Treat to target in Crohn’s disease:A practical guide for clinicians

A treat-to-target(T2T)approach applies the principles of early intervention and tight disease control to optimise long-term outcomes in Crohn's disease.The Selecting Therapeutic Targets in Inflammatory Bowel Disease(STRIDE)-II guidelines specify short,intermediate,and long-term treatment goals,documenting specific treatment targets to be achieved at each of these timepoints.Scheduled appraisal of Crohn’s disease activity against pre-defined treatment targets at these timepoints remains central to determining whether current therapy should be continued or modified.Consensus treatment targets in Crohn’s disease comprise combination clinical and patient-reported outcome remission,in conjunction with biomarker normalisation and endoscopic healing.Although the STRIDE-II guidelines endorse the pursuit of endoscopic healing,clinicians must consider that this may not always be appropriate,acceptable,or achievable in all patients.This underscores the need to engage patients at the outset in an effort to personalise care and individualise treatment targets.The use of non-invasive biomarkers such as faecal calprotectin in conjunction with cross-sectional imaging techniques,particularly intestinal ultrasound,holds great promise;as do emerging treatment targets such as transmural healing.Two randomised clinical trials,namely,CALM and STARDUST,have evaluated the efficacy of a T2T approach in achieving endoscopic endpoints in patients with Crohn’s disease.Findings from these studies reflect that patient subgroups and Crohn’s disease characteristics likely to benefit most from a T2T approach,remain to be clarified.Moreover,outside of clinical trials,data pertaining to the real-world effectiveness of a T2T approach remains scare,highlighting the need for pragmatic real-world studies.Despite the obvious promise of a T2T approach,a lack of guidance to support its integration into real-world clinical practice has the potential to limit its uptake.This highlights the need to describe strategies,processes,and models of care capable of supporting the integration and execution of a T2T approach in real-world clinical practice.Hence,this review seeks to examine the current and emerging literature to provide clinicians with practical guidance on how to incorporate the principles of T2T into routine clinical practice for the management of Crohn’s disease.

High-speed penetration of ogive-nose projectiles into thick concrete targets:Tests and a projectile nose evolution model

The majority of the projectiles used in the hypersonic penetration study are solid flat-nosed cylindrical projectiles with a diameter of less than 20 mm.This study aims to fill the gap in the experimental and analytical study of the evolution of the nose shape of larger hollow projectiles under hypersonic penetration.In the hypersonic penetration test,eight ogive-nose AerMet100 steel projectiles with a diameter of 40 mm were launched to hit concrete targets with impact velocities that ranged from 1351 to 1877 m/s.Severe erosion of the projectiles was observed during high-speed penetration of heterogeneous targets,and apparent localized mushrooming occurred in the front nose of recovered projectiles.By examining the damage to projectiles,a linear relationship was found between the relative length reduction rate and the initial kinetic energy of projectiles in different penetration tests.Furthermore,microscopic analysis revealed the forming mechanism of the localized mushrooming phenomenon for eroding penetration,i.e.,material spall erosion abrasion mechanism,material flow and redistribution abrasion mechanism and localized radial upsetting deformation mechanism.Finally,a model of highspeed penetration that included erosion was established on the basis of a model of the evolution of the projectile nose that considers radial upsetting;the model was validated by test data from the literature and the present study.Depending upon the impact velocity,v0,the projectile nose may behave as undistorted,radially distorted or hemispherical.Due to the effects of abrasion of the projectile and enhancement of radial upsetting on the duration and amplitude of the secondary rising segment in the pulse shape of projectile deceleration,the predicted DOP had an upper limit.

Mitophagy in intracerebral hemorrhage:a new target for therapeutic intervention

Intracerebral hemorrhage is a life-threatening condition with a high fatality rate and severe sequelae.However,there is currently no treatment available for intracerebral hemorrhage,unlike for other stroke subtypes.Recent studies have indicated that mitochondrial dysfunction and mitophagy likely relate to the pathophysiology of intracerebral hemorrhage.Mitophagy,or selective autophagy of mitochondria,is an essential pathway to preserve mitochondrial homeostasis by clearing up damaged mitochondria.Mitophagy markedly contributes to the reduction of secondary brain injury caused by mitochondrial dysfunction after intracerebral hemorrhage.This review provides an overview of the mitochondrial dysfunction that occurs after intracerebral hemorrhage and the underlying mechanisms regarding how mitophagy regulates it,and discusses the new direction of therapeutic strategies targeting mitophagy for intracerebral hemorrhage,aiming to determine the close connection between mitophagy and intracerebral hemorrhage and identify new therapies to modulate mitophagy after intracerebral hemorrhage.In conclusion,although only a small number of drugs modulating mitophagy in intracerebral hemorrhage have been found thus far,most of which are in the preclinical stage and require further investigation,mitophagy is still a very valid and promising therapeutic target for intracerebral hemorrhage in the long run.

Improved Weighted Local Contrast Method for Infrared Small Target Detection

In order to address the problem of high false alarm rate and low probabilities of infrared small target detection in complex low-altitude background,an infrared small target detection method based on improved weighted local contrast is proposed in this paper.First,the ratio information between the target and local background is utilized as an enhancement factor.The local contrast is calculated by incorporating the heterogeneity between the target and local background.Then,a local product weighted method is designed based on the spatial dissimilarity between target and background to further enhance target while suppressing background.Finally,the location of target is obtained by adaptive threshold segmentation.As experimental results demonstrate,the method shows superior performance in several evaluation metrics compared with six existing algorithms on different datasets containing targets such as unmanned aerial vehicles(UAV).

Distinct molecular targets of ProEGCG from EGCG and superior inhibition of angiogenesis signaling pathways for treatment of endometriosis

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.

Classification and technical target of water electrolysis for hydrogen production

Continuous efforts are underway to reduce carbon emissions worldwide in response to global climate change.Water electrolysis technology,in conjunction with renewable energy,is considered the most feasible hydrogen production technology based on the viable possibility of large-scale hydrogen production and the zero-carbon-emission nature of the process.However,for hydrogen produced via water electrolysis systems to be utilized in various fields in practice,the unit cost of hydrogen production must be reduced to$1/kg H_(2).To achieve this unit cost,technical targets for water electrolysis have been suggested regarding components in the system.In this paper,the types of water electrolysis systems and the limitations of water electrolysis system components are explained.We suggest guideline with recent trend for achieving this technical target and insights for the potential utilization of water electrolysis technology.

WSN Mobile Target Tracking Based on Improved Snake-Extended Kalman Filtering Algorithm

A wireless sensor network mobile target tracking algorithm(ISO-EKF)based on improved snake optimization algorithm(ISO)is proposed to address the difficulty of estimating initial values when using extended Kalman filtering to solve the state of nonlinear mobile target tracking.First,the steps of extended Kalman filtering(EKF)are introduced.Second,the ISO is used to adjust the parameters of the EKF in real time to adapt to the current motion state of the mobile target.Finally,the effectiveness of the algorithm is demonstrated through filtering and tracking using the constant velocity circular motion model(CM).Under the specified conditions,the position and velocity mean square error curves are compared among the snake optimizer(SO)-EKF algorithm,EKF algorithm,and the proposed algorithm.The comparison shows that the proposed algorithm reduces the root mean square error of position by 52%and 41%compared to the SOEKF algorithm and EKF algorithm,respectively.

Multi-Scale Approach for Gold Targeting in Côte d’Ivoire Paleoproterozoic Rocks

The aim of this study is to contribute to better targeting of gold prospecting areas using geospatial information. To this end, 3 mining sites were selected for the study. They are: the Sénoufo belt (Barrick Gold mine), the Yaouré complex (Perseus Mining mine) and the South Fetêkro belt (Bonikro, Hiré and Agbaou mines). For this study, a multi-scale approach was carried out at regional, mine and microscopic levels. At the regional scale, a comparative analysis of 1:200,000 scale geological maps revealed that 3 main lithologies are regularly repeated on and around the various mining sites. These are: undifferentiated volcanics, metagranodiorites and metasiltites dominated by meta-arenites. Most of these lithologies are affected by undifferentiated faults generally oriented NE-SW, N-S, ENE-WSW and WNW-ESE. In addition, gold and manganese occurrences are present on all the sites studied. At the mine scale, radarsat-1 images processing indicate that the main mining sites are generally located near or at the intersection of lineaments-oriented NE-SW or N-S on the one hand and E-W or ENE-WSW or WNW-ESE or again NW-SE on the other. These mines are also located at the interface between zones of high and low lineament density. At the microscopic scale, petrographic studies of undifferentiated volcanic samples from the various sites indicate that they consist of andesites, meta-andesites and tuffs.

To Analyze the Sensitivity of RT-PCR Assays Employing S Gene Target Failure with Whole Genome Sequencing Data during Third Wave by SARS-CoV-2 Omicron Variant

Introduction: Omicron is a highly divergent variant of concern (VOCs) of a severe acute respiratory syndrome SARS-CoV-2. It carries a high number of mutations in its spike protein hence;it is more transmissible in the community by immune evasion mechanisms. Due to mutation within S gene, most Omicron variants have reported S gene target failure (SGTF) with some commercially available PCR kits. Such diagnostic features can be used as markers to screen Omicron. However, Whole Genome Sequencing (WGS) is the only gold standard approach to confirm novel microorganisms at genetically level as similar mutations can also be found in other variants that are circulating at low frequencies worldwide. This Retrospective study is aimed to assess RT-PCR sensitivity in the detection of S gene target failure in comparison with whole genome sequencing to detect variants of Omicron. Methods: We have analysed retrospective data of SARS-CoV-2 positive RT-PCR samples for S gene target failure (SGTF) with TaqPath COVID-19 RT-PCR Combo Kit (ThermoFisher) and combined with sequencing technologies to study the emerged pattern of SARS-CoV-2 variants during third wave at the tertiary care centre, Surat. Results: From the first day of December 2021 till the end of February 2022, a total of 321,803 diagnostic RT-PCR tests for SARS-CoV-2 were performed, of which 20,566 positive cases were reported at our tertiary care centre with an average cumulative positivity of 6.39% over a period of three months. In the month of December 21 samples characterized by the SGTF (70/129) were suggestive of being infected by the Omicron variant and identified as Omicron (B.1.1.529 lineage) when sequence. In the month of January, we analysed a subset of samples (n = 618) with SGTF (24%) and without SGTF (76%) with Ct values Conclusions: During the COVID-19 pandemic, it took almost more than 15 days to diagnose infection and identify pathogen by sequencing technology. In contrast to that molecular assay provided quick identification with the help of SGTF phenomenon within 5 hours of duration. This strategy helps scientists and health policymakers for the quick isolation and identification of clusters. That ultimately results in a decreased transmission of pathogen among the community.

Overview of radar detection methods for low altitude targets in marine environments

In this paper,a comprehensive overview of radar detection methods for low-altitude targets in maritime environments is presented,focusing on the challenges posed by sea clutter and multipath scattering.The performance of the radar detection methods under sea clutter,multipath,and combined conditions is categorized and summarized,and future research directions are outlined to enhance radar detection performance for low-altitude targets in maritime environments.

Enhanced Precision Therapy of Multiple Myeloma Through Engineered Biomimetic Nanoparticles with Dual Targeting

Multiple myeloma(MM)is the second most prevalent hematological malignancy.Current MM treatment strategies are hampered by systemic toxicity and suboptimal therapeutic efficacy.This study addressed these limitations through the development of a potent MM-targeting chemotherapy strategy,which capitalized on the high binding affinity of alendronate for hydroxyapatite in the bone matrix and the homologous targeting of myeloma cell membranes,termed T-PB@M.The results from our investigations highlight the considerable bone affinity of T-PB@M,both in vitro and in vivo.Additionally,this material demonstrated a capability for drug release triggered by low pH conditions.Moreover,T-PB@M induced the generation of reactive oxygen species and triggered cell apoptosis through the poly(ADP-ribose)polymerase 1(PARP1)-Caspase-3-B-cell lymphoma-2(Bcl-2)pathway in MM cells.Notably,T-PB@M preferentially targeted bone-involved sites,thereby circumventing systemic toxic side effects and leading to prolonged survival of MM orthotopic mice.Therefore,this designed target-MM nanocarrier presents a promising and potentially effective platform for the precise treatment of MM.

Dependence of impact regime boundaries on the initial temperatures of projectiles and targets

Towards higher impact velocities,ballistic events are increasingly determined by the material temperatures.Related effects might range from moderate thermal softening to full phase transition.In particular,it is of great interest to quantify the conditions for incipient or full melting of metals during impact interactions,which result in a transition from still strength-affected to hydrodynamic material behavior.In this work,we investigate to which extent the respective melting thresholds are also dependent on the initial,and generally elevated,temperatures of projectiles and targets before impact.This is studied through the application of a model developed recently by the authors to characterize the transition regime between high-velocity and hypervelocity impact,for which the melting thresholds of materials were used as the defining quantities.The obtained results are expected to be of general interest for ballistic application cases where projectiles or targets are preheated.Such conditions might result,for example,from aerodynamic forces acting onto a projectile during atmospheric flight,explosive shapedcharge-jet formation or armor exposure to environmental conditions.The performed analyses also broaden the scientific understanding of the relevance of temperature in penetration events,generally known since the 1960s,but often not considered thoroughly in impact studies.

Short-time maritime target detection based on polarization scattering characteristics

In this paper,a detection method combining Cameron decomposition based on polarization scattering characteristics in sea clutter background is proposed.Firstly,the Cameron decomposition is exploited to fuse the radar echoes of full polarization channels at the data level.Due to the artificial material structure on the surface of the target,it can be shown that the non-reciprocity of the target cell is stronger than that of the clutter cell.Then,based on the analysis of the decomposition results,a new feature with scattering geometry characteristics in polarization domain,denoted as Cameron polarization decomposition scattering weight(CPD-SW),is extracted as the test statistic,which can achieve more detailed descriptions of the clutter scattering characteristics utilizing the difference between their scattering types.Finally,the superiority of the proposed CPD-SW detector over traditional detectors in improving detection performance is verified by the IPIX measured dataset,which has strong stability under short-time observation in threshold detection and can also improve the separability of feature space zin anomaly detection.

Mitochondrial targeting sequence of magnetoreceptor MagR:More than just targeting

Iron-sulfur clusters(ISC)are essential cofactors for proteins involved in various biological processes,such as electron transport,biosynthetic reactions,DNA repair,and gene expression regulation.ISC assembly protein IscA1(or MagR)is found within the mitochondria of most eukaryotes.Magnetoreceptor(MagR)is a highly conserved A-type iron and iron-sulfur cluster-binding protein,characterized by two distinct types of iron-sulfur clusters,[2Fe-2S]and[3Fe-4S],each conferring unique magnetic properties.MagR forms a rod-like polymer structure in complex with photoreceptive cryptochrome(Cry)and serves as a putative magnetoreceptor for retrieving geomagnetic information in animal navigation.Although the N-terminal sequences of MagR vary among species,their specific function remains unknown.In the present study,we found that the N-terminal sequences of pigeon MagR,previously thought to serve as a mitochondrial targeting signal(MTS),were not cleaved following mitochondrial entry but instead modulated the efficiency with which iron-sulfur clusters and irons are bound.Moreover,the N-terminal region of MagR was required for the formation of a stable MagR/Cry complex.Thus,the N-terminal sequences in pigeon MagR fulfil more important functional roles than just mitochondrial targeting.These results further extend our understanding of the function of MagR and provide new insights into the origin of magnetoreception from an evolutionary perspective.

A Real-Time Small Target Vehicle Detection Algorithm with an Improved YOLOv5m Network Model

To address the challenges of high complexity,poor real-time performance,and low detection rates for small target vehicles in existing vehicle object detection algorithms,this paper proposes a real-time lightweight architecture based on You Only Look Once(YOLO)v5m.Firstly,a lightweight upsampling operator called Content-Aware Reassembly of Features(CARAFE)is introduced in the feature fusion layer of the network to maximize the extraction of deep-level features for small target vehicles,reducing the missed detection rate and false detection rate.Secondly,a new prediction layer for tiny targets is added,and the feature fusion network is redesigned to enhance the detection capability for small targets.Finally,this paper applies L1 regularization to train the improved network,followed by pruning and fine-tuning operations to remove redundant channels,reducing computational and parameter complexity and enhancing the detection efficiency of the network.Training is conducted on the VisDrone2019-DET dataset.The experimental results show that the proposed algorithmreduces parameters and computation by 63.8% and 65.8%,respectively.The average detection accuracy improves by 5.15%,and the detection speed reaches 47 images per second,satisfying real-time requirements.Compared with existing approaches,including YOLOv5m and classical vehicle detection algorithms,our method achieves higher accuracy and faster speed for real-time detection of small target vehicles in edge computing.

An Efficient Radar Detection Method of Maneuvering Small Targets

Detection of maneuvering small targets has always been an important yet challenging task for radar signal processing.One primary reason is that target variable motions within coherent processing interval generate energy migrations across multiple resolution bins,which severely deteriorate the parameter estimation performance.A coarse-to-fine strategy for the detection of maneuvering small targets is proposed.Integration of small points segmented coherently is performed first,and then an optimal inter-segment integration is utilized to derive the coarse estimation of the chirp rate.Sparse fractional Fourier transform(FrFT)is then employed to refine the coarse estimation at a significantly reduced computational complexity.Simulation results verify the proposed scheme that achieves an efficient and reliable maneuvering target detection with-16dB input signal-to-noise ratio(SNR),while requires no exact a priori knowledge on the motion parameters.

Contact detumbling toward a nutating target through deformable effectors and prescribed performance controller

Detumbling operation toward a rotating target with nutation is meaningful for debris removal but challenging. In this study, a deformable end-effector is first designed based on the requirements for contacting the nutating target. A dual-arm robotic system installed with the deformable end-effectors is modeled and the movement of the end-tips is analyzed. The complex operation of the contact toward a nutating target places strict requirements on control accuracy and controller robustness. Thus, an improvement of the tracking error transformation is proposed and an adaptive sliding mode controller with prescribed performance is designed to guarantee the fast and precise motion of the effector during the contact detumbling.Finally, by employing the proposed effector and the controller,numerical simulations are carried out to verify the effectiveness and efficiency of the contact detumbling toward a nutating target.

Persymmetric adaptive polarimetric detection of subspace range-spread targets in compound Gaussian sea clutter

This paper focuses on the adaptive detection of range and Doppler dual-spread targets in non-homogeneous and nonGaussian sea clutter.The sea clutter from two polarimetric channels is modeled as a compound-Gaussian model with different parameters,and the target is modeled as a subspace rangespread target model.The persymmetric structure is used to model the clutter covariance matrix,in order to reduce the reliance on secondary data of the designed detectors.Three adaptive polarimetric persymmetric detectors are designed based on the generalized likelihood ratio test(GLRT),Rao test,and Wald test.All the proposed detectors have constant falsealarm rate property with respect to the clutter texture,the speckle covariance matrix.Experimental results on simulated and measured data show that three adaptive detectors outperform the competitors in different clutter environments,and the proposed GLRT detector has the best detection performance under different parameters.

Humanβ-defensin-1 affects the mammalian target of rapamycin pathway and autophagy in colon cancer cells through long noncoding RNA TCONS_00014506

BACKGROUND Colorectal cancer has a low 5-year survival rate and high mortality.Humanβ-defensin-1(hBD-1)may play an integral function in the innate immune system,contributing to the recognition and destruction of cancer cells.Long non-coding RNAs(lncRNAs)are involved in the process of cell differentiation and growth.AIM To investigate the effect of hBD-1 on the mammalian target of rapamycin(mTOR)pathway and autophagy in human colon cancer SW620 cells.METHODS CCK8 assay was utilized for the detection of cell proliferation and determination of the optimal drug concentration.Colony formation assay was employed to assess the effect of hBD-1 on SW620 cell proliferation.Bioinformatics was used to screen potentially biologically significant lncRNAs related to the mTOR pathway.Additionally,p-mTOR(Ser2448),Beclin1,and LC3II/I expression levels in SW620 cells were assessed through Western blot analysis.RESULTS hBD-1 inhibited the proliferative ability of SW620 cells,as evidenced by the reduction in the colony formation capacity of SW620 cells upon exposure to hBD-1.hBD-1 decreased the expression of p-mTOR(Ser2448)protein and increased the expression of Beclin1 and LC3II/I protein.Furthermore,bioinformatics analysis identified seven lncRNAs(2 upregulated and 5 downregulated)related to the mTOR pathway.The lncRNA TCONS_00014506 was ultimately selected.Following the inhibition of the lncRNA TCONS_00014506,exposure to hBD-1 inhibited p-mTOR(Ser2448)and promoted Beclin1 and LC3II/I protein expression.CONCLUSION hBD-1 inhibits the mTOR pathway and promotes autophagy by upregulating the expression of the lncRNA TCONS_00014506 in SW620 cells.

Loss of monopolar spindle-binding protein 3B expression promotes colorectal cancer malignant behaviors by activation of target of rapamycin kinase/autophagy signaling

BACKGROUND Monopolar spindle-binding protein 3B(MOB3B)functions as a signal transducer and altered MOB3B expression is associated with the development of human cancers.AIM To investigate the role of MOB3B in colorectal cancer(CRC).METHODS This study collected 102 CRC tissue samples for immunohistochemical detection of MOB3B expression for association with CRC prognosis.After overexpression and knockdown of MOB3B expression were induced in CRC cell lines,changes in cell viability,migration,invasion,and gene expression were assayed.Tumor cell autophagy was detected using transmission electron microscopy,while nude mouse xenograft experiments were performed to confirm the in-vitro results.RESULTS MOB3B expression was reduced in CRC vs normal tissues and loss of MOB3B expression was associated with poor CRC prognosis.Overexpression of MOB3B protein in vitro attenuated the cell viability as well as the migration and invasion capacities of CRC cells,whereas knockdown of MOB3B expression had the opposite effects in CRC cells.At the molecular level,microtubule-associated protein light chain 3 II/I expression was elevated,whereas the expression of matrix metalloproteinase(MMP)2,MMP9,sequestosome 1,and phosphorylated mechanistic target of rapamycin kinase(mTOR)was downregulated in MOB3B-overexpressing RKO cells.In contrast,the opposite results were observed in tumor cells with MOB3B knockdown.The nude mouse data confirmed these in-vitro findings,i.e.,MOB3B expression suppressed CRC cell xenograft growth,whereas knockdown of MOB3B expression promoted the growth of CRC cell xenografts.CONCLUSION Loss of MOB3B expression promotes CRC development and malignant behaviors,suggesting a potential tumor suppressive role of MOB3B in CRC by inhibition of mTOR/autophagy signaling.