Translational bioengineering strategies for peripheral nerve regeneration:opportunities,challenges,and novel concepts

Peripheral nerve injuries remain a challenging problem in need of better treatment strategies.Despite best efforts at surgical reconstruction and postoperative rehabilitation,patients are often left with persistent,debilitating motor and sensory deficits.There are currently no therapeutic strategies proven to enhance the regenerative process in humans.A clinical need exists for the development of technologies to promote nerve regeneration and improve functional outcomes.Recent advances in the fields of tissue engineering and nanotechnology have enabled biomaterial scaffolds to modulate the host response to tissue repair through tailored mechanical,chemical,and conductive cues.New bioengineered approaches have enabled targeted,sustained delivery of protein therapeutics with the capacity to unlock the clinical potential of a myriad of neurotrophic growth factors that have demonstrated promise in enhancing regenerative outcomes.As such,further exploration of combinatory strategies leveraging these technological advances may offer a pathway towards clinically translatable solutions to advance the care of patients with peripheral nerve injuries.This review first presents the various emerging bioengineering strategies that can be applied for the management of nerve gap injuries.We cover the rationale and limitations for their use as an alternative to autografts,focusing on the approaches to increase the number of regenerating axons crossing the repair site,and facilitating their growth towards the distal stump.We also discuss the emerging growth factor-based therapeutic strategies designed to improve functional outcomes in a multimodal fashion,by accelerating axonal growth,improving the distal regenerative environment,and preventing end-organs atrophy.

Integrative multi-omics and systems bioinformatics in translational neuroscience:A data mining perspective

Bioinformatic analysis of large and complex omics datasets has become increasingly useful in modern day biology by providing a great depth of information,with its application to neuroscience termed neuroinformatics.Data mining of omics datasets has enabled the generation of new hypotheses based on differentially regulated biological molecules associated with disease mechanisms,which can be tested experimentally for improved diagnostic and therapeutic targeting of neurodegenerative diseases.Importantly,integrating multi-omics data using a systems bioinformatics approach will advance the understanding of the layered and interactive network of biological regulation that exchanges systemic knowledge to facilitate the development of a comprehensive human brain profile.In this review,we first summarize data mining studies utilizing datasets from the individual type of omics analysis,including epigenetics/epigenomics,transcriptomics,proteomics,metabolomics,lipidomics,and spatial omics,pertaining to Alzheimer's disease,Parkinson's disease,and multiple sclerosis.We then discuss multi-omics integration approaches,including independent biological integration and unsupervised integration methods,for more intuitive and informative interpretation of the biological data obtained across different omics layers.We further assess studies that integrate multi-omics in data mining which provide convoluted biological insights and offer proof-of-concept proposition towards systems bioinformatics in the reconstruction of brain networks.Finally,we recommend a combination of high dimensional bioinformatics analysis with experimental validation to achieve translational neuroscience applications including biomarker discovery,therapeutic development,and elucidation of disease mechanisms.We conclude by providing future perspectives and opportunities in applying integrative multi-omics and systems bioinformatics to achieve precision phenotyping of neurodegenerative diseases and towards personalized medicine.

Advances in translational therapy for locally advanced gastric cancer

Translational therapy refers to a combination of chemotherapy,radiotherapy,targeted therapy,and immunotherapy for patients with advanced gastric cancer who are initially unable to undergo R0 resection.This treatment can achieve partial or complete remission of the unresectable tumors to meet the criteria for R0 resection,thus enabling the patients to prolong their survival time and improve their quality of life.In gastric cancer,translational therapy has been tried and improved.At present,there are a large number of patients with locally advanced gastric cancer in China,and the selection of suitable patients for transla-tional therapy to prolong objective survival and improve survival quality is one of the hot spots in the field of gastric cancer research.

Type Synthesis of Fully Decoupled Three Translational Parallel Mechanism with Closed-Loop Units and High Stifness

In order to solve the problem of weak stifness of the existing fully decoupled parallel mechanism, a new synthesis method of fully decoupled three translational (3T) parallel mechanisms (PMs) with closed-loop units and high stifness is proposed based on screw theory. Firstly, a new criterion for the full decoupled of PMs is presented that the reciprocal product of the transmission wrench screw matrix and the output twist screw matrix of PMs is a diagonal matrix, and all elements on the main diagonal are nonzero constants. The forms of the transmission wrench screws are determined by the criterion. Secondly, the forms of the actuated and unactuated screws can be obtained according to their relationships with the transmission wrench screws. The basic decoupled limbs are generated by combination of the above actuated and unactuated screws. Finally, a closed-loop units construction method is investigated to apply the decoupled mechanisms in a better way on the high stifness occasion. The closed-loop units are constructed in the basic decoupled limbs to generate a high-stifness fully decoupled 3T PM. Kinematic and stifness analyses show that the Jacobian matrix is a diagonal matrix, and the stifness is obviously higher than that of the coupling mechanisms, which verifes the correctness of the proposed synthesis method. The mechanism synthesized by this method has a good application prospect in vehicle durability test platform.

Translational research and innovation in modern transplant practice:Paradigms from Greece and around the world

The continuous clinical and technological advances,together with the social,health and economic challenges that the global population faces,have created an environment where the evolution of the field of transplantation is essentially necessary.The goal of this special issue is to provide a picture of the current status of transplantation in Greece as well as in many other countries in Europe and around the world.Authors from Greece and several other countries provide us with valuable insight into their respective areas of transplant expertise,with a main focus on the field of translational research and innovation.The papers that are part of this Special Issue“Translational Research and Innovation and the current status of Transplantation in Greece”have presented innovative and meaningful approaches in modern transplant research and practice.They provide us with a clear overview of the current landscape in transplantation,including liver transplantation in the context of a major pandemic,the evolution of living donor kidney transplantation or the evolution of the effect of hepatitis C virus infection in transplantation,while at the same time explore more recent challenges,such as the issue of frailty in the transplant candidate and the changes brought by newer treatments,such as immunotherapy,in transplant oncology.Additionally,they offer us a glimpse of the effect that technological innovations,such as virtual reality,can have on transplantation,both in terms of clinical and educational aspects.Just as critical is the fact that this Special Issue emphasizes the multidisciplinary,collaborative efforts currently taking place that link transplant research and innovation with other cutting-edge disciplines such as bioengineering,advanced information technology and artificial intelligence.In this Special Issue,in addition to the clinical and research evolution of the field of transplantation,we are witnessing the importance of interdisciplinary collaboration in medicine.

Regenerative Medicine in Orthopaedics: Microsurgery Achievements for Translational Animal Model

Purpose: Despite many scientific advances, Regenerative Medicine is still in the preclinical stages in many areas. In this article, we intend to discuss the role of microsurgery in the bench-to-bedside transition of such primary findings. Method: By searching the papers related to the history of Regenerative Medicine (RM) and the news of Tissue Engineering (TE) in orthopedics in Pubmed, Scopus, and Google Scholar databases, we accessed a complete archive of various topics related to this field. Result: We first assessed the history and achievements of regenerative medicine, then we realized the importance of translational medical sciences and the role of animal models in this incipient phenomenon. Finally, after mastering the capabilities of microsurgery and the useful contribution of this technique to the advancement of clinical applications of regenerative medicine in various branches such as skin, skeletal system, nerves, and blood vessels, we decided to express the gist of our studies through this article. Conclusion: Considering the widespread use of small animals in regenerative medicine projects and the inevitable role of microsurgery in performing the best intervention on these animal models, the significant progress of regenerative medicine clinical application requires special attention to microsurgery in associated research.

A comprehensive look at the psychoneuroimmunoendocrinology of spinal cord injury and its progression: mechanisms and clinical opportunities

Spinal cord injury(SCI)is a devastating and disabling medical condition generally caused by a traumatic event(primary injury).This initial trauma is accompanied by a set of biological mechanisms directed to ameliorate neural damage but also exacerbate initial damage(secondary injury).The alterations that occur in the spinal cord have not only local but also systemic consequences and virtually all organs and tissues of the body incur important changes after SCI,explaining the progression and detrimental consequences related to this condition.Psychoneuroimmunoendocrinology(PNIE)is a growing area of research aiming to integrate and explore the interactions among the different systems that compose the human organism,considering the mind and the body as a whole.The initial traumatic event and the consequent neurological disruption trigger immune,endocrine,and multisystem dysfunction,which in turn affect the patient's psyche and well-being.In the present review,we will explore the most important local and systemic consequences of SCI from a PNIE perspective,defining the changes occurring in each system and how all these mechanisms are interconnected.Finally,potential clinical approaches derived from this knowledge will also be collectively presented with the aim to develop integrative therapies to maximize the clinical management of these patients.

Tbx 4 and Tbx 5 gene expression associated with appendage development and its relationship with the absence of the pelvic fin in Pampus argenteus

The Tbx family is first known through the study of their functions in the body and limbs,and its members Tbx4 and Tbx5 genes are important factors in determining the characteristics of the appendages.Pampus argenteus is one of the important economical marine fishes widely distributed in offshore areas.Therefore,it is necessary to study the role of Tbx family genes in the deletion of pelvic fin in P.argenteus.In this study,we cloned Tbx4 and Tbx5 cDNA sequence of P.argenteus(GenBank:MH709128 and MH712458).The Western blot and real time PCR were used to detect the expressions of Tbx4 and Tbx5 in different developmental stages and tissues of P.argenteus.In addition,whole-mount in-situ hybridization was used to study the localization of Tbx4 and Tbx5 genes in different developmental stages of P.argenteus.Results show that the translation of Tbx4 mRNA was inhibited during the critical period of pelvic fin development.Among different tissues,Tbx4 protein levels were the lowest in the abdominal epithelium,and even lower than that in the pectoral fin,suggesting that the protein expression was also inhibited in the abdominal epithelium of adult P.argenteus.Therefore,the results indicated that upstream genes regulation led to the key stage-specific and low expression of Tbx4 during pelvic fin development and in the abdominal epithelium.

Behaviors of cavitation bubbles driven by high-intensity ultrasound

In a multi-bubble system, the bubble behavior is modulated by the primary acoustic field and the secondary acoustic field. To explore the translational motion of bubbles in cavitation liquids containing high-concentration cavitation nuclei,evolutions of bubbles are recorded by a high-speed camera, and translational trajectories of several representative bubbles are traced. It is found that translational motion of bubbles is always accompanied by the fragmentation and coalescence of bubbles, and for bubbles smaller than 10 μm, the possibility of bubble coalescence is enhanced when the spacing of bubbles is less than 30 μm. The measured signals and their spectra show the presence of strong negative pressure, broadband noise,and various harmonics, which implies that multiple interactions of bubbles appear in the region of high-intensity cavitation.Due to the strong coupling effect, the interaction between bubbles is random. A simplified triple-bubble model is developed to explore the interaction patterns of bubbles affected by the surrounding bubbles. Patterns of bubble interaction, such as attraction, repulsion, stable spacing, and rebound of bubbles, can be predicted by the theoretical analysis, and the obtained results are in good agreement with experimental observations. Mass exchange between the liquid and bubbles as well as absorption in the cavitation nuclei also plays an important role in multi-bubble cavitation, which may account for the weakening of the radial oscillations of bubbles.

The big data challenge-and how polypharmacology supports the translation from pre-clinical research into clinical use against neurodegenerative diseases and beyond

Introductory comments:The identification and validation of disease-modifying proteins are fundamental aspects in drug development.However,the m ultifactority of n eurodegen era tive diseases poses a real challenge for targeted therapies.Furthermore,the behavior of individually(over-)expressed to rget proteins in vitro is likely to differ from their actual functional behavior when embedded in cascades and pathways in vivo.

Neuron-to-astrocyte proteostatic stress signaling in response to tau pathology

Maintenance of protein homeostasis or“proteostasis”is essential for the functioning and viability of cells.This is in particular the case for cells like neurons that cannot self-renew and acquire unique functional properties during their lifetime.Cellular proteostatic stress responses are in place to protect cells from damage in case of proteostatic challenges.The integrated stress response(ISR)is one of the key proteostatic stress responses in the cell(Costa-Mattioli and Walter,2020).The ISR is the downstream convergence point for the four stress-induced eIF2αkinases(EIF2AK1-4)that control stress-regulated protein translation via phosphorylation of the translation factor eIF2α.ISR activation results in a transient reduction of global translation while it concomitantly enhances the translation of specific mRNAs,including that encoding the activating transcription factor 4(ATF4).Together,the translational control mediated by the ISR results in a temporary reduction of the overall protein load and the selectively increased expression of proteins that contribute to restoration of the proteostatic balance.

Multidisciplinary comprehensive treatment of massive hepatocellular carcinoma with hemorrhage:A case report and review of literature

BACKGROUND Hepatocellular carcinoma(HCC),a major contributor to cancer-related deaths,is particularly prevalent in Asia,largely due to hepatitis B virus infection.Its prognosis is generally poor.This case report contributes to the medical literature by detailing a unique approach in treating a large HCC through multidisciplinary collaboration,particularly in patients with massive HCC complicated by ruptured bleeding,a scenario not extensively documented previously.CASE SUMMARY The patient presented with large HCC complicated by intratumoral bleeding.Treatment involved a multidisciplinary approach,providing individualized care.The strategy included drug-eluting bead transarterial chemoembolization,sorafenib-targeted therapy,laparoscopic partial hepatectomy,and standardized sintilimab monoclonal antibody therapy.Six months after treatment,the patient achieved complete radiological remission,with significant symptom relief.Imaging studies showed no lesions or recurrence,and clinical assessments confirmed complete remission.This report is notable as possibly the first docu-mented case of successfully treating such complex HCC conditions through integrated multidisciplinary efforts,offering new insights and a reference for future similar cases.CONCLUSION This study demonstrated effective multidisciplinary treatment for massive HCC with intratumoral bleeding,providing insights for future similar cases.

RNPS1 stabilizes NAT10 protein to facilitate translation in cancer via tRNA ac^(4)C modification

Existing studies have underscored the pivotal role of N-acetyltransferase 10(NAT10) in various cancers. However, the outcomes of protein-protein interactions between NAT10 and its protein partners in head and neck squamous cell carcinoma(HNSCC) remain unexplored. In this study, we identified a significant upregulation of RNA-binding protein with serine-rich domain 1(RNPS1) in HNSCC, where RNPS1 inhibits the ubiquitination degradation of NAT10 by E3 ubiquitin ligase, zinc finger SWIM domain-containing protein 6(ZSWIM6), through direct protein interaction, thereby promoting high NAT10 expression in HNSCC. This upregulated NAT10 stability mediates the enhancement of specific tRNA ac^(4)C modifications, subsequently boosting the translation process of genes involved in pathways such as IL-6 signaling, IL-8 signaling, and PTEN signaling that play roles in regulating HNSCC malignant progression, ultimately influencing the survival and prognosis of HNSCC patients. Additionally, we pioneered the development of TRMC-seq, leading to the discovery of novel t RNA-ac^(4)C modification sites, thereby providing a potent sequencing tool for tRNAac^(4)C research. Our findings expand the repertoire of tRNA ac^(4)C modifications and identify a role of tRNA ac^(4)C in the regulation of mRNA translation in HNSCC.

Effective extraction of polyribosomes from astrocytes enables future discoveries on translation regulation

Translation regulation is an important layer of gene expression:Generation of genome-wide expression datasets at multi-omics levels in spatial,temporal,and cell-type resolution is essential for deciphering brain complexity.Regulation of gene expression is a highly dynamic process aiming at the production of precise levels of gene products to guarantee optimal cellular function,in response to physiological cues.Speedy advances in next-generation sequencing enabled the understanding of epigenomic and transcriptomic dynamic landscapes of different brain regions along development,aging,and disease progression.However,the correlation of the“transcriptome”with protein levels is poor because numerous mRNAs are subjected to manipulation of their translation efficiency,to warrant a favorable result under certain conditions.Hence,it is widely accepted that regulation at the translation level is a vital layer of gene expression.Quantification of actively translated mRNA populations(i.e.,“translatome”)is a more reliable predictor of the“proteome”(Wang et al.,2020).

Red cell distribution width/platelet ratio estimates the 3-year risk of decompensation in Metabolic Dysfunction-Associated Steatotic Liver Disease-induced cirrhosis

BACKGROUND For compensated advanced chronic liver disease(cACLD)patients,the first decompensation represents a dramatically worsening prognostic event.Based on the first decompensation event(DE),the transition to decompensated advanced chronic liver disease(dACLD)can occur through two modalities referred to as acute decompensation(AD)and non-AD(NAD),respectively.Clinically Significant Portal Hypertension(CSPH)is considered the strongest predictor of decompensation in these patients.However,due to its invasiveness and costs,CSPH is almost never evaluated in clinical practice.Therefore,recognizing noninvasively predicting tools still have more appeal across healthcare systems.The red cell distribution width to platelet ratio(RPR)has been reported to be an indicator of hepatic fibrosis in Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD).However,its predictive role for the decompensation has never been explored.AIM In this observational study,we investigated the clinical usage of RPR in predicting DEs in MASLD-related cACLD patients.METHODS Fourty controls and 150 MASLD-cACLD patients were consecutively enrolled and followed up(FUP)semiannually for 3 years.At baseline,biochemical,clinical,and Liver Stiffness Measurement(LSM),Child-Pugh(CP),Model for End-Stage Liver Disease(MELD),aspartate aminotransferase/platelet count ratio index(APRI),Fibrosis-4(FIB-4),Albumin-Bilirubin(ALBI),ALBI-FIB-4,and RPR were collected.During FUP,DEs(timing and modaities)were recorded.CSPH was assessed at the baseline and on DE occurrence according to the available Clinical Practice Guidelines.RESULTS Of 150 MASLD-related cACLD patients,43(28.6%)progressed to dACLD at a median time of 28.9 months(29 NAD and 14 AD).Baseline RPR values were significantly higher in cACLD in comparison to controls,as well as MELD,CP,APRI,FIB-4,ALBI,ALBI-FIB-4,and LSM in dACLD-progressing compared to cACLD individuals[all P<0.0001,except for FIB-4(P:0.007)and ALBI(P:0.011)].Receiving operator curve analysis revealed RPR>0.472 and>0.894 as the best cut-offs in the prediction respectively of 3-year first DE,as well as its superiority compared to the other non-invasive tools examined.RPR(P:0.02)and the presence of baseline-CSPH(P:0.04)were significantly and independently associated with the DE.Patients presenting baseline-CSPH and RPR>0.472 showed higher risk of decompensation(P:0.0023).CONCLUSION Altogether these findings suggest the RPR as a valid and potentially applicable non-invasive tool in the prediction of timing and modalities of decompensation in MASLD-related cACLD patients.

High-visibility ghost imaging with phase-controlled discrete classical light sources

We take phase modulation to create discrete phase-controlled sources and realize the super-bunching effect by a phasecorrelated method. From theoretical and numerical simulations, we find the space translation invariance of the bunching effect is a key point for the ghost imaging realization. Experimentally, we create the orderly phase-correlated discrete sources which can realize high-visibility second-order ghost imaging than the result with chaotic sources. Moreover, some factors affecting the visibility of ghost image are discussed in detail.

A STABILITY RESULT FOR TRANSLATINGSPACELIKE GRAPHS IN LORENTZ MANIFOLDS

In this paper,we investigate spacelike graphs defined over a domain Ω⊂M^(n) in the Lorentz manifold M^(n)×ℝ with the metric−ds^(2)+σ,where M^(n) is a complete Riemannian n-manifold with the metricσ,Ωhas piecewise smooth boundary,and ℝ denotes the Euclidean 1-space.We prove an interesting stability result for translating spacelike graphs in M^(n)×ℝ under a conformal transformation.

Unified deep learning model for predicting fundus fluorescein angiography image from fundus structure image

The prediction of fundus fluorescein angiography(FFA)images from fundus structural images is a cutting-edge research topic in ophthalmological image processing.Prediction comprises estimating FFA from fundus camera imaging,single-phase FFA from scanning laser ophthalmoscopy(SLO),and three-phase FFA also from SLO.Although many deep learning models are available,a single model can only perform one or two of these prediction tasks.To accomplish three prediction tasks using a unified method,we propose a unified deep learning model for predicting FFA images from fundus structure images using a supervised generative adversarial network.The three prediction tasks are processed as follows:data preparation,network training under FFA supervision,and FFA image prediction from fundus structure images on a test set.By comparing the FFA images predicted by our model,pix2pix,and CycleGAN,we demonstrate the remarkable progress achieved by our proposal.The high performance of our model is validated in terms of the peak signal-to-noise ratio,structural similarity index,and mean squared error.

An Exploration of How Practitioners Make Meaning in a Chinese Medicine Consultation and Treatment

In Chinese medicine, practitioners assess patients’ complaints, analyze their underlying problems, identify causes and come to a diagnosis, which then directs treatment. What is not obvious and not recorded in a consultation is the clinical reasoning process that practitioners use. The research filmed three practitioners in the UK while they conducted a consultation and treatment on new patients. The practitioners and researchers viewed the films and used them as aide-memoirs while the reasoning process throughout was discussed. In order to determine the pattern, practitioners used the four examinations to gather information from the patient in an iterative process;their aesthetic reasoning was highly developed. Through triangulation they checked the information they received against a detailed understanding of the qi-dynamic. They used highly analytical strategies of forward(inductive) and backward(deductive) reasoning against the prototypes of the signs and symptoms that indicate a specific Zheng. This was achieved through an abductive process that linked description with explanation and causal factors with pathological mechanisms. The feedback loop with the patient continued through the consultation and into the treatment. A process of translation and interpretation was needed to turn the patient’s story into the practitioner’s story of qi-dynamics that then directed the treatment. Awareness of our clinical reasoning process will mitigate against biases, improve our diagnoses and treatment choices and support the training of students.

Scoliocorrector Fatma-UI for correction of adolescent idiopathic scoliosis: Development, effectivity, safety and functional outcome

BACKGROUND Adolescent idiopathic scoliosis remains a major problem due to its high incidence,high risk,and high cost.One of the aims of the management in scoliosis is to correct the deformity.Many techniques are available to correct scoliosis deformity;however,they are all far from ideal to achieve three-dimensional correction in scoliosis.AIM To develop a set of tools named Scoliocorrector Fatma-UI(SCFUI)to aid threedimensional correction and to evaluate the efficacy,safety,and functional outcome.METHODS This study consists of two stages.In the first stage,we developed the SCFUI and tested it in finite element and biomechanical tests.The second stage was a single-blinded randomized clinical trial to evaluate the SCFUI compared to direct vertebral rotation(DVR).Forty-four subjects with adolescent idiopathic scoliosis were randomly allocated into the DVR group(n=23)and SCFUI group(n=21).Radiological,neurological,and functional outcome was compared between the groups.RESULTS Finite element revealed the maximum stress of the SCFUI components to be between 31.2-252 MPa.Biomechanical analysis revealed the modulus elasticity of SCFUI was 9561324±633277 MPa.Both groups showed improvement in Cobb angle and sagittal profile,however the rotation angle was lower in the SCFUI group(11.59±7.46 vs 18.23±6.39,P=0.001).Neurological and functional outcome were comparable in both groups.CONCLUSION We concluded that SCFUI developed in this study resulted in similar coronal and sagittal but better rotational correction compared to DVR.The safety and functional outcomes were also similar to DVR.