Poly (ADP-ribose): A double-edged sword governing cancer cell survival and death

Poly(ADP-ribose)(PAR),a polymer of ADP-ribose,is synthesized by PAR po-lymerase and is crucial for the survival of cancer cells due to its vital functions in DNA repair and post-translational modifications.Beyond its supportive role,PAR also triggers cancer cell death by excessive accumulation of PAR leading to an energy crisis and parthanatos.This phenomenon underscores the potential of targeting PAR regulation as a novel anticancer strategy,and the rationale would present an engaging topic in the field of anticancer research.Therefore,this editorial provides an overview of the mechanisms determining cancer cell fate,emphasizing the central role of PAR.It further introduces promising methods for modulating PAR concentrations that may pave the way for innovative anticancer therapies.

Low testing rates and high BRCA prevalence: Poly (ADP-ribose) polymerase inhibitor use in Middle East BRCA/homologous recombination deficiency-positive cancer patients

BACKGROUND Poly(ADP-ribose)polymerase inhibitors(PARPis)are approved as first-line therapies for breast cancer gene(BRCA)-positive,human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer.They are also effective for new and recurrent ovarian cancers that are BRCA-or homologous recombination deficiency(HRD)-positive.However,data on these mutations and PARPi use in the Middle East are limited.AIM To assess BRCA/HRD prevalence and PARPi use in patients in the Middle East with breast/ovarian cancer.METHODS This was a single-center retrospective study of 57 of 472 breast cancer patients tested for BRCA mutations,and 25 of 65 ovarian cancer patients tested for HRD.These adult patients participated in at least four visits to the oncology service at our center between August 2021 and May 2023.Data were summarized using descriptive statistics and compared using counts and percentages.Response to treatment was assessed using Response Evaluation Criteria in Solid Tumors criteria.RESULTS Among the 472 breast cancer patients,12.1%underwent BRCA testing,and 38.5%of 65 ovarian cancer patients received HRD testing.Pathogenic mutations were found in 25.6%of the tested patients:26.3%breast cancers had germline BRCA(gBRCA)mutations and 24.0%ovarian cancers showed HRD.Notably,40.0%of gBRCA-positive breast cancers and 66.0%of HRD-positive ovarian cancers were Middle Eastern and Asian patients,respectively.PARPi treatment was used in 5(33.3%)gBRCA-positive breast cancer patients as first-line therapy(n=1;7-months progression-free),for maintenance(n=2;>15-months progression-free),or at later stages due to compliance issues(n=2).Four patients(66.6%)with HRD-positive ovarian cancer received PARPi and all remained progression-free.CONCLUSION Lower testing rates but higher BRCA mutations in breast cancer were found.Ethnicity reflected United Arab Emirates demographics,with breast cancer in Middle Eastern and ovarian cancer in Asian patients.

Inhibition of CD38/Cyclic ADP-ribose Pathway Protects Rats against Ropivacaine-induced Convulsion

Background： The CD38/cyclic ADP-ribose （cADPR） pathway plays a role in various central nervous system diseases and in morphine tolerance, but its role in local anesthetic intoxication is unknown. The aim of this study was to determine the role of the CD38/cADPR pathway in ropivacaine-induced convulsion. Methods： Forty male Sprague-Dawley rats were randomly divided into five groups （n = 8 per group）： sham group, ropivacaine group, ropivacaine＋8-Br-cADPR （5 nmol） group, ropivacaine＋8-Br-cADPR （10 nmol） group, and ropivacaine＋8-Br-cADPR （20 nmol） group （no rats died）. Rats were intracerebroventricularly injected with normal saline or 8-Br-cADPR 30 min before receiving an intraperitoneal injection of ropivacaine. Electroencephalography and convulsion behavior scores were recorded. The hippocampus was harvested from each group and subjected to nicotinamide adenine dinucleotide and cADPR assays, Western blotting analysis, and malondialdehyde （MDA） and superoxide dismutase （SOD） assays. Results： Intraperitoneal injection of ropivacaine （33.8 mg/kg） induced convulsions in rats. CD38 and cADPR levels increased significantly following ropivacaine-induced convulsion （P = 0.031 and 0.020, respectively, compared with the sham group）. Intraventricular injection of 8-Br-cADPR （5, 10, and 20 nmol） significantly prolonged convulsion latency （P = 0.037, 0.034, and 0.000, respectively）, reduced convulsion duration （P = 0.005, 0.005, and 0.005, respectively）, and reduced convulsion behavior scores （P = 0.015, 0.015, and 0.000, respectively）. Intraventricular injection of 8-Br-cADPR （10 nmol） also increased the B-cell lymphoma-2 （Bcl-2）/Bcl-2-associated X protein ratio （P = 0.044） and reduced cleaved Caspase 3/Caspase 3 ratio, inducible nitric oxide synthase, MDAand SOD levels （P = 0.014, 0.044, 0.001, and 0.010, respectively） compared with the ropivacaine group. Conclusions： The CD38/cADPR pathway is activated in ropivacaine-induced convulsion. Inhibiting this pathway alleviates ropivacaine-induced convulsion and protects the brain from apoptosis and oxidative stress.

Structure-activity relationship of cyclic ADP-ribose, an update

Cyclic ADP-ribose (cADPR) is a universal Ca2+ mobilizing second messenger in many different cell types and organisms. cADPR activates Ca2+ release from endo/sarcoplasmic reticulum via ryanodine receptors. In addition, Ca2+ entry secondary to Ca2+ depletion is at least one of the mechanisms in which cADPR triggers Ca2+ inflow, too. Analogues of cADPR have been prepared by chemical and chemo-enzymatic routes. Most of the analogues were analyzed for biological activity in intact or permeabilized Jurkat T cells (a human T-lymphoma cell line). As a systematic approach, analogues were grouped according to alterations in the base, the northern ribose, the southern ribose, the pyrophosphate backbone, or in complex modifications, comprising more than one part of the molecule. Biological activity of the analogues is reviewed, with special emphasis on Jurkat T cells.

Damage evolution of rock-encased-backfill structure under stepwise cyclic triaxial loading

Rock-encased-backfill(RB)structures are common in underground mining,for example in the cut-andfill and stoping methods.To understand the effects of cyclic excavation and blasting activities on the damage of these RB structures,a series of triaxial stepwise-increasing-amplitude cyclic loading experiments was conducted with cylindrical RB specimens(rock on outside,backfill on inside)with different volume fractions of rock(VF=0.48,0.61,0.73,and 0.84),confining pressures(0,6,9,and 12 MPa),and cyclic loading rates(200,300,400,and 500 N/s).The damage evolution and meso-crack formation during the cyclic tests were analyzed with results from stress-strain hysteresis loops,acoustic emission events,and post-failure X-ray 3D fracture morphology.The results showed significant differences between cyclic and monotonic loadings of RB specimens,particularly with regard to the generation of shear microcracks,the development of stress memory and strain hardening,and the contact forces and associated friction that develops along the rock-backfill interface.One important finding is that as a function of the number of cycles,the elastic strain increases linearly and the dissipated energy increases exponentially.Also,compared with monotonic loading,the cyclic strain hardening characteristics are more sensitive to rising confining pressures during the initial compaction stage.Another finding is that compared with monotonic loading,more shear microcracks are generated during every reloading stage,but these microcracks tend to be dispersed and lessen the likelihood of large shear fracture formation.The transition from elastic to plastic behavior varies depending on the parameters of each test(confinement,volume fraction,and cyclic rate),and an interesting finding was that the transformation to plastic behavior is significantly lower under the conditions of 0.73 rock volume fraction,400 N/s cyclic loading rate,and 9 MPa confinement.All the findings have important practical implications on the ability of backfill to support underground excavations.

Liquefaction susceptibility and deformation characteristics of saturated coral sandy soils subjected to cyclic loadings-a critical review

Coral sandy soils widely exist in coral island reefs and seashores in tropical and subtropical regions.Due to the unique marine depositional environment of coral sandy soils,the engineering characteristics and responses of these soils subjected to monotonic and cyclic loadings have been a subject of intense interest among the geotechnical and earthquake engineering communities.This paper critically reviews the progress of experimental investigations on the undrained behavior of coral sandy soils under monotonic and cyclic loadings over the last three decades.The focus of coverage includes the contractive-dilative behavior,the pattern of excess pore-water pressure(EPWP)generation and the liquefaction mechanism and liquefaction resistance,the small-strain shear modulus and strain-dependent shear modulus and damping,the cyclic softening feature,and the anisotropic characteristics of undrained responses of saturated coral sandy soils.In particular,the advances made in the past decades are reviewed from the following aspects:(1)the characterization of factors that impact the mechanism and patterns of EPWP build-up;(2)the identification of liquefaction triggering in terms of the apparent viscosity and the average flow coefficient;(3)the establishment of the invariable form of strain-based,stress-based,or energy-based EPWP ratio formulas and the unique relationship between the new proxy of liquefaction resistance and the number of cycles required to reach liquefaction;(4)the establishment of the invariable form of the predictive formulas of small strain modulus and strain-dependent shear modulus;and(5)the investigation on the effects of stress-induced anisotropy on liquefaction susceptibility and dynamic deformation characteristics.Insights gained through the critical review of these advances in the past decades offer a perspective for future research to further resolve the fundamental issues concerning the liquefaction mechanism and responses of coral sandy sites subjected to cyclic loadings associated with seismic events in marine environments.

Enhancing capacitive deionization performance and cyclic stability of nitrogen-doped activated carbon by the electro-oxidation of anode materials

Electrode materials with high desalination capacity and long-term cyclic stability are the focus of capacitive deionization(CDI) community. Understanding the causes of performance decay in traditional carbons is crucial to design a high-performance material. Based on this, here, nitrogen-doped activated carbon(NAC) was prepared by pyrolyzing the blend of activated carbon powder(ACP) and melamine for the positive electrode of asymmetric CDI. By comparing the indicators changes such as conductivity, salt adsorption capacity, pH, and charge efficiency of the symmetrical ACP-ACP device to the asymmetric ACP-NAC device under different CDI cycles, as well as the changes of the electrochemical properties of anode and cathode materials after long-term operation, the reasons for the decline of the stability of the CDI performance were revealed. It was found that the carboxyl functional groups generated by the electro-oxidation of anode carbon materials make the anode zero-charge potential(E_(pzc)) shift positively,which results in the uneven distribution of potential windows of CDI units and affects the adsorption capacity. Furthermore, by understanding the electron density on C atoms surrounding the N atoms, we attribute the increased cyclic stability to the enhanced negativity of the charge of carbon atoms adjacent to quaternary-N and pyridinic-oxide-N.

Experimental study of the damage characteristics of rocks containing non-penetrating cracks under cyclic loading

The damage evolution process of non-penetrating cracks often causes some unexpected engineering disasters.Gypsum specimens containing non-penetrating crack(s)are used to study the damage evolution and characteristics under cyclic loading.The results show that under cyclic loading,the relationship between the number of non-penetrating crack(s)and the characteristic parameters(cyclic number,peak stress,peak strain,failure stress,and failure strain)of the pre-cracked specimens can be represented by a decreasing linear function.The damage evolution equation is fitted by calibrating the accumulative plastic strain for each cycle,and the damage constitutive equation is proposed by the concept of effective stress.Additionally,non-penetrating cracks are more likely to cause uneven stress distribution,damage accumulation,and local failure of specimen.The local failure can change the stress distribution and relieve the inhibition of non-penetrating crack extension and eventually cause a dramatic destruction of the specimen.Therefore,the evolution process caused by non-penetrating cracks can be regarded as one of the important reasons for inducing rockburst.These results are expected to improve the understanding of the process of spalling formation and rockburst and can be used to analyze the stability of rocks or rock structures.

Mechanical responses of anchoring structure under triaxial cyclic loading

Dynamic load on anchoring structures(AS)within deep roadways can result in cumulative damage and failure.This study develops an experimental device designed to test AS under triaxial loads.The device enables the investigation of the mechanical response,failure mode,instability assessment criteria,and anchorage effect of AS subjected to combined cyclic dynamic-static triaxial stress paths.The results show that the peak bearing strength is positively correlated with the anchoring matrix strength,anchorage length,and edgewise compressive strength.The bearing capacity decreases significantly when the anchorage direction is severely inclined.The free face failure modes are typically transverse cracking,concave fracturing,V-shaped slipping and detachment,and spallation detachment.Besides,when the anchoring matrix strength and the anchorage length decrease while the edgewise compressive strength,loading rate,and anchorage inclination angle increase,the failure intensity rises.Instability is determined by a negative tangent modulus of the displacement-strength curve or the continued deformation increase against the general downward trend.Under cyclic loads,the driving force that breaks the rock mass along the normal vector and the rigidity of the AS are the two factors that determine roadway stability.Finally,a control measure for surrounding rock stability is proposed to reduce the internal driving force via a pressure relief method and improve the rigidity of the AS by full-length anchorage and grouting modification.

Effect of NaCl Concentration on the Cumulative Strain and Pore Distribution of Clay under Cyclic Loading

Clay,as the most common soil used for foundationfill,is widely used in various infrastructure projects.The phy-sical and mechanical properties of clay are influenced by the pore solution environment.This study uses a GDS static/dynamic triaxial apparatus and nuclear magnetic resonance experiments to investigate the effects of cyclic loading on clay foundations.Moreover,the development of cumulative strain in clay is analyzed,and afitting model for cumulative plastic strain is introduced by considering factors such as NaCl solution concentration,con-solidation stress ratio,and cycle number.In particular,the effects of the NaCl solution concentration and con-solidation stress ratio on the pore distribution of the test samples before and after cyclic loading are examined,and the relationship between microscopic pore size and macroscopic cumulative strain is obtained accordingly.Our results show that as the consolidation stress ratio grows,an increasing number of large pores in the soil samples are transformed into small pores.As the NaCl solution concentration becomes higher,the number of small pores gradually decreases,while the number of large pores remains unchanged.Cyclic loading causes the disappearance of the large pores in the samples,and the average pore size before cyclic loading is posi-tively correlated with the axial cumulative strain after cyclic loading.The cumulative strain produced by the soil under cyclic loading is inversely proportional to the NaCl solution concentration and consolidation stress ratio.

The Performance of Small Diameter Aluminum Light Support Structures Containing Handholes under Cyclic Fatigue

Aluminum light poles play a pivotal role in modern infrastructure, ensuring proper illumination along highways and in populated areas during nighttime. These poles typically feature handholes near their bases, providing access to electrical wiring for installation and maintenance. While essential for functionality, these handholes introduce a vulnerability to the overall structure, making them a potential failure point. Although prior research and analyses on aluminum light poles have been conducted, the behavior of smaller diameter poles containing handholes remains unexplored. Recognizing this need, a research team at the University of Akron undertook a comprehensive experimental program involving aluminum light poles with handholes containing welded inserts in order to gain a better understanding of their fatigue life, mechanical behavior, and failure mechanisms. The research involved testing seven large-scale aluminum light poles each 8-inch diameter, with two separate handholes. These handholes included a reinforcement that was welded to the poles. Finite Element Analysis (FEA), statistical analysis, and comparison analysis with their large counterparts (10-inch diameter) were used to augment the experimental results. The results revealed two distinct failure modes: progressive crack propagation leading to ultimate failure, and rupture of the pole near the weld initiation/termination site around the handhole. The comparison analysis indicated that the 8-inch diameter specimens exhibited an average fatigue life exceeding that of their 10-inch counterparts by an average of 30.7%. The experimental results were plotted alongside the fatigue detail classifications outlined in the Aluminum Design Manual (ADM), enhancing understanding of the fatigue detail category of the respective poles/handholes.

Cyclic ADP-ribose and NAADP:fraternal twin messengers for calcium signaling

The concept advanced by Berridge and colleagues that intracellular Ca2+-stores can be mobilized in an agonist-dependent and messenger(IP3)-mediated manner has put Ca 2+-mobilization at the center stage of signal transduction mechanisms.During the late 1980s,we showed that Ca2+-stores can be mobilized by two other messengers unrelated to inositol trisphosphate(IP 3) and identified them as cyclic ADP-ribose(cADPR),a novel cyclic nucleotide from NAD,and nicotinic acid adenine dinucleotide phosphate(NAADP),a linear metabolite of NADP.Their messenger functions have now been documented in a wide range of systems spanning three biological kingdoms.Accumulated evidence indicates that the target of cADPR is the ryanodine receptor in the sarco/endoplasmic reticulum,while that of NAADP is the two pore channel in endolysosomes. As cADPR and NAADP are structurally and functionally distinct,it is remarkable that they are synthesized by the same enzyme.They are thus fraternal twin messengers.We first identified the Aplysia ADP-ribosyl cyclase as one such enzyme and,through homology,found its mammalian homolog,CD38.Gene knockout in mice confirms the important roles of CD38 in diverse physiological functions from insulin secretion,susceptibility to bacterial infection,to social behavior of mice through modulating neuronal oxytocin secretion.We have elucidated the catalytic mechanisms of the Aplysia cyclase and CD38 to atomic resolution by crystallography and site-directed mutagenesis.This article gives a historical account of the cADPR/NAADP/CD38-signaling pathway and describes current efforts in elucidating the structure and function of its components.

Poly(ADP-ribose) polymerase inhibition reveals a potential mechanism to promote neuroprotection and treat neuropathic pain

Neuropathic pain is triggered by the lesions to peripheral nerves which alter their structure and function. Neuroprotective approaches that jimit the pathological changes and improve the behavioral outcome have been well explained in different experimental models of neuropathy but translation of such strategies to clinics has been disappointing. Experimental evidences revealed the role of free radicals, especially per- oxynitrite after the nerve injury. They provoke oxidative DNA damage and consequent over-activation of the poly（ADP-ribose） polymerase （PARP） upregulates pro-inflammatory pathways, causing bioenergetic crisis and neuronal death. Along with these changes, it causes mitochondrial dysfunction leading to neu- ronal apoptosis. In related preclinical studies agents that neutralize the free radicals and pharmacological inhibitors of PARP have shown benefits in treating experimental neuropathy. This article reviews the in- volvement of PARP over-activation in trauma induced neuropathy and therapeutic significance of PARP inhibitors in the experimental neuropathy and neuropathic pain.

Multiple facets of poly(ADP-ribose) polymerase-1 in neurological diseases

The highly conserved abundant nuclear protein poly （ADP-ribose） polymerase-1 （PARP-1） is activated by DNA damage. PARP-1 activation is associated in DNA repair, cell death and inflammation. Since oxidative stress induced robust DNA damage and wide spread inflamma- tory responses are common pathologies of various CNS diseases, the attention towards PARP-1 as a therapeutic target has been amplifying. This review highlights the multiple roles of PARP- 1 in neurological diseases and po- tential of PARP- 1 inhibitors to enter clinical translation.

Inhibition of poly(ADP-Ribose)polymerase:A promising strategy targeting pancreatic cancer with BRCAness phenotype

The use of chemotherapeutic regimens for the treatment of pancreatic cancer is still limited because pancreatic cancer is usually diagnosed at an advanced stage as a refractory disease in which symptoms are difficult to recognize in the early stages.Furthermore,at advanced stages,there are important challenges to achieve clinical benefit and symptom resolution,even with the use of an expanded spectrum of anticancer drugs.Recently,a point of reduced susceptibility to conventional chemotherapies by breast cancer susceptibility gene(BRCA)mutations led to a new perspective for overcoming the resistance of pancreatic cancer within the framework of increased genome instability.Poly(ADP-Ribose)polymerase(PARP)-1 is an enzyme that can regulate intrinsic functions,such as response to DNA damage.Therefore,in an environment where germline mutations in BRCAs(BRCAness)inhibit homologous recombination in DNA damage,resulting in a lack of DNA damage response,a key role of PARP-1 for the adaptation of the genome instability could be further emphasized.Here,we summarized the key functional role of PARP-1 in genomic instability of pancreatic cancer with the BRCAness phenotype and listed clinical applications and outcomes of PARP-1 inhibitors to highlight the importance of targeting PARP-1 activity.

Hydraulic and volume change behaviors of compacted highly expansive soil under cyclic wetting and drying

The wide engineered application of compacted expansive soils necessitates understanding their behavior under field conditions.The results of this study demonstrate how seasonal climatic variation and stress and boundary conditions individually or collectively influence the hydraulic and volume change behavior of compacted highly expansive soils.The cyclic wetting and drying(CWD)process was applied for two boundary conditions,i.e.constant stress(CS)and constant volume(CV),and for a wide range of axial stress states.The adopted CWD process affected the hydraulic and volume change behaviors of expansive soils,with the first cycle of wetting and drying being the most effective.The CWD process under CS conditions resulted in shrinkage accumulation and reduction in saturated hydraulic conductivity(k sat).On the other hand,CWD under CV conditions caused a reduction of swell pressure while has almost no impact on k sat.An elastic response to CWD was achieved after the third cycle for saturated hydraulic conductivity(k sat),the third to fourth cycle for the volume change potential under the CV conditions,and the fourth to fifth cycle for the volume change potential under the CS conditions.Finally,both swell pressure(s s)and saturated hydraulic conductivity(k sat)are not fundamental parameters of the expansive soil but rather depend on stress,boundary and wetting conditions.

Poly(ADP-ribose) polymerase-1 gene polymorphism in various Chinese nationalities

Poly （ADP-ribose） polymerase-1 （PARP-1） can exacerbate ischemic brain injury and lessen ischemic neuronal death, which may be associated with PARP-1 polymorphisms. The present study investigated human PARP-1 gene polymorphisms in various Chinese nationalities, the results of which could potentially help in the treatment and prevention of neurologic diseases. Genetic polymorphisms of seven exons in the PARP-1 gene, in 898 Chinese Han, Buyi, Shui, Miao, and Zhuang subjects, were investigated by PCR-single-strand conformation polymorphism. A single-strand conformation polymorphism variant in exons 12, 13, 16, and 17 of the PARP-1 gene was identified in 148 people, with two stationary bands showing three degenerative single strands. Results showed that the PARP-1 gene polymorphisms exist in various nationalities, and may act as a biomarker for susceptibility to disease.

Influence of volume compression on the unloading deformation behavior of red sandstone under damage-controlled cyclic triaxial loading

A reasonable evaluation of unloading deformation characteristics is of great significance for the effective analysis of deformation and stability of surrounding rocks after underground excavation.In this study,the damage-controlled cyclic triaxial loading tests were conducted to investigate the pore compaction mechanism and its influences on the unloading deformation behavior of red sandstone,including Young’s modulus,Poisson’s ratio,volumetric strain,and irreversible strain.The experimental results show that the increases of volumetric and irreversible strains of rocks can be attributed to the compaction mechanism,which almost dominates the entire pre-peak deformation process.The unloading deformation consists of the reversible linear and nonlinear strains,and the irreversible strain under the influence of the porous grain structure.The pre-peak Young’s modulus tends to increase and then decrease due to the influence of the unloading irreversible strain.However,it hardly changes with the increasing volumetric strain compaction under the influence of reversible nonlinear strain.Instead,the initial unloading tangent modulus is highly related to the volumetric strain,and clearly reflects the compaction state of red sandstone.Furthermore,both the reversible nonlinear and irreversible unloading deformations are independent of confining pressure.This study is beneficial for the theoretical modeling and prediction of cyclic unloading deformation behavior of red sandstone.

Mechanical response and microscopic damage mechanism of pre-flawed sandstone subjected to monotonic and multilevel cyclic loading:A laboratory-scale investigation

This study aims to investigate the mechanical response and acoustic emission(AE)characteristic of pre-flawed sandstone under both monotonic and multilevel constant-amplitude cyclic loads.Specifically,we explored how coplanar flaw angle and load type impact the strength and deformation behavior and microscopic damage mechanism.Results indicated that being fluctuated before rising with increasing fissure angle under monotonic loading,the peak strength of the specimen first increased slowly and then steeply under cyclic loading.The effect of multilevel cyclic loading on the mechanical parameters was more significant.For a single fatigue stage,the specimen underwent greater deformation in early cycles,which subsequently stabilized.Similar variation pattern was also reflected by AE count/energy/b-value.Crack behaviors were dominated by the fissure angle and load type and medium-scale crack accounted for 74.83%–86.44%of total crack.Compared with monotonic loading,crack distribution of specimen under cyclic loading was more complicated.Meanwhile,a simple model was proposed to describe the damage evolution of sandstone under cyclic loading.Finally,SEM images revealed that the microstructures at the fracture were mainly composed of intergranular fracture,and percentage of transgranular fracture jumped under cyclic loading due to the rapid release of elastic energy caused by high loading rate.

Cyclic adenosine monophosphate-elevating agents inhibit amyloid-beta internalization and neurotoxicity:their action in Alzheimer's disease prevention

Recently,we have found that various intracellular cyclic adenosine monophosphate(cAMP)-e leva ting agents,both pharmacological(dibutyryl-cAMP,forskolin,and rolipram)and physiological(pituitary adenylate cyclase-activating polypeptide),decrease cell-surface levels of 67-kDa laminin receptor(67LR)and cellular prion protein(PrP~C).