Low Level of Cystic Fibrosis Transmembrane Conductance Regulator Is Associated with Human Sperm Autophagy and Vitality

Low sperm motility is one of the main causes of male infertility. Cystic fibrosis transmembrane conductance regulator (CFTR, an anion channel protein) is related to the progressive motility of sperm. CFTR disruptor CFTRinh-172 or forskolin (FSK) in this study were used to treat human sperm separately, and the rates of sperm autophagy and progressive motility, mitochondrial membrane potential (MMP) and ATP concentration, and the expression levels of related factors were detected to explore their relationship. It was showed that sperms treated with CFTRinh-172 or FSK reduced the levels of cAMP, CFTR and PKA, but increased sperm autophagy rate, expression levels of AMPK and LC3B. However, reactive oxygen species content had no significant difference. It was indicated that low level of CFTR performed with cAMP and its downstream effectors such as PKA and AMPK to regulate mitochondrial structure and function, leading to increased autophagy rate and reduced vitality of sperm.

Relationship between Authoritative Parenting Style and Preschool Children’s Emotion Regulation:A Moderated Mediation Model

An authoritative parenting style has been shown to promote children’s emotion regulation in European-American family studies.However,little is known about how sleep problems and the child’s sibling status in Chinese families affect this relationship.Based on family system theory,this study attempts to better understand the relationship between authoritative parenting style and emotion regulation.Mothers of preschool children in Chinese kindergartens completed questionnaires about their children’s sleep habits,their authoritative parenting styles,and children’s emotion regulation.A total of 531 children participated in this study.Results showed that authoritative parenting was positively associated with emotional regulation.Sleep problems mediated the effects of authoritative parenting style on emotion regulation.The child’s sibling status moderated the mediating effects of sleep problems in authoritative parenting and emotion regulation relationships.Specifically,the relationship between the authoritative parenting style and sleep problems was significant for only children,while birth order had no significant influence on the authoritative parenting style and sleep problems in two-child families.These findings suggest that a lowauthoritative parenting style predicts low emotion regulation through sleep problems,and this depends on the child’s sibling status,indicating that children without siblings may impair emotion regulation due to increased sleep problems.

Emerging role of cystic fibrosis transmembrane conductance regulator- an epithelial chloride channel in gastrointestinal cancers

Cystic fibrosis transmembrane conductance regulator(CFTR), a glycoprotein with 1480 amino acids, has been well established as a chloride channel mainly expressed in the epithelial cells of various tissues and organs such as lungs, sweat glands, gastrointestinal system, and reproductive organs. Although defective CFTR leads to cystic fibrosis, a common genetic disorder in the Caucasian population, there is accumulating evidence that suggests a novel role of CFTR in various cancers, especially in gastroenterological cancers, such as pancreatic cancer and colon cancer. In this review, we summarize the emerging findings that link CFTR with various cancers, with focus on the association between CFTR defects and gastrointestinal cancers as well as the underlying mechanisms. Further study of CFTR in cancer biology may help pave a new way for the diagnosis and treatment of gastrointestinal cancers.

Cystic fibrosis transmembrane conductance regulator chloride channel blockers:Pharmacological,biophysical and physiological relevance

Dysfunction of the cystic fibrosis transmembrane con-ductance regulator(CFTR) chloride channel causes cys-tic fibrosis, while inappropriate activity of this channeloccurs in secretory diarrhea and polycystic kidney dis-ease. Drugs that interact directly with CFTR are there-fore of interest in the treatment of a number of diseasestates. This review focuses on one class of small mol-ecules that interacts directly with CFTR, namely inhibi-tors that act by directly blocking chloride movementthrough the open channel pore. In theory such com-pounds could be of use in the treatment of diarrheaand polycystic kidney disease, however in practice allknown substances acting by this mechanism to inhibitCFTR function lack either the potency or specificity forin vivo use. Nevertheless, this theoretical pharmaco-logical usefulness set the scene for the developmentof more potent, specific CFTR inhibitors. Biophysically,open channel blockers have proven most useful as ex-perimental probes of the structure and function of theCFTR chloride channel pore. Most importantly, the useof these blockers has been fundamental in developing afunctional model of the pore that includes a wide innervestibule that uses positively charged amino acid sidechains to attract both permeant and blocking anionsfrom the cell cytoplasm. CFTR channels are also subjectto this kind of blocking action by endogenous anionspresent in the cell cytoplasm, and recently this blocking effect has been suggested to play a role in the physio-logical control of CFTR channel function, in particular as a novel mechanism linking CFTR function dynamically to the composition of epithelial cell secretions. It has also been suggested that future drugs could target this same pathway as a way of pharmacologically increasing CFTR activity in cystic fibrosis. Studying open channel blockers and their mechanisms of action has resulted in significant advances in our understanding of CFTR as a pharmacological target in disease states, of CFTR chan-nel structure and function, and of how CFTR activity is controlled by its local environment.

Ferroptosis mechanism and Alzheimer's disease

Regulated cell death is a genetically determined form of programmed cell death that commonly occurs during the development of living organisms.This process plays a crucial role in modulating homeostasis and is evolutionarily conserved across a diverse range of living organisms.Ferroptosis is a classic regulatory mode of cell death.Extensive studies of regulatory cell death in Alzheimer’s disease have yielded increasing evidence that fe rroptosis is closely related to the occurrence,development,and prognosis of Alzheimer’s disease.This review summarizes the molecular mechanisms of ferroptosis and recent research advances in the role of ferro ptosis in Alzheimer’s disease.Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for Alzheimer’s disease.

Chaotic Motion Analysis for a Coupled Magnetic-Flow-Mechanical Model of the Rectangular Conductive Thin Plate

The chaotic motion behavior of the rectangular conductive thin plate that is simply supported on four sides by airflow andmechanical external excitation in a magnetic field is studied.According to Kirchhoff’s thin plate theory,considering geometric nonlinearity and using the principle of virtualwork,the nonlinearmotion partial differential equation of the rectangular conductive thin plate is deduced.Using the separate variable method and Galerkin’s method,the system motion partial differential equation is converted into the general equation of the Duffing equation;the Hamilton system is introduced,and the Melnikov function is used to analyze the Hamilton system,and obtain the critical surface for the existence of chaos.The bifurcation diagram,phase portrait,time history response and Poincarémap of the vibration system are obtained by numerical simulation,and the correctness is demonstrated.The results showthatwhen the ratio of external excitation amplitude to damping coefficient is higher than the critical surface,the system will enter chaotic state.The chaotic motion of the rectangular conductive thin plate is affected by different magnetic field distributions and airflow.

Cystic fibrosis transmembrane conductance regulator prevents ischemia/reperfusion induced intestinal apoptosis via inhibiting PI3K/AKT/NF-κB pathway

BACKGROUND Intestinal ischemia/reperfusion(I/R)injury is a fatal syndrome that occurs under many clinical scenarios.The apoptosis of intestinal cells caused by ischemia can cause cell damage and provoke systemic dysfunction during reperfusion.However,the mechanism of I/R-induced apoptosis remains unclear.Cystic fibrosis transmembrane conductance regulator(CFTR)is a cAMP-activated chloride channel.Few researchers have paid attention to its role in intestinal I/R injury,or the relationship between CFTR and intestinal apoptosis induced by hypoxia/reoxygenation(H/R).AIM To investigate the effects of CFTR on I/R-induced intestinal apoptosis and its underlying molecular mechanisms.METHODS An intestinal I/R injury model was established in mice with superior mesenteric artery occlusion, and Caco2 cells were subjected to H/R for the simulation of I/R in vivo.RESULTSThe results suggested that CFTR overexpression significantly increased the Caco2 cell viability anddecreased cell apoptosis induced by the H/R. Interestingly, we found that the translocation of p65,an NF-κB member, from the cytoplasm to the nucleus after H/R treatment can be reversed by theoverexpression of CFTR, the NF-κB P65 would return from the nucleus to the cytoplasm asdetermined by immunostaining. We also discovered that CFTR inhibited cell apoptosis in theH/R-treated cells, and this effect was significantly curbed by the NF-κB activator BA, AKTinhibitor GSK690693 and the PI3K inhibitor LY294002. Moreover, we demonstrated that CFTRoverexpression could reverse the decreased PI3K/AKT expression induced by the I/R treatment invivo or H/R treatment in vitro.CONCLUSIONThe results of the present study indicate that the overexpression of CFTR protects Caco2 cells fromH/R-induced apoptosis;furthermore, it also inhibits H/R-induced apoptosis through thePI3K/AKT/NF-κB signaling pathway in H/R-treated Caco2 cells and intestinal tissues.

Expression of Cystic Fibrosis Transmembrane Conductance Regulator in Rat Ovary

The protein expression of cystic fibrosis transmembrane conductance regulator （CFTR）, a cAMP-activated Cl- channel, in ovarian stimulated premature female rat ovary during a cycle of follicle development and corpus luteum formation was investigated. Animals were injected with 10 U pregnant Mare＇s serum gonadotropin （PMSG） and subsequently 10 U hCG 48 h later. Time-dependent immunohistochemistry and Western blotting experiments were performed before and 24, 48, 72 h after hCG treatment. The immunohistochemistry revealed that administration of PMSG stimulated the CFTR expression in thecal cell layer and granulosa cell layer of mature follicles 48 h post injection, coincident with the PMSG-induced peak in follicular estradiol. However, the expression of CFTR in the granulose lutein cell layer and thecal lutein cell layer was time-dependently reduced following hCG injection, in accordance with the gradually increased progestogen level during luteum corpus formation. Western blotting analysis demonstrated that rat ovarian tissue expressed the special CFTR band at 170 kD. It is concluded that cAMP-dependent Cl- channels are involved in regulation of follicle development and luteum formation.

Cystic fibrosis transmembrane conductance regulator functional evaluations in a G542X+/-IVS8Tn:T7/9 patient with acute recurrent pancreatitis

BACKGROUND Acute recurrent pancreatitis(ARP)is characterized by episodes of acute pancreatitis in an otherwise normal gland.When no cause of ARP is identifiable,the diagnosis of"idiopathic"ARP is given.Mutations in the cystic fibrosis transmembrane conductance regulator(CFTR)gene increase the risk of ARP by 3-to 4-times compared to the general population,while cystic fibrosis(CF)patients present with a 40-to 80-times higher risk of developing pancreatitis.CASE SUMMARY In non-classical CF or CFTR-related disorders,CFTR functional tests can help to ensure a proper diagnosis.We applied an individualized combination of standardized and new CFTR functional bioassays for a patient referred to the Verona CF Center for evaluation after several episodes of acute pancreatitis.The CFTR genotype was G542X+/-with IVS8Tn:T7/9 polymorphism.The sweat(Cl-)values were borderline.Intestinal current measurements were performed according to the European Cystic Fibrosis Society Standardized Operating Procedure.Recent nasal surgery for deviated septum did not allow for nasal potential difference measurements.Lung function and sputum cultures were normal;azoospermia was excluded.Pancreas divisum was excluded by imaging but hypoplasia of the left hepatic lobe was detected.Innovative tests applied in this case include sweat rate measurement by image analysis,CFTR function in monocytes evaluated using a membrane potential-sensitive fluorescent probe,and the intestinal organoids forskolin-induced swelling assay.CONCLUSION Combination of innovative CFTR functional assays might support a controversial diagnosis when CFTR-related disorders and/or non-classical CF are suspected.

Two memory associated genes regulated by amyloid precursor protein intracellular domain Novel insights into the pathogenesis of learning and memory impairment in Alzheimer's disease

In this study, we employed chromatin immunoprecipitation, a useful method for studying the locations of transcription factors bound to specific DNA regions in specific cells, to investigate amyloid precursor protein intracellular domain binding sites in chromatin DNA from hippocampal neurons of rats, and to screen out five putative genes associated with the learning and memory functions. The promoter regions of the calcium/calmodulin-dependent protein kinase II alpha and glutamate receptor-2 genes were amplified by PCR from DNA products immunoprecipitated by amyloid precursor protein intracellular domain. An electrophoretic mobility shift assay and western blot analysis suggested that the promoter regions of these two genes associated with learning and memory were bound by amyloid precursor protein intracellular domain （in complex form）. Our experimental findings indicate that the amyloid precursor protein intracellular domain is involved in the transcriptional regulation of learning- and memory-associated genes in hippocampal neurons. These data may provide new insights into the molecular mechanism underlying the symptoms of progressive memory loss in Alzheimer＇s disease.

Tetramethylpyrazine stimulates cystic fibrosis transmembrane conductance regulator-mediated anion secretion in distal colon of rodents

AIM: To investigate the effect of tetramethylpyrazine (TMP), an active compound from Ligustiun Wollichii Franchat, on electrolyte transport across the distal colon of rodents and the mechanism involved.METHODS: The short-circuit current (ISC) technique in conjunction with pharmacological agents and specific inhibitors were used in analyzing the electrolyte transport across the distal colon of rodents. The underlying cellular signaling mechanism was investigated by radioimmunoassay analysis (RIA) and a special mouse model of cystic fibrosis.RESULTS: TMP stimulated a concentration-dependent rise in ISC, which was dependent on both Cl- and HCO3-, and inhibited by apical application of diphenylamine-2,2'-dicarboxylic acid (DPC) and glibenclamide, but resistant to 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid disodium salt hydrate (DIDS). Removal of Na+ from basolateral solution almost completely abolished the ISC response to TMP, but it was insensitive to apical Na+ replacement or apical Na+channel blocker, amiloride. Pretreatment of colonic mucosa with BAPTA-AM, a membrane-permeable selective Ca2+chelator, did not significantly alter the TMP-induced ISC. No additive effect of forskolin and 3-isobutyl-1-methylxanthine (IBMX) was observed on the TMP-induced ISc, but it was significantly reduced by a protein kinase A inhibitor, H89.RIA results showed that TMP (1 mmol/L) elicited a significant increase in cellular cAMP production, which was similar to that elicited by the adenylate cyclase activator, forskolin (10 μmol/L). The TMP-elicited ISC as well as forskolin- or IBMX-induced ISC were abolished in mice with homozygous mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) presenting defective CFTR functions and secretions.CONCLUSION: TMP may stimulate cAMP-dependent and CFTR-mediated Cl- and HCO3- secretion. This may have implications in the future development of alternative treatment for constipation.

Creatively conducting macro-level regulation in cotton industry

According to the report delivered at the 19th CPC National Congress,we adhere to the direction of socialist market economic reform and respect the decisive role of market in resource allocation while giving full play to the role of the government.We should optimize industrial policy and carry out

S型异质结MoSi_(2)N_(4)/GeC电子及光学特性的第一性原理研究

采用第一性原理计算方法研究了MoSi_(2)N_(4)/GeC异质结,对其进行结构、电子及光学特性的计算,并探究施加不同双轴应变和垂直电场对异质结能带结构及光吸收特性的影响,研究表明:MoSi_(2)N_(4)/GeC异质结是一种带隙为1.25 eV的间接带隙半导体,具有由GeC层指向MoSi_(2)N_(4)层的内建电场.此外,其光生载流子转移机制符合S型异质结机理,从而提高了光催化水分解的氧化还原电位,使其满足pH=0—14范围内的光催化水分解要求.双轴应变下,带隙随压缩应变的增加而先增大再减小,且在紫外区域的光吸收性能随压缩应变的增加而增强.带隙随拉伸应变的增大而减小,且可见光区域的光吸收性能较压缩应变时增强.垂直电场下,带隙随正电场的的增加而增大,随负电场的增大而减小.综上,MoSi_(2)N_(4)/GeC异质结可以作为一种高效的光催化材料应用于光电器件及光催化等领域.

Dimensional regulation in gigantic molybdenum blue wheels featuring{(W)Mo5}motifs for enhanced proton conductivity

Dimensional regulation in polyoxometalates is an effective strategy during the design and synthesis of polyoxometalates-based high proton conductors,but it is not available to date.Herein,the precise regulation of dimensionality has been realized in an unprecedented gigantic molybdenum blue wheel family featuring pentagonal{(W)Mo5}motifs through optimizing the molar ratio of Mo/W,including[Gd_(2)Mo_(124)W_(14)O_(422)(H_(2)O)62]38-(0D-{Mo_(124)W_(14)},1),[Mo_(126)W_(14)O441(H_(2)O)51]^(70-)(1D-{Mo_(126)W_(14)}n,2),and[Mo_(124)W_(14)O_(430)(H_(2)O)50]60-(2D-{Mo_(124)W_(14)}n,3).Such important{(W)Mo5}structural motif brings new reactivity into gigantic Mo blue wheels.There are different numbers and sites of{Mo2}defects in each wheel-shaped monomer in 1-3,which leads to the monomers of 2 and 3 to form 1D and 2D architectures via Mo-O-Mo covalent bonds driven by{Mo2}-mediated H_(2)O ligands substitution process,respectively,thus achieving the controllable dimensional regulation.As expected,the proton conductivity of 3 is 10 times higher than that of 1 and 1.7 times higher than that of 2.The continuous proton hopping sites in 2D network are responsible for the enhanced proton conductivity with lower activation energy.This study highlights that this dimensional regulation approach remains great potential in preparing polyoxometalates-based high proton conductive materials.

Conductivity reconstruction algorithms and numerical simulations for magneto–acousto–electrical tomography with piston transducer in scan mode

Conductivities tomography with the interactions of magnetic field, electrical field, and ultrasound field is presented in this paper. We utilize a beam of ultrasound in scanning mode instead of the traditional ultrasound field generated by point source. Many formulae for the reconstruction of conductivities are derived from the voltage signals detected by two electrodes arranged somewhere on tissue＇s surface. In a forward problem, the numerical solutions of ultrasound fields generated by the piston transducer are calculated using the angular spectrum method and its Green＇s function is designed approximately in far fields. In an inverse problems, the magneto-acousto-electrical voltage signals are proved to satisfy the wave equations if the voltage signals are extended to the whole region from the boundary locations of transducers. Thus the time-reversal method is applied to reconstructing the curl of the reciprocal current density. In addition, a least square iteration method of recovering conductivities from reciprocal current densities is discussed.

Gα_s signaling controls intramembranous ossification during cranial bone development by regulating both Hedgehog and Wnt/β-catenin signaling

How osteoblast cells are induced is a central question for understanding skeletal formation. Abnormal osteoblast differentiation leads to a broad range of devastating craniofacial diseases. Here we have investigated intramembranous ossification during cranial bone development in mouse models of skeletal genetic diseases that exhibit craniofacial bone defects. The GNAS gene encodes Gαs that transduces GPCR signaling. GNAS activation or loss-of-function mutations in humans cause fibrous dysplasia(FD) or progressive osseous heteroplasia(POH) that shows craniofacial hyperostosis or craniosynostosis, respectively. We find here that, while Hh ligand-dependent Hh signaling is essential for endochondral ossification, it is dispensable for intramembranous ossification, where Gαsregulates Hh signaling in a ligand-independent manner. We further show that Gαscontrols intramembranous ossification by regulating both Hh and Wnt/β-catenin signaling. In addition, Gαsactivation in the developing cranial bone leads to reduced ossification but increased cartilage presence due to reduced cartilage dissolution, not cell fate switch. Small molecule inhibitors of Hh and Wnt signaling can effectively ameliorate cranial bone phenotypes in mice caused by loss or gain of Gnas function mutations, respectively. Our work shows that studies of genetic diseases provide invaluable insights in both pathological bone defects and normal bone development, understanding both leads to better diagnosis and therapeutic treatment of bone diseases.

Long-term acupuncture treatment has a multitargeting regulation on multiple brain regions in rats with Alzheimer＇s disease：a positron emission tomography study

The acute effect of acupuncture on Alzheimer＇s disease,i.e.,on brain activation during treatment,has been reported.However,the effect of long-term acupuncture on brain activation in Alzheimer＇s disease is unclear.Therefore,in this study,we performed long-term needling at Zusanli（ST36）or a sham point（1.5 mm lateral to ST36）in a rat Alzheimer＇s disease model,for 30 minutes,once per day,for 30 days.The rats underwent 18F-fluorodeoxyglucose positron emission tomography scanning.Positron emission tomography images were processed with SPM2.The brain areas activated after needling at ST36 included the left hippocampus,the left orbital cortex,the left infralimbic cortex,the left olfactory cortex,the left cerebellum and the left pons.In the sham-point group,the activated regions were similar to those in the ST36 group.However,the ST36 group showed greater activation in the cerebellum and pons than the sham-point group.These findings suggest that long-term acupuncture treatment has targeted regulatory effects on multiple brain regions in rats with Alzheimer＇s disease.

Advances in molecular regulation of goat lipid metabolism and FAS structure and function regulation

Goat milk is widely recognized for its nutritional value.Fatty acid synthase(FAS)is the crucial enzyme of fatty acid de novo synthesis.It plays an important role in the formation of goat milk fat.In this paper,we first introduced the molecular regulation process of goat milk fat metabolism based on the structure research of FAS.Secondly,we reviewed some key factors in FAS transcription and post-transcriptional regulation of the goat mammary gland and preliminarily constructed the expression network of the goat mammary gland FAS gene.The purpose of this paper is to systematically introduce the role of FAS in goat milk fat metabolism and to provide a reference for future studies on the mechanism of goat milk fat metabolism.

Researches into the Proton Conductivity of Molybdovanadophosphoric Acids with Wells－Dawson Structure

Five kinds of molybdovanadophosphoric acids H_7[P_2Mo_(17)VO_(62)],H_8[P_2Mo_(16)·V_2O_(62)],H_9 [P_2Mo_(15)V_3O_(62)],H_8[P_2Mo_(14)V_4O_(61)(H_2O)]and H_9[P_2Mo_(13)V_5O_(61)(H_2O)]have been synthesized.Their protop conductivities(C) have been measured.The effects of three main factors (frequency,hydration numbers,temperature)on the conductivity have been investigated.In some degree,heteropoly compounds with different structures give a different conductivity.

MBF2转录调控小菜蛾谷胱甘肽S-转移酶代谢氯虫苯甲酰胺的功能

【目的】探究转录调控因子MBF2(multiprotein bridging factor 2)调控小菜蛾(Plutella xylostella)体内谷胱甘肽S-转移酶(glutathione S-transferase,GST)的功能,及其在小菜蛾抗氯虫苯甲酰胺中的作用,为阐明小菜蛾对氯虫苯甲酰胺的解毒代谢机制提供理论依据。【方法】采用浸叶法测定敏感(SS)、广东连州(LZ)、云南通海(TH)3个小菜蛾种群对氯虫苯甲酰胺的抗性水平,酶动力学法测定3个种群的GST活性;使用实时荧光定量PCR(RT-qPCR)分析MBF2在不同抗性种群小菜蛾中的表达差异;采用氯虫苯甲酰胺LC50诱导12 h,分析其对小菜蛾MBF2的诱导表达作用;应用RNA干扰(RNA interference,RNAi)技术研究MBF2对GST基因的调控作用,并测定沉默MBF2后小菜蛾的GST活性;结合沉默后小菜蛾对药剂的敏感性变化,验证MBF2在小菜蛾抗氯虫苯甲酰胺中的作用。【结果】两个抗性种群(TH和LZ)相较SS种群分别达到了中抗及高抗的水平,TH和LZ抗性倍数分别为54.27和289.58;TH和LZ小菜蛾种群体内GST活性均显著高于SS种群;与SS种群相比,MBF2在抗性种群小菜蛾体内显著上调表达,在中抗和高抗种群中的表达量分别为敏感种群4.6和9.4倍。小菜蛾短期暴露于LC50浓度氯虫苯甲酰胺中,敏感、中抗及高抗种群均在8 h内MBF2表达量显著上调,最高表达量升至对照的10倍。沉默MBF224 h,小菜蛾9个GST基因表达量显著降低,其中GSTZ1及GSTU1的下调量均达90%以上;处理组(ds MBF2)GST活性相较于阴性对照(ds GFP)降低57.76%;75 mg·L^(-1)氯虫苯甲酰胺处理后,处理组较对照组死亡率提升23.34%。【结论】MBF2可能通过调控GST的转录表达,提高小菜蛾对氯虫苯甲酰胺的代谢能力,从而参与小菜蛾对氯虫苯甲酰胺的解毒作用。研究结果可为小菜蛾抗药性机理的深入解析及新型药剂的研发提供依据。