Contributions to the knowledge of Antarctodon sobrali(Mammalia:Astrapotheria)from the Eocene of Antarctica

The Astrapotheria constitutes one of the five orders of extinct South American native ungulates,with a fossil record that also extends to the Eocene of the Antarctic Peninsula.In contrast to the abundant specimens known for litoptern Sparnotheriodontidae and metatherians,astrapotheres are represented by scant remains assigned to the endemic Antarctodon sobrali and indeterminate astrapotheres,restricted to levels 35C_(u0)and 35n of the Cucullaea I Allomember of the La Meseta Formation.The discovery of alower molar assignable to this species in the Eocene levels of Seymour(Marambio)Island,enables a revision of the diagnosis and the homologies of the dental characters used to describe this taxon.A reanalysis of its phylogenetic relationships reveals the nearly simultaneous presence of basal astrapotheres in the early Eocene of Itaboraí(Brazil),Patagonia,and West Antarctica.These taxa are characterized by lacking dental specializations usually associated with more abrasive diets like terminal forms of Uruguaytheriinae and Astrapotheriinae.Antarctodon appears to have thrived on the Antarctic continent during the Early Eocene Climatic Optimum within the paleoclimatic context of a hot-house world.Unlike present conditions in Antarctica where no terrestrial mammals inhabit,the early Eocene climate was characterized by warmer temperatures and a biologically diverse environment rich in primary producers,dominated by Nothofagus forests,encompassing both deciduous and evergreen forests,which supported a diverse assemblage of continental vertebrates.

A new look at the first dinosaur discovered in Antarctica:reappraisal of Antarctopelta oliveroi(Ankylosauria:Parankylosauria)

The first dinosaur discovered in the Antarctic continent was the ankylosaur Antarctopelta oliveroi in the 1980s.Nevertheless,since then several hypotheses of phylogenetical relationships have been proposed because these have been depended on how the skeletal remains have been interpreted.The main obstacle for clarifying its phylogenetic position is that many portions of the skeleton remain unknown,in addition to the presence of unknown characters in typical ankylosaurs.Considered an ankylosaurid,nodosaurid,or even a chimaera,a recent proposal based on mostly complete material of a new ankylosaur from Chilean Patagonia provided support for a novel phylogenetic hypothesis:Antarctopelta and other southern ankylosaurs are an early branching clade,the Parankylosauria,whose origin probably dates to the Late Jurassic.In the light of this new view,a redescription of the available skeletal remains is provided together with a new reconstruction of the first Antarctic dinosaur known to the science community.

MCRO-PUF:A Novel Modified Crossover RO-PUF with an Ultra-Expanded CRP Space

With the expanding use of the Internet of Things(IoT)devices and the connection of humans and devices to the Internet,the need to provide security in this field is constantly growing.The conventional cryptographic solutions need the IoT device to store secret keys in its non-volatile memory(NVM)leading the system to be vulnerable to physical attacks.In addition,they are not appropriate for IoT applications due to their complex calculations.Thus,physically unclonable functions(PUFs)have been introduced to simultaneously address these issues.PUFs are lightweight and easy-toaccess hardware security primitives which employ the unique characteristics of integrated circuits(ICs)to generate secret keys.Among all proposed PUFs,ring oscillator PUF(RO-PUF)has had amore suitable structure for hardware implementation because of its high reliability and easier providing of circuital symmetry.However,RO-PUF has not been so attractive for authentication purposes due to its limited supported challenge-response pairs(CRPs).A few efforts have been made in recent years that could successfully improve the RO-PUF CRP space,such as configurable RO-PUF(CRO-PUF).In this paper,by considerably improving the CRO-PUF structure and adding spare paths,we propose a novel strong RO-PUF structure that exponentially grows the CRP space and dramatically reduces the hardware cost.We implement our design on a simple and low-cost FPGA chip named XC6SLX9-2tqg144,stating that the proposed design can be used in IoT applications.In addition,to improve the CRP space,our design creates a suitable improvement in different security/performance terms of the generated responses,and dramatically outperforms the state-of-the-art.The average reliability,uniqueness,and uniformity of the responses generated are 99.55%,48.49%,and 50.99%,respectively.

Stochastic Models to Mitigate Sparse Sensor Attacks in Continuous-Time Non-Linear Cyber-Physical Systems

Cyber-Physical Systems are very vulnerable to sparse sensor attacks.But current protection mechanisms employ linear and deterministic models which cannot detect attacks precisely.Therefore,in this paper,we propose a new non-linear generalized model to describe Cyber-Physical Systems.This model includes unknown multivariable discrete and continuous-time functions and different multiplicative noises to represent the evolution of physical processes and randomeffects in the physical and computationalworlds.Besides,the digitalization stage in hardware devices is represented too.Attackers and most critical sparse sensor attacks are described through a stochastic process.The reconstruction and protectionmechanisms are based on aweighted stochasticmodel.Error probability in data samples is estimated through different indicators commonly employed in non-linear dynamics(such as the Fourier transform,first-return maps,or the probability density function).A decision algorithm calculates the final reconstructed value considering the previous error probability.An experimental validation based on simulation tools and real deployments is also carried out.Both,the new technology performance and scalability are studied.Results prove that the proposed solution protects Cyber-Physical Systems against up to 92%of attacks and perturbations,with a computational delay below 2.5 s.The proposed model shows a linear complexity,as recursive or iterative structures are not employed,just algebraic and probabilistic functions.In conclusion,the new model and reconstructionmechanism can protect successfully Cyber-Physical Systems against sparse sensor attacks,even in dense or pervasive deployments and scenarios.

Rock mass structural recognition from drill monitoring technology in underground mining using discontinuity index and machine learning techniques

A procedure to recognize individual discontinuities in rock mass from measurement while drilling(MWD)technology is developed,using the binary pattern of structural rock characteristics obtained from in-hole images for calibration.Data from two underground operations with different drilling technology and different rock mass characteristics are considered,which generalizes the application of the methodology to different sites and ensures the full operational integration of MWD data analysis.Two approaches are followed for site-specific structural model building:a discontinuity index(DI)built from variations in MWD parameters,and a machine learning(ML)classifier as function of the drilling parameters and their variability.The prediction ability of the models is quantitatively assessed as the rate of recognition of discontinuities observed in borehole logs.Differences between the parameters involved in the models for each site,and differences in their weights,highlight the site-dependence of the resulting models.The ML approach offers better performance than the classical DI,with recognition rates in the range 89%to 96%.However,the simpler DI still yields fairly accurate results,with recognition rates 70%to 90%.These results validate the adaptive MWD-based methodology as an engineering solution to predict rock structural condition in underground mining operations.

THz plasmonics and electronics in germanene nanostrips

Germanene nanostrips(GeNSs)have garnered significant attention in modern semiconductor technology due to their exceptional physical characteristics,positioning them as promising candidates for a wide range of applications.GeNSs exhibit a two-dimensional(buckled)honeycomb-like lattice,which is similar to germanene but with controllable bandgaps.The modeling of GeNSs is essential for developing appropriate synthesis methods as it enables understanding and controlling the growth process of these systems.Indeed,one can adjust the strip width,which in turn can tune the bandgap and plasmonic response of the material to meet specific device requirements.In this study,the objective is to investigate the electronic behav-ior and THz plasmon features of GeNSs(≥100 nm wide).A semi-analytical model based on the charge-carrier velocity of free-standing germanene is utilized for this purpose.The charge-carrier velocity of freestanding germanene is determined through the GW approximation(V_(F)=0.702×10^(6)m·s^(−1)).Within the width range of 100 to 500 nm,GeNSs exhibit narrow bandgaps,typi-cally measuring only a few meV.Specifically,upon analysis,it was found that the bandgaps of the investigated GeNSs ranged between 29 and 6 meV.As well,these nanostrips exhibit√q-like plasmon dispersions,with their connected plasmonic fre-quency(≤30 THz)capable of being manipulated by varying parameters such as strip width,excitation plasmon angle,and sam-ple quality.These manipulations can lead to frequency variations,either increasing or decreasing,as well as shifts towards larger momentum values.The outcomes of our study serve as a foundational motivation for future experiments,and further con-firmation is needed to validate the reported results.

The influence of CEO’s financial literacy on SMEs technological innovation:the mediating effects of MCS and risk‑taking

Previous literature showed mixed results about the impact of CEOs’financial literacy(CFL)on small and medium-sized enterprises’(SMEs)innovation.This relationship can be motivated by relevant variables,which are missing in the previous literature and make a difference as mediators.In this sense,based on the theoretical framework related to upper echelon theory and resource-based view,this study focuses on the mediating effect of risk-taking attitude and management control systems(MCS)varia-bles.Empirical data from 310 SMEs gathered using a qualitative research questionnaire are analyzed using structural equation modeling methodology.Specifically,estimations are carried out considering the partial least square method.Findings show that MCS and managers’risk attitudes fully mediate the relationship between financial literacy(FL)and innovation.Between these two mediating variables,the implementation of MCS stands out because it also enables the mediating effect of CEOs’risk-taking in the CFL–technological innovation relationship.As the results do not support the significant direct relationship between FL and risk attitude,they confirm an indirect effect through MCS.Furthermore,based on the study findings,SMEs’directors and owners,business associations,and public authorities can improve SMEs’technological innovation by implementing training programs and policies to foster CFL.They can also acknowledge the interdependency between organizational factors and individual characteristics to enhance SMEs’technological innovation.

A Novel Attack on Complex APUFs Using the Evolutionary Deep Convolutional Neural Network

As the internet of things(IoT)continues to expand rapidly,the significance of its security concerns has grown in recent years.To address these concerns,physical unclonable functions(PUFs)have emerged as valuable tools for enhancing IoT security.PUFs leverage the inherent randomness found in the embedded hardware of IoT devices.However,it has been shown that some PUFs can be modeled by attackers using machine-learning-based approaches.In this paper,a new deep learning(DL)-based modeling attack is introduced to break the resistance of complex XAPUFs.Because training DL models is a problem that falls under the category of NP-hard problems,there has been a significant increase in the use of meta-heuristics(MH)to optimize DL parameters.Nevertheless,it is widely recognized that finding the right balance between exploration and exploitation when dealing with complex problems can pose a significant challenge.To address these chal-lenges,a novel migration-based multi-parent genetic algorithm(MBMPGA)is developed to train the deep convolutional neural network(DCNN)in order to achieve a higher rate of accuracy and convergence speed while decreas-ing the run-time of the attack.In the proposed MBMPGA,a non-linear migration model of the biogeography-based optimization(BBO)is utilized to enhance the exploitation ability of GA.A new multi-parent crossover is then introduced to enhance the exploration ability of GA.The behavior of the proposed MBMPGA is examined on two real-world optimization problems.In benchmark problems,MBMPGA outperforms other MH algorithms in convergence rate.The proposed model are also compared with previous attacking models on several simulated challenge-response pairs(CRPs).The simulation results on the XAPUF datasets show that the introduced attack in this paper obtains more than 99%modeling accuracy even on 8-XAPUF.In addition,the proposed MBMPGA-DCNN outperforms the state-of-the-art modeling attacks in a reduced timeframe and with a smaller number of required sets of CRPs.The area under the curve(AUC)of MBMPGA-DCNN outperforms other architectures.MBMPGA-DCNN achieved sensitivities,specificities,and accuracies of 99.12%,95.14%,and 98.21%,respectively,in the test datasets,establishing it as the most successful method.

Early-Age Properties Development of Recycled Glass Powder Blended Cement Paste:Strengths,Shrinkage,Nanoscale Characteristics,and Environmental Analysis

Recycling solid waste in cement-based materials cannot only ease its load on the natural environment but also reduce the carbon emissions of building materials.This study aims to investigate the effect of recycled glass powder(RGP)on the early-age mechanical properties and autogenous shrinkage of cement pastes,where cement is replaced by 10%,20%and 30%of RGP.In addition,the microstructure and nano-mechanical properties of cement paste with different RGP content and water to binder(W/B)ratio were also evaluated using SEM,MIP and nanoindentation techniques.The results indicate that the early-age autogenous shrinkage decreases with the increase of RGP content and W/B ratio.While the mechanical strength deteriorates due to the addition of RGP,it can be compensated by reducing the W/B ratio.Although the addition of RGP increases the total porosity of the hardened paste,it reduces the small size porosity(<50 nm).In addition,the proportions of different types of C-S-H are changed,and the volume fraction of porosity is increased,but that of hydration products of cement paste is reduced due to the incorporation of RGP.Besides its pozzolanic activity,the mitigated shrinkage deformation that RGP is generating in cement pastes is encouraging for its use as a novel supplementary cementitious material that reduces the early-age cracking risk of cement-based materials.Meanwhile,the life cycle assessments indicate that the RGP-cement component is an economical and eco-friendly novel engineering material.

Biological insights in non-small cell lung cancer

Lung oncogenesis relies on intracellular cysteine to overcome oxidative stress.Several tumor types,including non-small cell lung cancer(NSCLC),upregulate the system x-c cystine/glutamate antiporter(xCT)through overexpression of the cystine transporter SLC7A11,thus sustaining intracellular cysteine levels to support glutathione synthesis.Nuclear factor erythroid 2-related factor 2(NRF2)serves as a master regulator of oxidative stress resistance by regulating SLC7A11,whereas Kelch-like ECH-associated protein(KEAP1)acts as a cytoplasmic repressor of the oxidative responsive transcription factor NRF2.Mutations in KEAP1/NRF2 and p53 induce SLC7A11 activation in NSCLC.Extracellular cystine is crucial in supplying the intracellular cysteine levels necessary to combat oxidative stress.Disruptions in cystine availability lead to iron-dependent lipid peroxidation,thus resulting in a type of cell death called ferroptosis.Pharmacologic inhibitors of xCT(either SLC7A11 or GPX4)induce ferroptosis of NSCLC cells and other tumor types.When cystine uptake is impaired,the intracellular cysteine pool can be sustained by the transsulfuration pathway,which is catalyzed by cystathionine-B-synthase(CBS)and cystathionine g-lyase(CSE).The involvement of exogenous cysteine/cystine and the transsulfuration pathway in the cysteine pool and downstream metabolites results in compromised CD8^(+)T cell function and evasion of immunotherapy,diminishing immune response and potentially reducing the effectiveness of immunotherapeutic interventions.Pyroptosis is a previously unrecognized form of regulated cell death.In NSCLCs driven by EGFR,ALK,or KRAS,selective inhibitors induce pyroptotic cell death as well as apoptosis.After targeted therapy,the mitochondrial intrinsic apoptotic pathway is activated,thus leading to the cleavage and activation of caspase-3.Consequently,gasdermin E is activated,thus leading to permeabilization of the cytoplasmic membrane and cell-lytic pyroptosis(indicated by characteristic cell membrane ballooning).Breakthroughs in KRAS G12C allele-specific inhibitors and potential mechanisms of resistance are also discussed herein.

Quantum Codes Do Not Increase Fidelity against Isotropic Errors

In this article, we study the ability of error-correcting quantum codes to increase the fidelity of quantum states throughout a quantum computation. We analyze arbitrary quantum codes that encode all qubits involved in the computation, and we study the evolution of n-qubit fidelity from the end of one application of the correcting circuit to the end of the next application. We assume that the correcting circuit does not introduce new errors, that it does not increase the execution time (i.e. its application takes zero seconds) and that quantum errors are isotropic. We show that the quantum code increases the fidelity of the states perturbed by quantum errors but that this improvement is not enough to justify the use of quantum codes. Namely, we prove that, taking into account that the time interval between the application of the two corrections is multiplied (at least) by the number of qubits n (due to the coding), the best option is not to use quantum codes, since the fidelity of the uncoded state over a time interval n times smaller is greater than that of the state resulting from the quantum code correction.

Ostrowski’s Method for Solving Nonlinear Equations and Systems

The dynamic characteristics and the efficiency of the Ostrowski’s method allow it to be crowned as an excellent tool for solving nonlinear problems.This article shows different versions of the classic method that allow it to be applied to a wide range of engineering problems.Among them stands out the derivative-free definition applying divided differences,the introduction of memory and its extension to the resolution of nonlinear systems of equations.All of these versions are compared in a numerical simulations section where the results obtained are compared with other classic methods.

Fe含量对粉末冶金Cu-Fe合金显微组织与性能的影响

研究Fe含量对粉末冶金Cu-Fe合金显微组织及性能的影响。采用电火花等离子烧结、冷轧以及时效处理工艺制备4种不同铁含量(5%、10%、20%和40%,质量分数)的Cu-Fe合金。研究结果表明,随着Fe含量从5%(质量分数)增加到40%(质量分数),Fe相由离散球形分布演变为连续交错分布,Fe相尺寸从0.29μm增加到1.20μm;时效态的Cu-Fe合金的屈服强度从411.5 MPa提高到788.8 MPa,电导率从62.5%(IACS)降低到42.0%(IACS)。在以上结果的基础上,提出一种混合法则计算Cu基体、初级Fe相和次级Fe相对屈服强度的贡献,可较好地预测Fe含量高于10%(质量分数)合金的力学性能。

Challenges in the Detection and Attribution of Northern Hemisphere Surface Temperature Trends Since 1850

Since 2007,the Intergovernmental Panel on Climate Change(IPCC)has heavily relied on the comparison between global climate model hindcasts and global surface temperature(ST)estimates for concluding that post-1950s global warming is mostly human-caused.In Connolly et al.,we cautioned that this approach to the detection and attribution of climate change was highly dependent on the choice of Total Solar Irradiance(TSI)and ST data sets.We compiled 16 TSI and five ST data sets and found by altering the choice of TSI or ST,one could(prematurely)conclude anything from the warming being“mostly human-caused”to“mostly natural.”Richardson and Benestad suggested our analysis was“erroneous”and“flawed”because we did not use a multilinear regression.They argued that applying a multilinear regression to one of the five ST series re-affirmed the IPCC's attribution statement.They also objected that many of the published TSI data sets were out-of-date.However,here we show that when applying multilinear regression analysis to an expanded and updated data set of 27 TSI series,the original conclusions of Connolly et al.are confirmed for all five ST data sets.Therefore,it is still unclear whether the observed warming is mostly human-caused,mostly natural or some combination of both.

Assessment of compressive strength of jet grouting by machine learning

Jet grouting is one of the most popular soil improvement techniques,but its design usually involves great uncertainties that can lead to economic cost overruns in construction projects.The high dispersion in the properties of the improved material leads to designers assuming a conservative,arbitrary and unjustified strength,which is even sometimes subjected to the results of the test fields.The present paper presents an approach for prediction of the uniaxial compressive strength(UCS)of jet grouting columns based on the analysis of several machine learning algorithms on a database of 854 results mainly collected from different research papers.The selected machine learning model(extremely randomized trees)relates the soil type and various parameters of the technique to the value of the compressive strength.Despite the complex mechanism that surrounds the jet grouting process,evidenced by the high dispersion and low correlation of the variables studied,the trained model allows to optimally predict the values of compressive strength with a significant improvement with respect to the existing works.Consequently,this work proposes for the first time a reliable and easily applicable approach for estimation of the compressive strength of jet grouting columns.

Electrifying Ba_(0.5)Sr_(0.5)Co_(0.8)Fe_(0.2)O_(3-δ) for focalized heating in oxygen transport membranes

Industry decarbonization requires the development of highly efficient and flexible technologies relying on renewable energy resources,especially biomass and solar/wind electricity.In the case of pure oxygen production,oxygen transport membranes(OTMs)appear as an alternative technology for the cryogenic distillation of air,the industrially-established process of producing oxygen.Moreover,OTMs could provide oxygen from different sources(air,water,CO_(2),etc.),and they are more flexible in adapting to current processes,producing oxygen at 700^(-1)000℃.Furthermore,OTMs can be integrated into catalytic membrane reactors,providing new pathways for different processes.The first part of this study was focused on electrification on a traditional OTM material(Ba_(0.5)Sr_(0.5)Co_(0.8)Fe_(0.2)O_(3-δ)),imposing different electric currents/voltages along a capillary membrane.Thanks to the emerging Joule effect,the membrane-surface temperature and the associated O_(2) permeation flux could be adjusted.Here,the OTM is electrically and locally heated and reaches 900℃on the surface,whereas the surrounding of the membrane was maintained at 650℃.The O_(2)permeation flux reached for the electrified membranes was~3.7 NmL min^(-1)cm^(-2),corresponding to the flux obtained with an OTM non-electrified at 900℃.The influence of depositing a porous Ce_(0.8)Tb_(0.2)O_(2-δ) catalytic/protective layer on the outer membrane surface revealed that lower surface temperatures(830℃)were detected at the same imposed electric power.Finally,the electrification concept was demonstrated in a catalytic membrane reactor(CMR)where the oxidative dehydrogenation of ethane(ODHE)was carried out.ODHE reaction is very sensitive to temperature,and here,we demonstrate an improvement of the ethylene yield by reaching moderate temperatures in the reaction chamber while the O_(2) injection into the reaction can be easily fine-tuned.

Kinematic analysis of flexible bipedal robotic systems

In spite of its intrinsic complexities,the passive gait of bipedal robots on a sloping ramp is a subject of interest for numerous researchers.What distinguishes the present research from similar works is the consideration of flexibility in the constituent links of this type of robotic systems.This is not a far-fetched assumption because in the transient(impact)phase,due to the impulsive forces which are applied to the system,the likelihood of exciting the vibration modes increases considerably.Moreover,the human leg bones that are involved in walking are supported by viscoelastic muscles and ligaments.Therefore,for achieving more exact results,it is essential to model the robot links with viscoelastic properties.To this end,the Gibbs-Appell formulation and Newton's kinematic impact law are used to derive the most general form of the system's dynamic equations in the swing and transient phases of motion.The most important issue in the passive walking motion of bipedal robots is the determination of the initial robot configuration with which the system could accomplish a periodic and stable gait solely under the effect of gravitational force.The extremely unstable nature of the system studied in this paper and the vibrations caused by the impulsive forces induced by the impact of robot feet with the inclined surface are some of the very serious challenges encountered for achieving the above-mentioned goal.To overcome such challenges,an innovative method that uses a combination of the linearized equations of motion in the swing phase and the algebraic motion equations in the transition phase is presented in this paper to obtain an eigenvalue problem.By solving this problem,the suitable initial conditions that are necessary for the passive gait of this bipedal robot on a sloping surface are determined.The effects of the characteristic parameters of elastic links including the modulus of elasticity and the Kelvin-Voigt coefficient on the walking stability of this type of robotic systems are also studied.The findings of this parametric study reveal that the increase in the Kelvin-Voigt coefficient enhances the stability of the robotic system,while the increase in the modulus of elasticity has an opposite effect.

A symmetric substructuring method for analyzing the natural frequencies of conical origami structures

Conical origami structures are characterized by their substantial out-of-plane stiffness and energy-absorptioncapacity.Previous investigations have commonly focused on the static characteristics of these lightweight struc-tures.However,the efficient analysis of the natural vibrations of these structures is pivotal for designing conicalorigami structures with programmable stiffness and mass.In this paper,we propose a novel method to analyzethe natural vibrations of such structures by combining a symmetric substructuring method(SSM)and a gener-alized eigenvalue analysis.SSM exploits the inherent symmetry of the structure to decompose it into a finiteset of repetitive substructures.In doing so,we reduce the dimensions of matrices and improve computationalefficiency by adopting the stiffness and mass matrices of the substructures in the generalized eigenvalue analysis.Finite element simulations of pin-jointed models are used to validate the computational results of the proposedapproach.Moreover,the parametric analysis of the structures demonstrates the influences of the number of seg-ments along the circumference and the radius of the cone on the structural mass and natural frequencies of thestructures.Furthermore,we present a comparison between six-fold and four-fold conical origami structures anddiscuss the influence of various geometric parameters on their natural frequencies.This study provides a strategyfor efficiently analyzing the natural vibration of symmetric origami structures and has the potential to contributeto the efficient design and customization of origami metastructures with programmable stiffness.

Origin of nucleation and growth of extension twins in grains unsuitably oriented for twinning during deformation of Mg-1%Al

A large number of anomalous extension twins,with low or even negative twinning Schmid factors,were found to nucleate and grow in a strongly textured Mg-1Al alloy during tensile deformation along the extruded direction.The deformation mechanisms responsible for this behaviour were investigated through in-situ electron back-scattered diffraction,grain reference orientation deviation,and slip trace-modified lattice rotation.It was found that anomalous extension twins nucleated mainly at the onset of plastic deformation at or near grain boundary triple junctions.They were associated with the severe strain incompatibility between neighbour grains as a result from the differentbasal slip-induced lattice rotations.Moreover,the anomalous twins were able to grow with the applied strain due to the continuous activation ofbasal slip in different neighbour grains,which enhanced the strain incompatibility.These results reveal the complexity of the deformation mechanisms in Mg alloys at the local level when deformed along hard orientations.

Blockade of Rho-associated kinase prevents inhibition of axon regeneration of peripheral nerves induced by anti-ganglioside antibodies

Anti-ganglioside antibodies are associated with delayed/poor clinical recovery in Guillain-Barrèsyndrome,mostly related to halted axon regeneration.Cross-linking of cell surface gangliosides by anti-ganglioside antibodies triggers inhibition of nerve repair in in vitro and in vivo paradigms of axon regeneration.These effects involve the activation of the small GTPase Rho A/ROCK signaling pathways,which negatively modulate growth cone cytoskeleton,similarly to well stablished inhibitors of axon regeneration described so far.The aim of this work was to perform a proof of concept study to demonstrate the effectiveness of Y-27632,a selective pharmacological inhibitor of ROCK,in a mouse model of axon regeneration of peripheral nerves,where the passive immunization with a monoclonal antibody targeting gangliosides GD1a and GT1b was previously reported to exert a potent inhibitory effect on regeneration of both myelinated and unmyelinated fibers.Our results demonstrate a differential sensitivity of myelinated and unmyelinated axons to the pro-regenerative effect of Y-27632.Treatment with a total dosage of 9 mg/kg of Y-27632 resulted in a complete prevention of anti-GD1a/GT1b monoclonal antibody-mediated inhibition of axon regeneration of unmyelinated fibers to skin and the functional recovery of mechanical cutaneous sensitivity.In contrast,the same dose showed toxic effects on the regeneration of myelinated fibers.Interestingly,scale down of the dosage of Y-27632 to 5 mg/kg resulted in a significant although not complete recovery of regenerated myelinated axons exposed to anti-GD1a/GT1b monoclonal antibody in the absence of toxicity in animals exposed to only Y-27632.Overall,these findings confirm the in vivo participation of Rho A/ROCK signaling pathways in the molecular mechanisms associated with the inhibition of axon regeneration induced by anti-GD1a/GT1b monoclonal antibody.Our findings open the possibility of therapeutic pharmacological intervention targeting Rho A/Rock pathway in immune neuropathies associated with the presence of anti-ganglioside antibodies and delayed or incomplete clinical recovery after injury in the peripheral nervous system.