New approaches to identification and characterization of tioconazole in raw material and in pharmaceutical dosage forms

Tioconazole(TCZ), a broad-spectrum antifungal agent, has significant activity against Candida albicans and other Candida species, and therefore, it is indicated for the topical treatment of superficial mycoses.The main goal of this work is to report an exhaustive identification and characterization procedure to improve and facilitate the online quality control and continuous process monitoring of TCZ in bulk material and loaded in two different dosage forms: ovules and nail lacquer. The methodologies were based on thermal(differential scanning calorimetry(DSC), melting point, and thermogravimetry(TG)),spectroscopic(ultraviolet(UV), Raman, near infrared(NIR), infrared spectroscopy coupled to attenuated total reflectance(FTIR-ATR), and nuclear magnetic resonance(NMR)), microscopic and X-ray diffraction(XRD). The TCZ bulk powder showed a high crystallinity, as observed by XRD, with a particles size distribution(3–95 mm) resolved by microscopic measurements. TCZ melting point(82.8 °C) and a degradation peak centered at 297.8 °C were obtained by DSC and DTG, respectively. An unambiguous structure elucidation of TCZ was obtained by mono-and two-dimensional1 H and13 C NMR spectral data analysis. The FTIR-ATR, Raman and NIR spectra of both the raw material and the commercial products were analyzed and their characteristic bands were tabulated. The best methods for TCZ identification in ovules were DSC, TG, XRD, NIR and Raman, while NIR and FTIR-ATR were the most appropriate techniques to analyze it in the nail lacquer. DSC, TG, DRX, Raman, FTIR-ATR and NIR spectroscopy are effective techniques to be used in online process analysis, because they do not require sample preparation, and they are considerably sensitive to analyze complex samples.

Hydration status,body composition,and anxiety status in aeronautical military personnel from Spain:a crosss-ectional study

Background: An adequate hydration status is critical to ensure efficiency during mental and physical activities.Our goal was to assess the hydration status of a Spanish group of aeronautical military men and to determine the association of hydration status with body composition and anxiety.Methods: A total of 188 men were evaluated through a validated hydration questionnaire, anthropometric and biochemical parameters, and an anxiety questionnaire. Based on these methods, the criteria of hydration were established.Results: Of the total sample, 81% met the hydration criteria(urine color = well hydrated, water balance ≥0 ml, and total water intake/weight ≥35 ml/kg), and 19% did not meet the hydration criteria(urine color = not sufficiently hydrated or dehydrated, water balance <0 ml, and total water intake/weight <35 ml/kg). Subjects not meeting the hydration criteria had lower urine pH, negative water balance, and lower water intake. The latter also had higher anxiety status(score=4 vs. 3, P=0.026), weight [(84.7±10.5) kg vs.(80.5±10.2) kg], body mass index [(26.3±3.1) kg/m;vs.(25.2±2.8) kg/m;], body fat [(22.3±5.6)% vs.(18.3±6.5)%], urine specific gravity, and urine color. Using a logistic binary regression model, hydration status was related significantly with the percentage of body fat(P=0.004), but no relation was found with age, comorbidities, or medications. Furthermore, total water intake/weight was positively correlated with percentage of body water(r=0.357, P=0.000) and negatively with body fat(kg)(r=–0.427, P=0.000), percentage of body fat(r=–0.405, P=0.000), and waist/hip ratio(r=–0.223, P=0.002). Based on a linear regression model, total water intake/weight was related significantly with percentage of body fat(P=0.001) and percentage of body water content(P=0.035). No relation was found, however, with waist/hip ratio, age, comorbidities, or medications.Conclusions: These findings all suggest a relationship between hydration status and body composition but also set the bases for future studies that relate hydration status and anxiety status. These results can be used to improve the hydration status and body composition of military personnel.

薄壁杆件屈曲模态分析的力特征约束有限条法

整体、畸变、局部等基本变形模式的划分是条理化开展薄壁杆件工程计算的必要手段。薄壁杆件的基本变形模式传统上基于简化应力-应变关系,采用变形、应变等几何特征进行定义,不利于因应复杂化应力-应变关系。提出一套完全基于力特征和正交完备性原则的基本模式定义。与广义梁理论和约束有限条法相比,提出的整体、畸变、局部3种基本变形模式关于刚度严格正交,且完整覆盖薄壁杆件全变形域。基于该定义实现了针对薄壁杆件有限条模型的屈曲模态分解和识别。算例表明,提出的基本模式定义和屈曲模态分析方法具有开、闭口和折、曲线形截面的一致适应能力,剪应变和横向伸缩的影响在基本屈曲模式中得到合理表达,曲线形截面薄壁构件具有与多边形截面薄壁构件一致的整体、畸变和局部屈曲机理。

Resistive field generation in intense proton beam interaction with solid targets

The Brown-Preston-Singleton(BPS)stopping power model is added to our previously developed hybrid code to model ion beam-plasma interaction.Hybrid simulations show that both resistive field and ion scattering effects are important for proton beam transport in a solid target,in which they compete with each other.When the target is not completely ionized,the self-generated resistive field effect dominates over the ion scattering effect.However,when the target is completely ionized,this situation is reversed.Moreover,it is found that Ohmic heating is important for higher current densities and materials with high resistivity.The energy fraction deposited as Ohmic heating can be as high as 20%-30%.Typical ion divergences with half-angles of about 5°-10°will modify the proton energy deposition substantially and should be taken into account.

Gene expression analysis of cytokines and MMPs in melatonin and rhBMP-2 enhanced bone remodeling

BACKGROUND In the medical and dental fields,there is a need for studies of new therapeutic approaches for the treatment of bone defects that cause extensive bone loss.Melatonin may be an important endogenous biological factor for bone remodeling,and growth factors may enhance the repair process.AIM To evaluate the gene expression of cytokines(IL-1β,IL-6,IL-10 and TNF-α),markers of osteoclastogenesis(RANK,RANKL and OPG)and MMPs(MMP-1,MMP-2,MMP-8 and MMP-13)from the treatment of melatonin associated with an osteogenic membrane and rhBMP-2 on the recovery of a bone injury.METHODS Sixty-four rats were used and divided into 9 experimental groups and were formed according to the treatment carried out in the region of the bone lesion,which varied between the combination of 1,10 and 100μmol/L of melatonin.Gene Expression analysis was performed using real time-PCR by reading the concentration of total RNA and reverse transcription.RESULTS There were differences between groups when compared with clot or scaffold control,and improvement with a higher concentration of melatonin or rhBMP-2.The combination melatonin(1μg)with 5μg of rhBMP-2,using the guided bone regeneration technique,demonstrated some effects,albeit mild,on bone repair of critical bone defects.CONCLUSION This indicates that the approach for administering these substances needs to be reassessed,with the goal of ensuring their direct application to the affected area.Therefore,future research must be carried out,seeking to produce materials with these ideal characteristics.

冷弯型钢受压构件几何缺陷研究综述

随着国家乡村振兴战略的实施,农房建设成为美丽乡村建设的重要内容。大力推广绿色装配式冷弯薄壁型钢结构体系,对我国美丽乡村建设及实现“碳达峰碳中和”目标均有助力,冷弯薄壁型钢结构具有自重轻、强度高、装配方便、绿色环保等优势。然而,冷弯型钢受压构件由于其轻质特性,初始几何缺陷对其稳定性影响极大,进而影响整体结构的承载能力,因此国内外学者均对冷弯型钢受压构件的初始几何缺陷进行了相关研究。通过综述缺陷测量技术、缺陷特征分类与分析、几何缺陷仿真及现有数值模拟方法、中美欧规范比较等方面,总结了国内外缺陷已有成果,对国内外多种初始几何缺陷进行了统计与分析,进而对冷弯型钢受压构件几何缺陷研究与随机缺陷分析方法、高精度仿真分析与缺陷下的构件的二阶分析时的承载力设计的发展方向提出了一些见解,希望为绿色装配式冷弯薄壁型钢结构体系的技术发展与设计方法提供一定参考。

Whole mount of adult ear skin as a model to study vascular malformations

Background:Genetic analysis in human patients has linked mutations in PIK3CA,the catalytic subunit of PI-3′Kinase,to sporadic incidences of vascular malformations.Methods:We have developed a mouse model with inducible and endothelial-specific expression of PIK3CA H1047R,resulting in the development of vascular malformations.Systemic induction of this mutation in adult mice results in rapid lethality,limiting our ability to track and study these lesions;therefore,we developed a topical and local induction protocol using the active metabolite of tamoxifen,4OH-T,on the ear skin of adults.Results:This approach allows us to successfully model the human disease in a mature and established vascular bed and track the development of vascular malformations.To validate the utility of this model,we applied a topical rapamycin ointment,as rapamycin is therapeutically beneficial to patients in clinical trials.We found that the induced ear lesions showed significant attenuation after treatment,which was easily quantified.Conclusions:These data collectively provide evidence of a new model to study vascular malformations in adult tissues,which should be particularly useful in environments lacking specialized small-animal imaging facilities.

工程教育认证背景下土木工程专业人才培养体系构建

从海南大学土木工程专业认证工作入手,结合工程教育专业认证背景,针对培养目标、毕业要求、实践教学体系、教学方法等多个环节进行深入研究与实践。同时,比较分析了美国纽约州立大学理工学院(SUNY Poly)与海南大学土木工程专业本科教育在专业设置、目标等方面的异同,体现了SUNY Poly计划的优点及其潜在优势,吸收转化其优良经验,科学构建以产出为导向,适应市场需求,具有鲜明区域特色的土木工程专业人才培养体系。

表达心脏SCN5A基因的人胚肾细胞钠电流特性及其对钠通道阻滞剂的反应性

目的利用人胚肾293细胞表达心脏钠通道SCN5A基因并研究其钠电流特性和对钠通道阻滞剂的反应性。方法野生型SCN5A基因和SCN1B基因共表达于人胚肾293细胞,应用全细胞膜片钳技术记录给药(氟卡尼与利多卡因)前后的钠电流。结果 SCN5A基因转染效率约为60%;测试电压为-40mV时记录到钠电流峰值大小约为-8nA;100μmol/L的氟卡尼轻度抑制钠电流,使钠电流峰值减少(21.1±4.6)%[(-435.8±30.5)pA/pF vs.(-343.9±27.1)pA/pF,P<0.01];氟卡尼使钠通道激活曲线和失活曲线均呈负向移动,改变的幅值分别是-6.08mV[(-51.88±1.20)mVvs.(-57.96±0.79)mV,P<0.05]和-9.08mV[(-94.12±0.13)mVvs.(-103.20±0.11)mV,P<0.05];1Hz和10Hz频率刺激时,氟卡尼使钠电流分别减少(64.5±10.7)%和(83.5±12.2)%(P<0.01);30μmol/L利多卡因使钠通道失活后快恢复时间常数和慢恢复时间常数分别延长2倍和3倍。结论表达心脏钠通道SCN5A基因的人胚肾293细胞模型可用于基因特异性的钠通道阻滞剂安全性与药效学筛查。

先天性长QT综合征的新进展

先天性长QT综合征(LQTS)是发病率在1/2 500左右的恶性遗传性心脏疾病。LQTS的典型心脏表现包括可导致心脏骤停和心脏猝死的晕厥发作,以及包括QT间期延长和T波异常在内的心电图异常。90年代中期,LQTS的治病基因被首次发现,至今已有13型被确认。致病基因主要是离子通道和转运相关蛋白。对于具有典型特征的患者,医生并无诊断困难。对于模棱两可的病例,需要参照特殊诊断标准,比如心电图,病史和家族史等等。此外,基因扫描正日益成为诊断过程的一部分。除非有明确的禁忌证,治疗上还是要首选β受体阻滞剂。若在接受足量β受体阻滞剂期间,还有1次以上的晕厥,需立即采取左侧交感神经切除术,并根据病人特征(年龄、性别、临床病史、24 h Holter在内的心电图特征、基因表型等)考虑安装埋藏式心脏转复除颤器。病人接受适当治疗后,一般预后较好。但是LQTS8(Timothy综合征)病人,携带KCNQ1突变的Jervel Lange-Nielsen综合征患者,以及伴有2∶1房室传导阻滞,病窦综合征或Brugada综合征的LQT3病患的预后极其不容乐观。

维拉帕米减少2型长 QT 综合征楔形心肌块模型跨室壁复极离散度并预防尖端扭转型室速

目的探讨维拉帕米治疗2型长QT综合征(LQT2)的作用机制。方法制备兔左心室楔形心肌块,稳定1 h后灌注E-4031 0.5μmol·L-1建立LQT2心肌块模型;同时按照分组分别灌注维拉帕米0.5,1.0和2.5μmol·L-1,30 min后开始采集数据,采集时间持续30 min。以2000 ms基础步长连续起搏(S1S1刺激),同步记录心内、外膜下心肌的跨膜动作电位和跨壁心电图,测量动作电位复极达90%的时程(APD90)、跨壁复极离散度(TDR)和心电图QT间期,并观察各组自发和程序刺激(S1S2刺激)诱发的早期后除极(EAD)和尖端扭转型室速(TdP)的发生率。结果灌注E-4031 0.5μmol·L-1后,左心室楔形心肌块心内、外膜下APD90和QT间期均显著延长(P<0.01),TDR显著增加(P<0.01),并观察到自发或程序刺激诱发的EAD及TdP发作。同时灌注维拉帕米0.5,1.0和2.5μmol·L-1,LQT2模型内、外膜下心肌APD90和QT间期呈浓度依赖性地缩短(P<0.01),TDR显著减小(P<0.01),自发或程序刺激诱发的EAD和TdP明显受到抑制。硝苯地平1.0μmol·L-1有类似作用,且强度更大。结论维拉帕米可通过缩小心肌TDR和抑制EAD减少LQT2患者TdP的发生。

Hepatic drug transporters and nuclear receptors:Regulation by therapeutic agents

The canalicular membrane represents the excretory pole of hepatocytes.Bile is an important route of elimination of potentially toxic endo-and xenobiotics(including drugs and toxins),mediated by the major canalicular transporters:multidrug resistance protein 1(MDR1, ABCB1),also known as P-glycoprotein,multidrug resistance-associated protein 2(MRP2,ABCC2),and the breast cancer resistance protein(BCRP,ABCG2).Their activities depend on regulation of expression and proper localization at the canalicular membrane,as regulated by transcriptional and post-transcriptional events,respectively.At transcriptional level,specific nuclear receptors(NR)s modulated by ligands,co-activators and co-repressors,mediate the physiological requirements of these transporters.This complex system is also responsible for alterations occurring in specific liver pathologies.We briefly describe the major ClassⅡNRs, pregnane X receptor(PXR)and constitutive androstane receptor(CAR),and their role in regulating expression of multidrug resistance proteins.Several therapeutic agents regulate the expression of relevant drug transporters through activation/inactivation of these NRs.We provide some representative examples of the action of therapeutic agents modulating liver drug transporters, which in addition,involve CAR or PXR as mediators.

Aquaporins:Their role in cholestatic liver disease

This review focuses on current knowledge on hepato-cyte aquaporins(AQPs)and their significance in bile formation and cholestasis.Canalicular bile secretion results from a combined interaction of several solute transporters and AQP water channels that facilitate water flow in response to the osmotic gradients created. During choleresis,hepatocytes rapidly increase their canalicular membrane water permeability by modulating the abundance of AQP8.The question was raised as to whether the opposite process,i.e.a decreased canalicular AQP8 expression would contribute to the development of cholestasis.Studies in several experimental models of cholestasis,such as extrahepatic obstructive cholestasis,estrogen-induced cholestasis, and sepsis-induced cholestasis demonstrated that the protein expression of hepatocyte AQP8 was impaired. In addition,biophysical studies in canalicular plasma membranes revealed decreased water permeability associated with AQP8 protein downregulation.The combined alteration in hepatocyte solute transporters and AQP8 would hamper the efficient coupling of osmotic gradients and canalicular water flow.Thus cholestasis may result from a mutual occurrence of impaired solute transport and decreased water permeability.

The Basic Principles of Kin Sociality and Eusociality: Human Evolution

The paper posits that kin sociality and eusociality are derived from the handicap-care principles based on the need-based care to the handicappers from the caregivers for the self-interest of the caregivers. In this paper, handicap is defined as the difficulty to survive and reproduce independently. Kin sociality is derived from the childhood handicap-care principle where the children are the handicapped children who receive the care from the kin caregivers in the inclusive kin group to survive. The caregiver gives care for its self-interest to reproduce its gene. The individual’s gene of kin sociality contains the handicapped childhood and the caregiving adulthood. Eusociality is derived from the adulthood handicap-care principle where responsible adults are the handicapped adults who give care and receive care at the same time in the interdependent eusocial group to survive and reproduce its gene. Queen bees reproduce, but must receive care from worker bees that work but must rely on queen bees to reproduce. A caregiver gives care for its self-interest to survive and reproduce its gene. The individual’s gene of eusociality contains the handicapped childhood-adulthood and the caregiving adulthood. The chronological sequence of the sociality evolution is individual sociality without handicap, kin sociality with handicapped childhood, and eusociality with handicapped adulthood. Eusociality in humans is derived from bipedalism and the mixed habitat. The chronological sequence of the eusocial human evolution is 1) the eusocial early hominins with bipedalism and the mixed habitat, 2) the eusocial early Homo species with bipedalism, the larger brain, and the open habitat, 3) the eusocial late Homo species with bipedalism, the largest brain, and the unstable habitat, and 4) extended eusocial Homo sapiens with bipedalism, the shrinking brain, omnipresent imagination, and the harsh habitat. The omnipresence of imagination in human culture converts eusociality into extended eusociality with both perception and omnipresent imagination.

强烈淬火:改善了硬度和残余应力(英文)

通过数值模拟和试验研究结果确定使用强烈淬火方法在表面形成最佳压应力,根据这些结果,提出了改善零件的热处理和设备的一些建议。除了探讨最大表面压应力的形成外,对使用可控淬透性钢的优点也进行了讨论。

Dynamic localization of hepatocellular transporters in health and disease

Vesicle-based traffi cking of hepatocellular transporters involves delivery of the newly-synthesized carriers from the rough endoplasmic reticulum to either the plasma membrane domain or to an endosomal,submembrane compartment,followed by exocytic targeting to the plasma membrane. Once delivered to the plasma membrane,the transporters usually undergo recycling between the plasma membrane and the endosomal compartment,which usually serves as a reservoir of pre-existing transporters available on demand. The balance between exocytic targeting and endocytic internalization from/to this recycling compartment is therefore a chief determinant of the overall capability of the liver epithelium to secrete bile and to detoxify endo and xenobiotics. Hence,it is a highly regulated process. Impaired regulation of this balance may lead to abnormal localization of these transporters,which results in bile secretory failure due to endocytic internalization of key transporters involved in bile formation. This occurs in several experimental models of hepatocellular cholestasis,and in most human cholestatic liver diseases. This review describes the molecular bases involved in the biology of the dynamic localization of hepatocellular transporters and its regulation,with a focus on the involvement of signaling pathways in this process. Their alterations in different experimental models of cholestasis and in human cholestatic liver disease are reviewed. In addition,the causes explaining the pathological condition (e.g. disorganization of actin or actin-transporter linkers) and the mediators involved (e.g. activation of cholestatic signaling transduction pathways) are also discussed. Finally,several experimental therapeutic approaches based upon the administration of compounds known to stimulate exocytic insertion of canalicular transporters (e.g. cAMP,tauroursodeoxycholate) are described.

Renal elimination of organic anions in cholestasis

The disposition of most drugs is highly dependent on specialized transporters. OAT1 and OAT3 are two organic anion transporters expressed in the basolateral membrane of renal proximal tubule cells, identified as contributors to xenobiotic and endogenous organic anion secretion. It is well known that cholestasis may cause renal damage. Impairment of kidney function produces modifications in the renal elimination of drugs. Recent studies have demonstrated that the renal abundance of OAT1 and OAT3 plays an important role in the renal elimination of organic anions in the presence of extrahepatic cholestasis. Time elapsed after obstructive cholestasis has an important impact on the regulation of both types of organic anion transporters. The renal expression of OAT1 and OAT3 should be taken into account in order to improve pharmacotherapeutic efficacy and to prevent drug toxicity during the onset of this hepatic disease.

The Eight Stages of Psychosocial Protective Development: Developmental Psychology

The proposed universal psychological mechanism for developmental psychology is the mental protective system whose different parts emerge and mature in the eight different stages of psychosocial protective development under different social interactions. The proposed eight stages of psychosocial protective development are childhood (infancy, toddlerhood, pre-juvenile age, and juvenile age), adolescence, early young adulthood, late young adulthood, early middle adulthood, late middle adulthood, early late adulthood, and late late adulthood. The mental protection system consists of four socialities (collectivistic, individualistic, interdependent, and generativity), three worldviews (territorial, competitive, and cooperative), and the mental immune system for four regulated and unregulated countermeasures (hyperactivity, phobia, comforter, and rationality) against adversities. During childhood, dependent children have collectivistic sociality under the protection of committed parents and territorial worldview with the boundary of family. Children start with the unregulated mental immune system without delayed gratification due to mental immaturity, and gradually acquire the regulated mental immune system with delayed gratification through mental maturity. Adolescents transit to adulthood. Independent adults have the regulated metal immune system, individualistic sociality with reciprocity, and competitive-cooperative worldviews without boundary. After the age of 50, older people as elder leaders-mentors develop generativity sociality to protect next generation. The paper shows that the mental protective system as the universal psychological mechanism for developmental psychology explains clearly psychosocial protective development, the human evolution, the Piaget’s cognitive development, the Erikson’s psychosocial (ego-social) development, the Confucius’ (educated person’s) six milestones of life, and parent-child relation in the Abrahamic religions (Judaism, Christianity, and Islam) and Confucianism.

Evaluation by ICP-MS of Essential, Nonessential and Toxic Elements in Brazilian Fish and Seafood Samples

Fish is considered one of the healthiest foods due to the high levels of several important cardioprotective compounds such as long chain omega-3 polyunsaturated fatty acids and vitamin E. However, due to widespread environmental pollution, high levels of contaminants may also be present in fish and seafood samples, which may counteract the beneficial effects of consumption of this food. With this in mind, the aims of this study were: 1) to examine both toxic and essential chemical elements in seafood and river and sea fish samples sold in different Brazilian regions by inductively coupled plasma mass spectrometer (ICP-MS);2) to estimate the daily intake of these chemical elements by Brazilians. The toxic elements Ba, Cd, Pb, Sr, V and Sb were found in higher concentrations in seafood than in either sea or river fish, while As concentrations were higher in both seafood and sea fish than in river fish. On the other hand, Hg levels were higher in river and sea fish. Concentrations of the essential chemical elements Co, Mn, Cu, Fe, Mg, Zn and Mo were significantly higher in seafood compared with both sorts of fish except for Se, whose levels were similar in seafood and sea fish. Daily intake of all chemical elements was estimated on the basis of a calculation of the amount of fish consumed by Brazilian households (mean fish and seafood consumption of 11.0 g/person/day). The amount of toxic element in fish and seafood did not represent a risk for the Brazilian people. Moreover, fish and seafood seem to be a good source of selenium.

Recursive Approximation of Complex Behaviours With IoT-Data Imperfections

This paper presents an approach to recursively estimate the simplest linear model that approximates the time-varying local behaviors from imperfect(noisy and incomplete) measurements in the internet of things(IoT) based distributed decision-making problems. We first show that the problem of finding the lowest order model for a multi-input single-output system is a cardinality(l0) optimization problem, known to be NP-hard.To solve the problem a simpler approach is proposed which uses the recently developed atomic norm concept and the modified Frank-Wolfe(mFW) algorithm is introduced. Further, the paper computes the minimum data-rate required for computing the models with imperfect measurements. The proposed approach is illustrated on a building heating, ventilation, and air-conditioning(HVAC) control system that aims at optimizing energy consumption in commercial buildings using IoT devices in a distributed manner. The HVAC control application requires recursive thermal dynamical model updates due to frequently changing conditions and non-linear dynamics. We show that the method proposed in this paper can approximate such complex dynamics on single-board computers interfaced to sensors using unreliable communication channels. Real-time experiments on HVAC systems and simulation studies are used to illustrate the proposed method.