Clustered Regularly Interspaced Short Palindromic Repeats(CRISPR):A critical overview on the most promising applications of molecular scissors in oral medicine

The scientific community is continuously working to translate the novel biomedical techniques into effective medical treatments.CRISPR-Cas9 system(Clustered Regularly Interspaced Short Palindromic Repeats-9),commonly known as the“molecular scissor”,represents a recently developed biotechnology able to improve the quality and the efficacy of traditional treatments,related to several human diseases,such as chronic diseases,neurodegenerative pathologies and,interestingly,oral diseases.Of course,dental medicine has notably increased the use of biotechnologies to ensure modern and conservative approaches:in this landscape,the use of CRISPR-Cas9 system may speed and personalize the traditional therapies,ensuring a good predictability of clinical results.The aim of this critical overview is to provide evidence on CRISPR efficacy,taking into specific account its applications in oral medicine.

The Products of Regularly Solvable Operators with Their Spectra in Direct Sum Spaces

In this paper, we consider the general quasi-differential expressions each of order n with complex coefficients and their formal adjoints on the interval (a,b). It is shown in direct sum spaces of functions defined on each of the separate intervals with the cases of one and two singular end-points and when all solutions of the equation and its adjoint are in (the limit circle case) that all well-posed extensions of the minimal operator have resolvents which are HilbertSchmidt integral operators and consequently have a wholly discrete spectrum. This implies that all the regularly solvable operators have all the standard essential spectra to be empty. These results extend those of formally symmetric expression studied in [1-10] and those of general quasi-differential expressions in [11-19].

Relationship among intermittent pulse,regularly intermittent pulse,and bradyarrhythmia

Pulse diagnosis is an important basis for the diagnosis of Chinese medicine.It is the rich experience accumulated by the predecessors in the long and continuous practice,and it is a unique diagnosis method of Chinese medicine.There are many names of pulse conditions in traditional Chinese medicine.The four elements are analyzed and summarized in terms of position,number,shape,and momentum.The four elements are used as 28 kinds of pulses.Among them,the regularly intermittent pulse and the intermittent pulse are characterized by arrhythmia and intermittent stop of the pulse.Intermittent pulse means irregular intervals;when a pulse comes,Regularly Intermittent pulse have regular stops.This kind of phenomenon is similar to the bradyarrhythmia in modern medicine.The knot pulse is an irregular pulse stopping,which can be seen clinically in sinus arrest,second-degree type I sinus block,second-degree type I atrioventricular block,and escape beats and so on.On the other hand,Regularly Intermittent pulse is a regular pulse stopping,which can be clinically found in the second degree type II sinus block,the second degree type II sinus block,and the second degree type I atrioventricular block with a special 2:1 type of atrioventricular block type and so on.

Tail Distortion Risk Measure for Portfolio with Multivariate Regularly Variation

For the multiplicative background risk model,a distortion-type risk measure is used to measure the tail risk of the portfolio under a scenario probability measure with multivariate regular variation.In this paper,we investigate the tail asymptotics of the portfolio loss ∑_(i=1)^(d)R_(i)S,where the stand-alone risk vector R=(R_(1),...,R_(d))follows a multivariate regular variation and is independent of the background risk factor S.An explicit asymptotic formula is established for the tail distortion risk measure,and an example is given to illustrate our obtained results.

Overexpression of proteasome 26S subunit non-ATPase 6 protein and its clinicopathological significance in intrahepatic cholangiocarcinoma

BACKGROUND Currently,intrahepatic cholangiocarcinoma(ICC)poses a continuing,significant health challenge,but the relationship has yet to be established between ICC and the proteasome 26S subunit non-ATPase 6(PSMD6).AIM To investigate the protein expression and clinicopathological significance of PSMD6 in ICC.METHODS The potential impact of the PSMD6 gene on the growth of ICC cell lines was analyzed using clustered regularly interspaced short palindromic repeat knockout screening technology.Forty-two paired specimens of ICC and adjacent noncancerous tissues were collected.PSMD6 protein expression was determined by immunohistochemistry.Receiver operating characteristic curve analysis was performed to validate PSMD6 expression level,and its association with ICC patients’various clinicopathological characteristics was investigated.RESULTS The PSMD6 gene was found to be essential for the growth of ICC cell lines.PSMD6 protein was significantly overexpressed in ICC tissues(P<0.001),but showed no significant association with patient age,gender,pathological grade,or tumor-node-metastasis stage(P>0.05).CONCLUSION PSMD6 can promote the growth of ICC cells,thus playing a pro-oncogenic role.

The Applications of CRISPR Screening in Aging Research

The advancement of Clustered Regularly Interspaced Short Palindromic Repeats(CRISPR)gene editing technology has revolutionized the comprehension of human genome,propelling molecular and cellular biology research into unexplored realms and accelerating progress in life sciences and medicine.CRISPR-based gene screening,recognized for its efficiency and practicality,is widely utilized across diverse biological fields.Aging is a multifaceted process governed by a myriad of genetic and epigenetic factors.Unraveling the genes regulating aging holds promise for understanding this intricate phenomenon and devising strategies for its assessment and intervention.This review provides a comprehensive overview of the progress in CRISPR screening and its applications in aging research,while also offering insights into future directions.CRISPR-based genetic-manipulation tools are positioned as indispensable instruments for mitigating aging and managing age-related diseases.

转录因子HNF1A、HNF4A和FOXA2调节肝细胞蛋白质N-糖基化

Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulatory transcriptional loop.The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes.Our in silico analysis of HNF1A,HNF4A.and FOXA2 binding to the ten candidate glyco-genes studied in this work confirms a significant enrich-ment of these transcription factors specifically in the liver.Our previous studies identified HNF1A as a master regulator of fucosylation,glycan branching,and galactosylation of plasma glycoproteins.Here,we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype.We used the state-of-the-art clus-tered regularly interspaced short palindromic repeats/dead Cas9(CRISPR/dCas9)molecular tool for the downregulation of the HNF1A,HNF4A,and FOXA2 genes in HepG2 cells-a human liver cancer cell line.The results show that the downregulation of all three genes individually and in pairs affects the transcrip-tional activity of many glyco-genes,although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures.The effect is better seen as an overall change in the total HepG2 N-glycome,primarily due to the extension of biantennary glycans.We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure.We also propose a model showing feedback loops with the mutual activation of HNF1A-FOXA2 and HNF4A-FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.

Is 26S proteasome non-ATPase regulatory subunit 6 a potential molecular target for intrahepatic cholangiocarcinoma?

In this editorial we comment on the article by Tang et al published in the recent issue of World Journal of Hepatology.Drug therapy of intrahepatic cholangiocarcinoma(iCCA)poses an enormous challenge since only a small proportion of patients demonstrate beneficial responses to therapeutic agents.Thus,there has been a sustained search for novel molecular targets for iCCA.The study by Tang et al evaluated the role of 26S proteasome non-ATPase regulatory subunit 6(PSMD6),a 19S regulatory subunit of the proteasome,in human iCCA cells and specimens.The authors employed clustered regularly interspaced short palindromic repeat(CRISPR)knockout screening technology integrated with the computational CERES algorithm,and analyzed the human protein atlas(THPA)database and tissue microarrays.The results show that PSMD6 is a gene essential for the proliferation of 17 iCCA cell lines,and PSMD6 protein was overexpressed in iCCA tissues without a significant correlation with the clinicopathological parameters.The authors conclude that PSMD6 may play a promoting role in iCCA.The major limitations and defects of this study are the lack of detailed information of CRISPR knockout screening,in vivo experiments,and a discussion of plausible mechanistic cues,which,therefore,dampen the significance of the results.Further studies are required to verify PSMD6 as a molecular target for developing novel therapeutics for iCCA.In addition,the editorial article summarizes the latest advances in molecular targeted drugs and recently emerging immunotherapy in the clinical management of iCCA,development of proteasome inhibitors for cancer therapy,and advantages of CRISPR screening technology,computational methods,and THPA database as experimental tools for fighting cancer.We hope that these comments may provide some clues for those engaged in the field of basic and clinical research into iCCA.

Decoding the genetic landscape of autism:A comprehensive review

BACKGROUND Autism spectrum disorder(ASD)is a complex neurodevelopmental condition characterized by heterogeneous symptoms and genetic underpinnings.Recent advancements in genetic and epigenetic research have provided insights into the intricate mechanisms contributing to ASD,influencing both diagnosis and therapeutic strategies.AIM To explore the genetic architecture of ASD,elucidate mechanistic insights into genetic mutations,and examine gene-environment interactions.METHODS A comprehensive systematic review was conducted,integrating findings from studies on genetic variations,epigenetic mechanisms(such as DNA methylation and histone modifications),and emerging technologies[including Clustered Regularly Interspaced Short Palindromic Repeats(CRISPR)-Cas9 and single-cell RNA sequencing].Relevant articles were identified through systematic searches of databases such as PubMed and Google Scholar.RESULTS Genetic studies have identified numerous risk genes and mutations associated with ASD,yet many cases remain unexplained by known factors,suggesting undiscovered genetic components.Mechanistic insights into how these genetic mutations impact neural development and brain connectivity are still evolving.Epigenetic modifications,particularly DNA methylation and non-coding RNAs,also play significant roles in ASD pathogenesis.Emerging technologies like CRISPR-Cas9 and advanced bioinformatics are advancing our understanding by enabling precise genetic editing and analysis of complex genomic data.CONCLUSION Continued research into the genetic and epigenetic underpinnings of ASD is crucial for developing personalized and effective treatments.Collaborative efforts integrating multidisciplinary expertise and international collaborations are essential to address the complexity of ASD and translate genetic discoveries into clinical practice.Addressing unresolved questions and ethical considerations surrounding genetic research will pave the way for improved diagnostic tools and targeted therapies,ultimately enhancing outcomes for individuals affected by ASD.

Distributed Optimal Formation Control for Unmanned Surface Vessels by a Regularized Game-Based Approach

Dear Editor,This letter explores optimal formation control for a network of unmanned surface vessels(USVs).By designing an individual objective function for each USV,the optimal formation problem is transformed into a noncooperative game.Under this game theoretic framework,the optimal formation is achieved by seeking the Nash equilibrium of the regularized game.A modular structure consisting of a distributed Nash equilibrium seeker and a regulator is proposed.

Analytical Method for the Wave Diffraction of Asymmetrically Arranged Breakwaters

The layout forms of several breakwater structures can be generalized as asymmetrical arrangements in actual engineering.However,the problem of wave diffraction around asymmetrically arranged breakwaters has not been adequately investigated.In this study,we propose an analytical method of wave diffraction for regular waves passing through asymmetrically arranged breakwaters,and we use the Nyström method to obtain the analytical solution numerically.We compared the results of this method with those of previous analytical solutions and with numerical results to demonstrate the validity of our approach.We also provided diffraction coefficient diagrams of breakwaters with different layout forms.Moreover,we described the analytical expression for the problem of diffraction through long-wave incident breakwaters and presented an analysis of the relationship between the diffraction coefficients and the widths of breakwater gates.The analytical method presented in this study contributes to the limited literature on the theory of wave diffraction through asymmetrically arranged breakwaters.

Insufficient Physical Activity among Students Aged 6-17 Years in China,2016-2017

Regular physical activity of sufficient duration and intensity can provide health benefits such as improved physical fitness,which promotes bone health,prevents hypertension,improves mental health,and reduces adiposity^([1]).Furthermore,the benefits of regular physical exercise during youth may persist into adulthood^([2]).

THE GLOBAL EXISTENCE AND ANALYTICITY OF A MILD SOLUTION TO THE 3D REGULARIZED MHD EQUATIONS

In this paper,we study the three-dimensional regularized MHD equations with fractional Laplacians in the dissipative and diffusive terms.We establish the global existence of mild solutions to this system with small initial data.In addition,we also obtain the Gevrey class regularity and the temporal decay rate of the solution.

THE SMOOTHING EFFECT IN SHARP GEVREY SPACE FOR THE SPATIALLY HOMOGENEOUS NON-CUTOFF BOLTZMANN EQUATIONS WITH A HARDPOTENTIAL

In this article, we study the smoothing effect of the Cauchy problem for the spatially homogeneous non-cutoff Boltzmann equation for hard potentials. It has long been suspected that the non-cutoff Boltzmann equation enjoys similar regularity properties as to whose of the fractional heat equation. We prove that any solution with mild regularity will become smooth in Gevrey class at positive time, with a sharp Gevrey index, depending on the angular singularity. Our proof relies on the elementary L^(2) weighted estimates.

ELLIPTIC EQUATIONS IN DIVERGENCE FORM WITH DISCONTINUOUS COEFFICIENTS IN DOMAINS WITH CORNERS

We study equations in divergence form with piecewise Cαcoefficients.The domains contain corners and the discontinuity surfaces are attached to the edges of the corners.We obtain piecewise C^(1,α) estimates across the discontinuity surfaces and provide an example to illustrate the issue regarding the regularity at the corners.

Thrust estimate method of an on-orbit Hall thruster using Hall drift current

In order to realize the thrust estimation of the Hall thruster during its flight mission,this study establishes an estimation method based on measurement of the Hall drift current.In this method,the Hall drift current is calculated from an inverse magnetostatic problem,which is formulated according to its induced magnetic flux density detected by sensors,and then the thrust is estimated by multiplying the Hall drift current with the characteristic magnetic flux density of the thruster itself.In addition,a three-wire torsion pendulum micro-thrust measurement system is utilized to verify the estimate values obtained from the proposed method.The errors were found to be less than 8%when the discharge voltage ranged from 250 V to 350 V and the anode flow rate ranged from 30 sccm to 50 sccm,indicating the possibility that the proposed thrust estimate method could be practically applied.Moreover,the measurement accuracy of the magnetic flux density is suggested to be lower than 0.015 mT and improvement on the inverse problem solution is required in the future.

SHARP MORREY REGULARITY THEORY FOR A FOURTH ORDER GEOMETRICAL EQUATION

This paper is a continuation of recent work by Guo-Xiang-Zheng[10].We deduce the sharp Morrey regularity theory for weak solutions to the fourth order nonhomogeneous Lamm-Rivière equation △^{2}u=△(V▽u)+div(w▽u)+(▽ω+F)·▽u+f in B^(4),under the smallest regularity assumptions of V,ω,ω,F,where f belongs to some Morrey spaces.This work was motivated by many geometrical problems such as the flow of biharmonic mappings.Our results deepens the Lp type regularity theory of[10],and generalizes the work of Du,Kang and Wang[4]on a second order problem to our fourth order problems.

A STRONG POSITIVITY PROPERTY AND A RELATED INVERSE SOURCE PROBLEM FOR MULTI-TERM TIME-FRACTIONAL DIFFUSION EQUATIONS

In this article,we consider the diffusion equation with multi-term time-fractional derivatives.We first derive,by a subordination principle for the solution,that the solution is positive when the initial value is non-negative.As an application,we prove the uniqueness of solution to an inverse problem of determination of the temporally varying source term by integral type information in a subdomain.Finally,several numerical experiments are presented to show the accuracy and efficiency of the algorithm.

A novel algorithm for evaluating cement azimuthal density based on perturbation theory in horizontal well

Cement density monitoring plays a vital role in evaluating the quality of cementing projects,which is of great significance to the development of oil and gas.However,the presence of inhomogeneous cement distribution and casing eccentricity in horizontal wells often complicates the accurate evaluation of cement azimuthal density.In this regard,this paper proposes an algorithm to calculate the cement azimuthal density in horizontal wells using a multi-detector gamma-ray detection system.The spatial dynamic response functions are simulated to obtain the influence of cement density on gamma-ray counts by the perturbation theory,and the contribution of cement density in six sectors to the gamma-ray recorded by different detectors is obtained by integrating the spatial dynamic response functions.Combined with the relationship between gamma-ray counts and cement density,a multi-parameter calculation equation system is established,and the regularized Newton iteration method is employed to invert casing eccentricity and cement azimuthal density.This approach ensures the stability of the inversion process while simultaneously achieving an accuracy of 0.05 g/cm^(3) for the cement azimuthal density.This accuracy level is ten times higher compared to density accuracy calculated using calibration equations.Overall,this algorithm enhances the accuracy of cement azimuthal density evaluation,provides valuable technical support for the monitoring of cement azimuthal density in the oil and gas industry.

A Recurrent Neural Network for Multimodal Anomaly Detection by Using Spatio-Temporal Audio-Visual Data

In video surveillance,anomaly detection requires training machine learning models on spatio-temporal video sequences.However,sometimes the video-only data is not sufficient to accurately detect all the abnormal activities.Therefore,we propose a novel audio-visual spatiotemporal autoencoder specifically designed to detect anomalies for video surveillance by utilizing audio data along with video data.This paper presents a competitive approach to a multi-modal recurrent neural network for anomaly detection that combines separate spatial and temporal autoencoders to leverage both spatial and temporal features in audio-visual data.The proposed model is trained to produce low reconstruction error for normal data and high error for abnormal data,effectively distinguishing between the two and assigning an anomaly score.Training is conducted on normal datasets,while testing is performed on both normal and anomalous datasets.The anomaly scores from the models are combined using a late fusion technique,and a deep dense layer model is trained to produce decisive scores indicating whether a sequence is normal or anomalous.The model’s performance is evaluated on the University of California,San Diego Pedestrian 2(UCSD PED 2),University of Minnesota(UMN),and Tampere University of Technology(TUT)Rare Sound Events datasets using six evaluation metrics.It is compared with state-of-the-art methods depicting a high Area Under Curve(AUC)and a low Equal Error Rate(EER),achieving an(AUC)of 93.1 and an(EER)of 8.1 for the(UCSD)dataset,and an(AUC)of 94.9 and an(EER)of 5.9 for the UMN dataset.The evaluations demonstrate that the joint results from the combined audio-visual model outperform those from separate models,highlighting the competitive advantage of the proposed multi-modal approach.