiction studies. An investigation into the fundamental cytoskeletal parameters of migration, adhesion and proliferation were studied to determine the cytoskeletal and cytotoxic basis of cocaine in cardiac cells. Treatment of cardiac myocytes with cocaine increased cell migration and adhesion (p < 0.05), with no effect on cell proliferation, except with higher doses eliciting (1–10 μg/mL) its diminution and increase in cell death. Cocaine downregulated phosphorylation of cofilin, decreased expression of adhesion modulators (integrin-β3) and increased expression of ezirin within three hours of 1 μg/mL treatments. These functional responses were associated with changes in cellular morphology, including alterations in membrane stability and a stellate-like phenotype with less compaction between cells. Higher dose treatments of cocaine (5–10 μg/mL) were associated with significant cardiomyocyte cell death (p < 0.05) and loss of cellular architecture. These results highlight the importance of cocaine in mediating cardiomyocyte function and cytotoxicity associated with the possible loss of intercellular contacts required to maintain normal cell viability, with implications for cardiotoxicity relating to hypertrophy and fibrogenesis.     

A Case of Double Standard: Sex Differences in Multiple Sclerosis Risk Factors

Multiple sclerosis is a complex, multifactorial, dysimmune disease prevalent in women. Its etiopathogenesis is extremely intricate, since each risk factor behaves as a variable that is interconnected with others. In order to understand these interactions, sex must be considered as a determining element, either in a protective or pathological sense, and not as one of many variables. In particular, sex seems to highly influence immune response at chromosomal, epigenetic, and hormonal levels. Environmental and genetic risk factors cannot be considered without sex, since sex-based immunological differences deeply affect disease onset, course, and prognosis. Understanding the mechanisms underlying sex-based differences is necessary in order to develop a more effective and personalized therapeutic approach.     

On the Enzymatic Formation of Metal Base Pairs with Thiolated and pKa-Perturbed Nucleotides

The formation of artificial metal base pairs is an alluring and versatile method for the functionalization of nucleic acids. Access to DNA functionalized with metal base pairs is granted mainly by solid-phase synthesis. An alternative, yet underexplored method, envisions the installation of metal base pairs through the polymerization of modified nucleoside triphosphates. Herein, we have explored the possibility of using thiolated and pK_a-perturbed nucleotides for the enzymatic construction of artificial metal base pairs. The thiolated nucleotides S2C, S6G, and S4T as well as the fluorinated analogue 5FU are readily incorporated opposite a templating S4T nucleotide through the guidance of metal cations. Multiple incorporation of the modified nucleotides along with polymerase bypass of the unnatural base pairs are also possible under certain conditions. The thiolated nucleotides S4T, S4T, S2C, and S6G were also shown to be compatible with the synthesis of modified, high molecular weight single-stranded (ss)DNA products through TdT-mediated tailing reactions. Thus, sulfur-substitution and pK_a perturbation represent alternative strategies for the design of modified nucleotides compatible with the enzymatic construction of metal base pairs.     

基于分支定界法的相控阵雷达事件调度算法

为解决相控阵雷达事件调度问题中调度成功率、时间偏移率与算法时效性三者之间的矛盾，本文提出一种基于分支定界法的调度算法；该算法首先在现有调度结果上调取所有可执行事件，即获得若干"节点"，多步递推后由多"层"节点形成若干条备选"分支"，扩大解空间范围，提高算法性能；然后通过"删减"操作删减掉收益较低分支，将解空间控制在一适当范围内，减小搜索盲目性，降低算法计算量.仿真实验表明，与基于综合优先级算法的调度结果相比，利用本文算法调度时调度成功率提升了52%；与基于时间指针算法的调度结果相比，本身算法时间偏移率降低了61%；与基于遗传算法的调度结果相比，本文算法调度耗时仅为前者1~2%.     

基于博弈分析的流域水资源配置

针对传统规划方法难以体现水资源配置过程中多种复杂因素的问题,基于博弈理论建立宏观调控和市场经济相结合的水资源配置动态博弈模型,求解其子博弈精炼纳什均衡下各博弈参与人的策略,并运用改进量子遗传算法求解该博弈模型。对A河流域水资源配置结果表明,在保证流域公共生态用水2.0×10~8 m~3的基础上,各用水子区自发约束自身的取水量,达到均衡时,社会总收益为11.27亿元,相比自由取水模型,社会总收益增加了0.95亿元,增幅为9.2%。     

How Far Are We from Prescribing Fasting as Anticancer Medicine?

(1) Background: the present review provides a comprehensive and up-to date overview of the potential exploitation of fasting as an anticancer strategy. The rationale for this concept is that fasting elicits a differential stress response in the setting of unfavorable conditions, empowering the survival of normal cells, while killing cancer cells. (2) Methods: the present narrative review presents the basic aspects of the hormonal, molecular, and cellular response to fasting, focusing on the interrelationship of fasting with oxidative stress. It also presents nonclinical and clinical evidence concerning the implementation of fasting as adjuvant to chemotherapy, highlighting current challenges and future perspectives. (3) Results: there is ample nonclinical evidence indicating that fasting can mitigate the toxicity of chemotherapy and/or increase the efficacy of chemotherapy. The relevant clinical research is encouraging, albeit still in its infancy. The path forward for implementing fasting in oncology is a personalized approach, entailing counteraction of current challenges, including: (i) patient selection; (ii) fasting patterns; (iii) timeline of fasting and refeeding; (iv) validation of biomarkers for assessment of fasting; and (v) establishment of protocols for patients’ monitoring. (4) Conclusion: prescribing fasting as anticancer medicine may not be far away if large randomized clinical trials consolidate its safety and efficacy.     

Assessing smoke toxicity of burning combustibles by four expressions for fractional effective dose

Toxicity of smoke generated in a fire is difficult to measure accurately. That is because gas sensors for measuring rapidly varying concentrations of toxic gases are not yet developed. Simple expressions are searched for quick measurement in assessing smoke toxicity practically. Four equations on calculating fractional effective dose (FED) related to toxic effluents were reported in the literature, each based on different assumptions. FED value was proposed to be calculated based on peak carbon monoxide concentration and peak carbon dioxide concentration, and transient carbon monoxide, carbon dioxide, and oxygen concentrations. The four values were compared in this article using literature data on toxic gases from different materials measured by (i) cone calorimeter; (ii) full-scale burning tests; and (iii) tunnel full-scale tests. Measured carbon monoxide, carbon dioxide, and oxygen concentrations by standard equipment of oxygen consumption calorimeters were used to calculate the four FED values. It is found that the values of FED based on peak carbon monoxide and carbon dioxide concentrations (denoted as FED₂) are similar to the average values of FED calculated from the updated equation in the literature using the oxygen consumption calorimeters. Putting the values of FED₂ in fire safety design guides is then recommended.     

Self-Assembly and Neurotoxicity of β-Amyloid (21–40) Peptide Fragment: The Regulatory Role of GxxxG Motifs

The three GxxxG repeating motifs from the C-terminal region of β-amyloid (Aβ) peptide play a significant role in regulating the aggregation kinetics of the peptide. Mutation of these glycine residues to leucine greatly accelerates the fibrillation process but generates a varied toxicity profile. Using an array of biophysical techniques, we demonstrated the uniqueness of the composite glycine residues in these structural repeats. We used solvent relaxation NMR spectroscopy to investigate the role played by the surrounding water molecules in determining the corresponding aggregation pathway. Notably, the conformational changes induced by Gly³³ and Gly³⁷ mutations result in significantly decreased toxicity in a neuronal cell line. Our results indicate that G³³xxxG³⁷ is the primary motif responsible for Aβ neurotoxicity, hence providing a direct structure–function correlation. Targeting this motif, therefore, can be a promising strategy to prevent neuronal cell death associated with Alzheimer's and other related diseases, such as type II diabetes and Parkinson's.     

煤化工烟道气毒性成分对Chlorella pyrenoidosa生长和细胞成分的影响

探究煤化工烟道气中毒性成分对微藻的影响是利用微藻固定煤化工烟道气CO₂实现减排的关键。本文利用不同浓度的NaHS、Na₂SO₃和NH₃·H₂O培养Chlorella pyrenoidosa（C. pyrenoidosa），以探究煤化工烟道气主要毒性成分H₂S、SO₂和NH₃气体水溶物的毒性。实验结果表明：NaHS、Na₂SO₃和NH₃·H₂O浓度分别低于1mmol/(L·d)、40mmol/(L·d)和7mmol/(L·d)时对C. pyrenoidosa生长无抑制作用，而且Na₂SO₃[＜40mmol/(L·d)]会显著促进 C. pyrenoidosa的生长；NaHS 添加4mmol/(L·d)时会在生长初期抑制C. pyrenoidosa的生长，NH₃·H₂O添加35mmol/(L·d)则会直接造成藻细胞的破碎死亡。与对照组相比，NaHS和Na₂SO₃浓度分别低于1mmol/(L·d)、10mmol/(L·d)时对C. pyrenoidosa的细胞成分无影响；NaHS添加4mmol/(L·d)使藻蛋白含量提高7.13%；Na₂SO₃添加40mmol/(L·d)使藻蛋白降低13.45%，总糖含量提高42.90%；NH₃·H₂O的添加会使藻蛋白含量降低，总糖含量提高。微藻生物质整体蛋白质含量较高，可作为蛋白饲料来源。研究结果表明，C. pyrenoidosa对煤化工烟道气中的主要毒性气体有较好的耐受性，利用煤化工烟道气培养微藻具有可行性。