Translational Approach Research Articles

Translational insights into the hormetic potential of carbon dioxide: from physiological mechanisms to innovative adjunct therapeutic potential for cancer.

Carbon dioxide (CO2), traditionally viewed as a mere byproduct of cellular respiration, plays a multifaceted role in human physiology beyond simple elimination through respiration. CO2 may regulate the tumor microenvironment by significantly affecting the release of oxygen (O2) to tissues through the Bohr effect and by modulating blood pH and vasodilation. Previous studies suggest hypercapnia (elevated CO2 levels) might trigger optimized cellular mechanisms with potential therapeutic benefits. The role of CO2 in cellular stress conditions within tumor environments and its impact on O2 utilization offers a new investigative area in oncology. This study aims to explore CO2's role in the tumor environment, particularly how its physiological properties and adaptive responses can influence therapeutic strategies. By applying a structured translational approach using the Work Breakdown Structure method, the study divided the analysis into six interconnected work packages to comprehensively analyze the interactions between carbon dioxide and the tumor microenvironment. Methods included systematic literature reviews, data analyses, data integration for identifying critical success factors and exploring extracellular environment modulation. The research used SMART criteria for assessing innovation and the applicability of results. The research revealed that the human body's adaptability to hypercapnic conditions could potentially inform innovative strategies for manipulating the tumor microenvironment. This could enhance O2 utilization efficiency and manage adaptive responses to cellular stress. The study proposed that carbon dioxide's hormetic potential could induce beneficial responses in the tumor microenvironment, prompting clinical protocols for experimental validation. The research underscored the importance of pH regulation, emphasizing CO2 and carbonic acid's role in modulating metabolic and signaling pathways related to cancer. The study underscores CO2 as vital to our physiology and suggests potential therapeutic uses within the tumor microenvironment. pH modulation and cellular oxygenation optimization via CO2 manipulation could offer innovative strategies to enhance existing cancer therapies. These findings encourage further exploration of CO2's therapeutic potential. Future research should focus on experimental validation and exploration of clinical applications, emphasizing the need for interdisciplinary and collaborative approaches to tackle current challenges in cancer treatment.

New Modifiable Risk Factors Influencing Coronary Artery Disease Severity.

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide with coronary artery disease (CAD) being the first culprit in this group. In terms of CAD, not only its presence but also its severity plays a role in the patient's treatment and prognosis. CAD complexity can be assessed with the indicator named the SYNTAX score (SS). A higher SS is associated with major adverse cardiovascular event (MACE) occurrence in short- and long-term observations. Hence, the risk factors affecting CAD severity based on SS results may help lower the risk among patients with already developed CAD to reduce their impact on coronary atherosclerosis progression. The well-established risk factors of CAD are consistent with those associated with the coronary plaque burden. However, recently, it was shown that new indicators exist, which we present in this paper, that significantly contribute to CAD complexity such as inflammatory parameters, C-reactive protein (CRP), ratios based on blood smear results, and uric acid. Moreover, microbiota alteration, vitamin D deficiency, and obstructive sleep apnea (OSA) also predicted CAD severity. However, sometimes, certain indicators were revealed as significant only in terms of chronic coronary syndromes (CCSs) or specific acute coronary syndromes (ACSs). Importantly, there is a need to apply the interdisciplinary and translational approach to the novel CAD severity risk assessment to maximize the impact of secondary prevention among patients at risk of coronary atherosclerosis progression.

Translational Pharmacokinetic-Toxicodynamic Model of Myelosuppression for Dose Optimization in Combination Chemotherapy of Capecitabine and Oxaliplatin from Rats to Humans.

XELOX therapy, which comprises capecitabine and oxaliplatin, is the standard first-line chemotherapeutic regimen for colorectal cancer. However, its myelosuppressive effects pose challenges for its clinical management. Mathematical modeling combining pharmacokinetics (PK) and toxicodynamics (TD) is a promising approach for optimizing dosing strategies and reducing toxicity. This study aimed to develop a translational PK-TD model using rat data to inform dosing strategies and TD implications in humans. The rats were administered capecitabine, oxaliplatin, or XELOX combination regimen, and PK and TD data were collected. PK parameters were analyzed using sequential compartment analysis, whereas TD responses were assessed using Friberg's semiphysiological model. A toxicity intensity-based nomogram recommends optimal dosing strategies. Translational modeling techniques using the hybrid PK-TD model were employed to predict clinical responses. The PK-TD model successfully predicted the time-course profiles of hematological responses in rats following monotherapy and XELOX combination treatment. Interactive effects on lymphocytopenia were identified with the coadministration of capecitabine and oxaliplatin. A model-based recommended combination of the dose reduction rate for escaping severe lymphocytopenia was proposed as 40% and 60% doses of capecitabine and oxaliplatin, respectively. The current translational model techniques successfully simulated the time-course profiles of blood cell counts with confidence intervals in patients using rat data. Our study provides valuable insights into dose optimization strategies for each individual drug within the XELOX regimen and underscores the potential of translational modeling to improve patient outcomes. In addition to dose determination, these data will lay the groundwork for advancing drug development processes in oncology. SIGNIFICANCE STATEMENT: This study introduced a novel translational modeling approach rooted in a rat PK-TD model to optimize dosing strategies for the XELOX regimen for colorectal cancer treatment. Our findings highlight the interactive effects on lymphocytopenia and suggest a toxicity intensity-based nomogram for dose reduction, thus advancing precision medicine. This translational modeling paradigm enhances our understanding of drug interactions, offering a tool to tailor dosing, minimize hematological toxicity, and improve therapeutic outcomes in patients undergoing XELOX therapy.

P53 at the crossroads of tumor immunity.

The p53 tumor suppressor protein has a plethora of cell-intrinsic functions and consequences that impact diverse cell types and tissues. Recent studies are beginning to unravel how wild-type and mutant p53 work in distinct ways to modulate tumor immunity. This sets up a disequilibrium between tumor immunosurveillance and escape therefrom. The ability to exploit this emerging knowledge for translational approaches may shape immunotherapy and targeted therapeutics in the future, especially in combinatorial settings.

A Translational Approach to Using Endocannabinoid Modulators for Targeting Opioid-Associated Memory

A Translational Approach to Using Endocannabinoid Modulators for Targeting Opioid-Associated Memory

Issues of translation for the ISO/TS 12913–2:2018 Attributes: Paradox of Equivalence, Non-Equivalence and suggested approaches to Construct Equivalence in Cross-Cultural soundscape research

ISO/TS 12913–2:2018 includes selected attributes for the characterization of the perceived affective quality of soundscapes. The Soundscape Attributes Translation Project (SATP) is an international collaboration of researchers that aims to provide translations of the ISO/TS 12913–2:2018 attributes in a growing number of languages. However, in the translation process, various issues may arise. ‘Paradox of equivalence’ refers to the issue that if a form of a test or other measure is demanded to yield comparable results in two cultures, then the more equivalent two forms become the less the probability of finding cultural differences. ‘Non-equivalence’, refers to the issue of the target language having no direct equivalent for a source language word, making absolute equivalence unattainable. This study presents and discusses examples of potential issues of equivalence in translations of ISO/TS 12913–2:2018 attributes. Α translation approach is suggested at a theoretical and practical level based on construct equivalence of attributes between source and target language, a prerequisite for valid comparisons in cross-cultural studies. In addition, suggested translation approaches for the issues of ‘paradox of equivalence’ and ‘non-equivalence’ are included. Finally, considering the above, this work discusses and supports the need for standardization of the translation process in soundscape research.

TelMedAI

Telemedicine is the practice of technology-enabled remote communication between patient and doctor. This phenomenon in healthcare has the potential to make services affordable and save time and money. Besides telemedicine allows care givers and family members to join conversations with doctors. Indian government initiated the National Telemedicine Network (NTN) to serve remote areas in healthcare by integrating existing healthcare facilities.Literature has revealed that existing works lack in an integrated approach for patient speech translation in language-independent fashion and automatic detection of disease and symptoms based on speech.There is a need for an automated system using Artificial Intelligence (AI) to recognize patient's speech and identify symptoms based on given audio description. We proposed a framework known as TelMedAI which is designed to recognize patient speech to comprehend disease symptoms besides converting the speech text into desired language. The framework is useful for realizing a telemedicine system. Speech to Speech (STS) module takes the patient's audio content into English audio. STS module exploits the Bi-LSTM model with an encoder, decoder and attention mechanism for translation. Then Google Speech API is used to convert English audio into English text. Then the framework exploits Natural Language Processing (NLP) to improve the quality of text. Afterwards, the disease and symptoms miner module eventually recognizes a list of diseases and corresponding symptoms. We proposed an algorithm known as Learning based Disease and Symptom Recognition from Patient Speech (LbDSRPS). This algorithm has the functionality to develop TelMedAI which helps doctors in telemedicine. Our empirical study has revealed that TelMedAI takes technology-driven telemedicine research forward significantly. The highest accuracy achieved by the proposed framework is 68.13% which is much better than the baseline LSTM model used for voice translation.

Monoclonal Antibodies in the Management of Inflammation in Wound Healing: An Updated Literature Review.

Chronic wounds pose a significant clinical challenge due to their complex pathophysiology and the burden of long-term management. Monoclonal antibodies (mAbs) are emerging as a novel therapeutic option in managing difficult wounds, although comprehensive data on their use in wound care are lacking. This study aimed to explore existing scientific knowledge of mAbs in treating chronic wounds based on a rationale of direct inhibition of the main molecules involved in the underlying inflammatory pathophysiology. We performed a literature review excluding primary inflammatory conditions with potential ulcerative outcomes (e.g., hidradenitis suppurativa). mAbs were effective in treating wounds from 16 different etiologies. The most commonly treated conditions were pyoderma gangrenosum (treated with 12 different mAbs), lipoid necrobiosis, and cutaneous vasculitis (each treated with 3 different mAbs). Fourteen mAbs were analyzed in total. Rituximab was effective in 43.75% of cases (7/16 diseases), followed by tocilizumab (25%, 4/16 diseases), and both etanercept and adalimumab (18.75%, 3/16 conditions each). mAbs offer therapeutic potential for chronic wounds unresponsive to standard treatments. However, due to the complex molecular nature of wound healing, no single target molecule can be identified. Therefore, the use of mAbs should be considered as a translational approach for limited cases of multi-resistant conditions.

Combinatorial macrophage induced innate immunotherapy against Ewing sarcoma: Turning “Two Keys” simultaneously

BackgroundMacrophages play important roles in phagocytosing tumor cells. However, tumors escape macrophage phagocytosis in part through the expression of anti-phagocytic signals, most commonly CD47. In Ewing sarcoma (ES), we found that tumor cells utilize dual mechanisms to evade macrophage clearance by simultaneously over-expressing CD47 and down-regulating cell surface calreticulin (csCRT), the pro-phagocytic signal. Here, we investigate the combination of a CD47 blockade (magrolimab, MAG) to inhibit the anti-phagocytic signal and a chemotherapy regimen (doxorubicin, DOX) to enhance the pro-phagocytic signal to induce macrophage phagocytosis of ES cells in vitro and inhibit tumor growth and metastasis in vivo.MethodsMacrophages were derived from human peripheral blood monocytes by granulocyte–macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF). Flow cytometry- and microscopy-based in-vitro phagocytosis assays were performed to evaluate macrophage phagocytosis of ES cells. Annexin-V assay was performed to evaluate apoptosis. CD47 was knocked out by CRISPR/Cas9 approach. ES cell-based and patient-derived-xenograft (PDX)-based mouse models were utilized to assess the effects of MAG and/or DOX on ES tumor development and animal survival. RNA-Seq combined with CIBERSORTx analysis was utilized to identify changes in tumor cell transcriptome and tumor infiltrating immune cell profiling in MAG and/or DOX treated xenograft tumors.ResultsWe found that MAG significantly increased macrophage phagocytosis of ES cells in vitro (p < 0.01) and had significant effect on reducing tumor burden (p < 0.01) and increasing survival in NSG mouse model (p < 0.001). The csCRT level on ES cells was significantly enhanced by DOX in a dose- and time-dependent manner (p < 0.01). Importantly, DOX combined with MAG significantly enhanced macrophage phagocytosis of ES cells in vitro (p < 0.01) and significantly decreased tumor burden (p < 0.01) and lung metastasis (p < 0.0001) and extended animal survival in vivo in two different mouse models of ES (p < 0.0001). Furthermore, we identified CD38, CD209, CD163 and CD206 as potential markers for ES-phagocytic macrophages. Moreover, we found increased M2 macrophage infiltration and decreased expression of Cd209 in the tumor microenvironment of MAG and DOX combinatorial therapy treated tumors.ConclusionsBy turning “two keys” simultaneously to reactivate macrophage phagocytic activity, our data demonstrated an effective and highly translatable alternative therapeutic approach utilizing innate (tumor associated macrophages) immunotherapy against high-risk metastatic ES.

Uncovering the wider impact of COVID-19 measures on the lives of children with complex care needs and their families: A mixed-methods study protocol.

Existing barriers to care were exacerbated by the development and implementation of necessary public health restrictions during the COVID-19 pandemic. Children with complex care needs and their families represent a small portion of the paediatric population, and yet they require disproportionately high access to services. Little is known about the impact of COVID-19 public health measures on this population. This study will generate evidence to uncover the wider impact of COVID-19 measures on the lives of children with complex care needs and their families in relation to policy and service changes. This multi-site sequential mixed methods study will take place across the Canadian Maritime provinces and use an integrated knowledge translation approach. There are two phases to this study: 1) map COVID-19 public health restrictions and service changes impacting children with complex care needs by conducting an environmental scan of public health restrictions and service changes between March 2020 and March 2022 and interviewing key informants involved in the development or implementation of restrictions and service changes, and 2) explore how children with complex care needs and their families experienced public health restrictions and service changes to understand how their health and well-being were impacted.

P-200 Vitrification induces a deviation in cleavage morphokinetic patterns and transcriptomic signatures along mouse embryo development

Abstract Study question Are there cellular, molecular and/or epigenetic risks associated with cryopreservation that may affect embryo development and compromise the health of future newborns? Summary answer Cryopreservation significantly impacted mice pre-implantation embryo morphokinetics, altered transcriptomic profiles, and cell lineage distribution. However, global DNA methylation remained unaffected by cryopreservation. What is known already Cryopreservation is currently widely used in assisted reproduction. However, epidemiological studies suggest a negative impact in the long-term health of children born after frozen-embryo transfer (FET). Recent population-based register studies have reported: 1) an increased risk of infant mortality from birth up to 1 year of life in singletons conceived using cryopreserved embryos vs natural conceptions; 2) high birth weights for gestational age associated with FET; 3) an increased risk of obstetrical complications in singletons conceived using cryopreserved embryos; 4) a higher incidence of childhood cancer and imprinting disorders associated with FET. Study design, size, duration F1 hybrid (B6/CBA) mice zygotes were collected following uterus dissection (n = 200 embryos/collection), and half of those were vitrified for comparison. Each embryo’s morphokinetics was assessed through time-lapse imaging using GERI, at 37 °C, 6% CO2, 5% O2, up to 105 hours. Extended culture beyond blastocyst stage was also performed. Fresh and cryopreserved blastocysts at E5.0 were cultured up to E9.0-E10 in static conditions (IVC1 and IVC2 medium). Participants/materials, setting, methods Fresh and cryopreserved embryos at several developmental stages were used for: 1) immunofluorescence staining, 2) gene expression analysis through RT-qPCR and 3) single-cell RNAseq. Global methylation activity, cell lineage distribution and single-cell transcriptome were assessed using one of the previously described methodologies. Main results and the role of chance The morphokinetics of preimplantation embryos were examined by tracking the time required to reach 4-cell, 8-cell, compactation, morula, full blastocyst, and expanded blastocyst stage. A comprehensive analysis revealed notable delays in the developmental rhythm of cryopreserved embryos compared to fresh embryos (p &amp;lt; 0.01). Applying single-cell RNA sequencing (scRNAseq), transcriptomic profiles were generated for fresh and cryopreserved embryos, covering the zygote to blastocyst stages. Notably, distinct transcriptomic signatures for fresh and frozen embryos emerged within separate clusters at different developmental stages. These findings suggest a potential functional impact of cryopreservation on embryo development. To complement this, gene expression analysis of DNA methyltransferases and MAT enzymes was conducted through RT-qPCR at 8-cell and blastocyst stages. No significant differences were detected between fresh and cryopreserved conditions. Furthermore, immunofluorescence staining of nuclear 5mC and DNMT1 in 8-cell embryos and blastocysts demonstrated similar levels between fresh and cryopreserved embryos. Additionally, differential staining of embryonic and extraembryonic cells (OCT4, GATA6 and GATA3) in extended embryos (E9 and E10) revealed distinct cell distribution patterns between fresh and cryopreserved conditions. Limitations, reasons for caution Our research, conducted using a mouse experimental model, has limited applicability to humans due to considerable species differences in embryonic development. Additional research is needed to validate our findings and establish their relevance to human embryos, facilitating translational approaches. Wider implications of the findings Our study highlights a noticeable functional impact of vitrification on mouse embryos. Given the global incorporation of this method in fertility clinics and its potential association with increased disease risks, our findings emphasize the need for increased research to reduce uncertainties regarding the health of children born from cryopreservation methods. Trial registration number Not applicable

Gut Pathobiont–Derived Outer Membrane Vesicles Drive Liver Inflammation and Fibrosis in Primary Sclerosing Cholangitis–Associated Inflammatory Bowel Disease

Background & AimsPrimary sclerosing cholangitis (PSC), often associated with inflammatory bowel disease (IBD), presents a multifactorial etiology involving genetic, immunological, and environmental factors. Gut dysbiosis and bacterial translocation have been implicated in PSC-IBD, yet the precise mechanisms underlying their pathogenesis remain elusive. Here, we describe the role of gut pathobionts in promoting liver inflammation and fibrosis due to the release of bacterial outer membrane vesicles (OMVs). MethodsPreclinical mouse models in addition to ductal organoids were used to acquire mechanistic data. A proof-of-concept study including serum and liver biopsies of a patient cohort of PSC (n=22), PSC-IBD (n=45) and control individuals (n=27) was performed to detect OMVs in the systemic circulation and liver. ResultsIn both, preclinical model systems and in human PSC-IBD patients, the translocation of OMVs to the liver correlated with enhanced bacterial sensing and accumulation of the NLRP3 inflammasome. Using ductal organoids, we were able to precisely attribute the pro-inflammatory and pro-fibrogenic properties of OMVs to signaling pathways dependent on TLR4 and NLRP3-GSDMD. The immunostimulatory potential of OMVs could be confirmed in macrophages and hepatic stellate cells. Furthermore, when we administered gut pathobiont-derived OMVs to Mdr2-/- mice, we observed a significant enhancement in liver inflammation and fibrosis. In a translational approach, we substantiated the presence of OMVs in the systemic circulation and hepatic regions of severe fibrosis using a PSC-IBD patient cohort. ConclusionThis study demonstrates the contribution of gut pathobionts in releasing OMVs that traverse the mucosal barrier, and thus, promote liver inflammation and fibrosis in PSC-IBD. OMVs might represent a critical new environmental factor that interacts with other disease factors to cause inflammation and thus define potential new targets for fibrosis therapy.

Knowledge translation in Indigenous health research: voices from the field.

To better understand what knowledge translation activities are effective and meaningful to Indigenous communities and what is required to advance knowledge translation in health research with, for, and by Indigenous communities. Workshop and collaborative yarning. Lowitja Institute International Indigenous Health Conference, Cairns, June 2023. About 70 conference delegates, predominantly Indigenous people involved in research and Indigenous health researchers who shared their knowledge, experiences, and recommendations for knowledge translation through yarning and knowledge sharing. Four key themes were developed using thematic analysis: knowledge translation is fundamental to research and upholding community rights; knowledge translation approaches must be relevant to local community needs and ways of mobilising knowledge; researchers and research institutions must be accountable for ensuring knowledge translation is embedded, respected and implemented in ways that address community priorities; and knowledge translation must be planned and evaluated in ways that reflect Indigenous community measures of success. Knowledge translation is fundamental to making research matter, and critical to ethical research. It must be embedded in all stages of research practice. Effective knowledge translation approaches are Indigenous-led and move beyond Euro-Western academic metrics. Institutions, funding bodies, and academics should embed structures required to uphold Indigenous knowledge translation. We join calls for reimaging health and medical research to embed Indigenous knowledge translation as a prerequisite for generative knowledge production that makes research matter.

Assessment of implant internal stresses under physiological femoral loading: Translation to a simplified bending load model

The success of surgical treatment for fractures hinges on various factors, notably accurate surgical indication. The process of developing and certifying a new osteosynthesis device is a lengthy and costly process that requires multiple cycles of review and validation. Current methods, however, often rely on predecessor standards rather than physiological loads in specific anatomical locations. This study aimed to determine actual loads experienced by an osteosynthesis plate, exemplified by a standard locking plate for the femoral shaft, utilizing finite elements analysis (FEA) and to obtain the bending moments for implant development standard tests. A protocol was developed, involving the creation and validation of a fractured femur model fixed with a locking plate, mechanical testing, and FEA. The model’s validation demonstrated exceptional accuracy in predicting deformations, and the FEA revealed peak stresses in the fracture bridging zone. Results of a parametric analysis indicate that larger fracture gaps significantly impact implant mechanical behavior, potentially compromising stability. This study underscores the critical need for realistic physiological conditions in implant evaluations, providing an innovative translational approach to identify internal loads and optimize implant designs. In conclusion, this research contributes to enhancing the understanding of implant performance under physiological conditions, promoting improved designs and evaluations in fracture treatments.

The Representation Of Translating Quranic Verses Based On Javanese Literature In The Form Of Tembang Macapat

The approach of Koran translation using Javanese literature needs to be represented in order to increase the potential for better acceptance of Koran translation by the Javanese community. The purpose of this study is to represent some Qur'anic verses to be translated using several types of tembang macapat, including tembang pangkur, tembang maskumambang, tembang dhandhanggula, and tembang megatruh. The method in this study uses a descriptive qualitative type of Koran verses that have been translated into Javanese based on the rules of tembang macapat, to then be analyzed using a content analysis approach to the rules in tembang macapat, as well as the suitability of the rules of guru gatra, guru lagu, and guru wilangan. The results of this research become one of the alternatives to the representation of how the Koran is translated into tembang macapat, as when translated it needs to contain a translation that does not violate the core meaning of the verse, and Javanese grammar that conforms to the level of use of krama and ngoko language, but still follows the rules of guru gatra, guru lagu, and guru wilangan in each type of tembang macapat.

Realist process evaluation of the knowledge translation programme of a patient-oriented research network.

The Knowledge Translation (KT) Programme of a pan-Canadian strategic patient-oriented research network focused on brain-based developmental disabilities aimed to mobilize knowledge relevant to the network members. The programme also promotes and studies integrated Knowledge Translation (iKT) approaches involving different interested parties, such as researchers, patient-partnersand decision-makers, in all parts of the knowledge creation process. The objective of this study is to advance research programme evaluation methods through a realist evaluation of the process of implementing iKT activities. Realist process evaluation included: (1) development of initial programme theories (using the partnership synergy theory); (2) data collection and analysis; (3) synthesis and refinement of theories through engagement with literature; and (4) presentation of findings in context-mechanism-outcome (C-M-O) configurations. A range of project documentation records were reviewed for analysis, and three co-leads, a programme coordinator, and a senior research associate were consulted to contextualize the implementation process of relevant KT activities. Based on the developed C-M-O configurations, we identified five key mechanisms of generating synergy in the iKT processes: (1) Visible shared leadership that embodies what iKT looks like; (2) Researchers'readiness for iKT; (3) Adaptation and flexible allocation of resources to emerging needs; (4) Power sharing to create practical and creative knowledge; and (5) Collective voice for potential transformative impacts at the policy level. The current realist evaluation demonstrated how partnerships between researchers, patient-partnersand other interested parties can synergistically generate new ways of thinking among all interested parties, actionable strategies to integrate users in research, and solutions to disseminate knowledge. In particular, we identified a pivotal role for patient-partners to act as equal decision-maker helps building and maintaining partnerships and consolidating KT strategies.

Qualitative Analysis for the Solutions of Fractional Stochastic Differential Equations

Fractional pantograph stochastic differential equations (FPSDEs) combine elements of fractional calculus, pantograph equations, and stochastic processes to model complex systems with memory effects, time delays, and random fluctuations. Ensuring the well-posedness of these equations is crucial as it guarantees meaningful, reliable, and applicable solutions across various disciplines. In differential equations, regularity refers to the smoothness of solution behavior. The averaging principle offers an approximation that balances complexity and simplicity. Our research contributes to establishing the well-posedness, regularity, and averaging principle of FPSDE solutions in Lp spaces with p≥2 under Caputo derivatives. The main ingredients in the proof include the use of Hölder, Burkholder–Davis–Gundy, Jensen, and Grönwall–Bellman inequalities, along with the interval translation approach. To understand the theoretical results, we provide numerical examples at the end.

Mitigating the Functional Deficit after Neurotoxic Motoneuronal Loss by an Inhibitor of Mitochondrial Fission.

Amyotrophic lateral sclerosis (ALS) is an extremely complex neurodegenerative disease involving different cell types, but motoneuronal loss represents its main pathological feature. Moreover, compensatory plastic changes taking place in parallel to neurodegeneration are likely to affect the timing of ALS onset and progression and, interestingly, they might represent a promising target for disease-modifying treatments. Therefore, a simplified animal model mimicking motoneuronal loss without the other pathological aspects of ALS has been established by means of intramuscular injection of cholera toxin-B saporin (CTB-Sap), which is a targeted neurotoxin able to kill motoneurons by retrograde suicide transport. Previous studies employing the mouse CTB-Sap model have proven that spontaneous motor recovery is possible after a subtotal removal of a spinal motoneuronal pool. Although these kinds of plastic changes are not enough to counteract the functional effects of the progressive motoneuron degeneration, it would nevertheless represent a promising target for treatments aiming to postpone ALS onset and/or delay disease progression. Herein, the mouse CTB-Sap model has been used to test the efficacy of mitochondrial division inhibitor 1 (Mdivi-1) as a tool to counteract the CTB-Sap toxicity and/or to promote neuroplasticity. The homeostasis of mitochondrial fission/fusion dynamics is indeed important for cell integrity, and it could be affected during neurodegeneration. Lesioned mice were treated with Mdivi-1 and then examined by a series of behavioral test and histological analyses. The results have shown that the drug may be capable of reducing functional deficits after the lesion and promoting synaptic plasticity and neuroprotection, thus representing a putative translational approach for motoneuron disorders.

Suppressing Pro-Apoptotic Proteins by siRNA in Corneal Endothelial Cells Protects against Cell Death.

Corneal endothelial cells (CE) are critical for the cornea's transparency. For severe corneal damage, corneal tissue transplantation is the most promising option for restoring vision. However, CE apoptotic cell death occurs during the storage of donor corneas for transplantation. This study used small interfering (si)RNA-mediated silencing of pro-apoptotic proteins as a novel strategy to protect CE against apoptosis. Therefore, the pro-apoptotic proteins Bax and Bak were silenced in the human corneal endothelial cell line (HCEC-12) by transfection with Accell™siRNA without any adverse effects on cell viability. When apoptosis was induced, e.g., etoposide, the caspase-3 activity and Annexin V-FITC/PI assay indicated a significantly reduced apoptosis rate in Bax+Bak-siRNA transfected HCECs compared to control (w/o siRNA). TUNEL assay in HCECs exposed also significantly lower cell death in Bax+Bak-siRNA (7.5%) compared to control (w/o siRNA: 32.8%). In ex vivo donor corneas, a significant reduction of TUNEL-positive CEs in Bax+Bak-siRNA corneas (8.1%) was detectable compared to control-treated corneas (w/o siRNA: 27.9%). In this study, we demonstrated that suppressing pro-apoptotic siRNA leads to inhibiting CE apoptosis. Gene therapy with siRNA may open a new translational approach for corneal tissue treatment in the eye bank before transplantation, leading to graft protection and prolonged graft survival.

Single-instant spatial wave height forecast using machine learning: An image-to-image translation approach based on generative adversarial networks

An innovative single-instant approach for spatial significant wave height forecast based on a Generative Adversarial Networks (GANs) model is presented. The model's most distinctive feature is its ability to provide spatial wave height forecast with only a single snapshot of wind field input, eliminating the need for continuous wind field sequences while simultaneously maintaining high accuracy and enhanced efficiency. The proposed model architecture comprises an image-to-image translation generator and a patch-style discriminator, working in tandem to forecast high-quality wave height data. The model is trained using a 20-year ECMWF Reanalysis v5 (ERA5) wind and wave dataset. A vast sea area covering 15°-40°N, 105°-130°E in West Pacific is used for this study. The presented model is carefully tested against a 10-year period historical dataset and the results are discussed. The model exhibits outstanding overall performances with Mean Absolute Error (MAE) of 0.16 m, Root Mean Square Error (RMSE) of 0.24 m, and Mean Absolute Percentage Error (MAPE) of 13.4 %. The model proves particularly effective in forecasting extreme wave heights during tropical cyclones, capturing the structure of typhoon-driven waves and providing wave heights with favorable accuracy. It is also proficient at delivering satisfactory statistical wave height forecasts for long-term periods.