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.

Exploring the groundwater response to rainfall in a translational landslide using the master recession curve method and cross-correlation function

Rainfall is a common trigger for landslide reactivation,as it raises groundwater levels and reduces bedrock or soil shear resistance.This study focuses on the Kualiangzi landslide in the southern region of Sichuan Province,China.Real-time monitoring of groundwater levels and rainfall from July 2013 to September 2016 is analyzed.Groundwater table increments,considering groundwater drainage rate,were calculated using the water-table fluctuation and master recession curve method and the response time of the groundwater table to rainfall events was estimated using the cross-correlation function.Results reveal that groundwater level declines from tension troughs to landslide fronts in the rainy season,with a significant positive correlation between the groundwater level in the tension trough and landslide surface displacement.Evaluated spring elevations for groundwater discharge range from 410 m to 440 m,which is in agreement with the actual spring elevations(390-423 m).Lag times of groundwater response to rainfall decreases with cumulative rainfall of the rainy periods.In the middle part of the landslide,two responses between rainfall and groundwater levels indicate two water movement pathways:Vertical cracks or fractures resulting from the slow landslide movement,and matrix pore space in unconsolidated sediment.Variations in peak values of the cross-correlation function suggest early dominance of the uniform matrix flow and later dominance of preferential flow during the rainy period.

A human translational model based on neuroplasticity for pharmacological agents potentially effective in Treatment-Resistant Depression: focus on dopaminergic system

Major depressive disorder(MDD)is a common psychiatric condition characterized by two main symptoms,low mood and anhedonia.About 15–30%of people suffering from MDD do not respond to standard-of-care antidepressants,e.g.,the serotonin re-uptake inhibitors(SSRI),and are considered affected by Treatment-Resistant Depression(TRD).The neurobiology of this condition is presently unknown.Recent attempts of developing novel treatments for TRD have been driven by four major breakthroughs:(1)Increasing dopaminergic neurotransmission improves TRD symptoms;(2)Anhedonia occurs when central dopaminergic neurotransmission is low;(3)Enhanced neuroplasticity is critical for the action of antidepressants;(4)Ketamine shows antidepressant properties in TRD patients and triggers neuroplasticity in preclinical animal models.These breakthroughs are at the basis of a putative human translational cellular model for antidepressant agents that we are proposing in this article.The rationale is briefly described here.

Motor tract reorganization after acute central nervous system injury: a translational perspective

Acute central nervous system injuries are among the most common causes of disability worldwide,with widespread social and economic implications.Motor tract injury accounts for the majority of this disability;therefore,there is impetus to understand mechanisms underlying the pathophysiology of injury and subsequent reorganization of the motor tract that may lead to recovery.After acute central nervous system injury,there are changes in the microenvironment and structure of the motor tract.For example,ischemic stroke involves decreased local blood flow and tissue death from lack of oxygen and nutrients.Traumatic injury,in contrast,causes stretching and shearing injury to microstructures,including myelinated axons and their surrounding vessels.Both involve blood-brain barrier dysfunction,which is an important initial event.After acute central nervous system injury,motor tract reorganization occurs in the form of cortical remapping in the gray matter and axonal regeneration and rewiring in the white matter.Cortical remapping involves one cortical region taking on the role of another.cAMP-response-element binding protein is a key transcription factor that can enhance plasticity in the peri-infarct cortex.Axonal regeneration and rewiring depend on complex cell-cell interactions between axons,oligodendrocytes,and other cells.The RhoA/Rho-associated coiled-coil containing kinase signaling pathway plays a central role in axon growth/regeneration through interactions with myelin-derived axonal growth inhibitors and regulation of actin cytoskeletal dynamics.Oligodendrocytes and their precursors play a role in myelination,and neurons are involved through their voltage-gated calcium channels.Understanding the pathophysiology of injury and the biology of motor tract reorganization may allow the development of therapies to enhance recovery after acute central nervous system injury.These include targeted rehabilitation,novel pharmacotherapies,such as growth factors and axonal growth inhibitor blockade,and the implementation of neurotechnologies,such as central nervous system stimulators and robotics.The translation of these advances depends on careful alignment of preclinical studies and human clinical trials.As experimental data mount,the future is one of optimism.

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.

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.

Translational regulation of DNA repair systems by eIF3a in cancer chemotherapeutic response

OBJECTIVE To investigate the role of e IF3a in the regulation of DNA repair pathways in cancer chemotherapeutic response.METHODS Immunohistochemistry was used to determine the expression of e IF3a in lung and breast cancer tissues followed by association analysis of e IF3a expression with patient′s response to chemotherapy.Ectopic overexpression and RNA interference knockdown of e IF3a were carried out in NIH3T3and H1299 cell lines,respectively,to determine the effect of altered e IF3a expression on cellular response to chemotherapeutic drugs by using MTT assay.The DNA repair capacity of these cells was evaluated by using host-cell reactivation,NHEJ and HR assay.Real-time reverse transcriptase PCR and Western Blot analyses were carried out to determine the effect of e IF3a on the DNA repair genes by using cells with altered e IF3a expression.RESULTS e IF3a expression associates with response of lung and breast cancer patients to platinum and anthracycline.e IF3a knockdown or overexpression,respectively,increased and decreased the cellular resistance to cisplatin and anthracycline anticancer drugs,DNA repair activity,and expression of NER and NHEJ DNA repair proteins.CONCLUSION e IF3a plays an important role in regulating the expression of NER and NHEJ DNA repair proteins which,in turn,contributes to cellular response to DNA-damaging anticancer drugs and patients′response to platinum and anthracycline chemotherapy.

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.

BME2.1: The Need for a Systems Approach to Addressing Race-Based Disparities in Health and Health Care

The recent article by Miller et al.[1]in BMEF on reimagining the Biomedical Engineering(BME)curriculum of the future proposes several exciting and transformative core principles.These include(a)incorporating modern molecular biology and analytical/computational modeling,(b)providing instruction in data science fundamentals,(c)integrating clinical needs for innovation and translation,(d)fostering an educational culture of inclusive excellence,and(e)ensuring that new research discoveries inform the core curriculum.

Research on system combination of machine translation based on Transformer

Influenced by its training corpus,the performance of different machine translation systems varies greatly.Aiming at achieving higher quality translations,system combination methods combine the translation results of multiple systems through statistical combination or neural network combination.This paper proposes a new multi-system translation combination method based on the Transformer architecture,which uses a multi-encoder to encode source sentences and the translation results of each system in order to realize encoder combination and decoder combination.The experimental verification on the Chinese-English translation task shows that this method has 1.2-2.35 more bilingual evaluation understudy(BLEU)points compared with the best single system results,0.71-3.12 more BLEU points compared with the statistical combination method,and 0.14-0.62 more BLEU points compared with the state-of-the-art neural network combination method.The experimental results demonstrate the effectiveness of the proposed system combination method based on Transformer.

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.

Intelligent Sign Multi-Language Real-Time Prediction System with Effective Data Preprocessing

A multidisciplinary approach for developing an intelligent sign multi-language recognition system to greatly enhance deaf-mute communication will be discussed and implemented. This involves designing a low-cost glove-based sensing system, collecting large and diverse datasets, preprocessing the data, and using efficient machine learning models. Furthermore, the glove is integrated with a user-friendly mobile application called “Life-sign” for this system. The main goal of this work is to minimize the processing time of machine learning classifiers while maintaining higher accuracy performance. This is achieved by using effective preprocessing algorithms to handle noisy and inconsistent data. Testing and iterating approaches have been applied to various classifiers to refine and improve their accuracy in the recognition process. Additionally, the Extra Trees (ET) classifier has been identified as the best algorithm, with results proving successful gesture prediction at an average accuracy of about 99.54%. A smart optimization feature has been implemented to control the size of data transferred via Bluetooth, allowing for fast recognition of consecutive gestures. Real-time performance has been measured through extensive experimental testing on various consecutive gestures, specifically referring to Arabic Sign Language (ArSL). The results have demonstrated that the system guarantees consecutive gesture recognition with a lower delay of 50 milliseconds.

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.