Frontiers in Physiology最新文献

Prostate cancer (PCa) is a major world-wide health concern. Current diagnostic methods involve Prostate-Specific Antigen (PSA) blood tests, biopsies, and Magnetic Resonance Imaging (MRI) to assess cancer aggressiveness and guide treatment decisions. MRI aligns with in silico medicine, as patient-specific image biomarkers can be obtained, contributing towards the development of digital twins for clinical practice. This work presents a novel framework to create a personalized PCa model by integrating clinical MRI data, such as the prostate and tumour geometry, the initial distribution of cells and the vasculature, so a full representation of the whole prostate is obtained. On top of the personalized model construction, our approach simulates and predicts temporal tumour growth in the prostate through the Finite Element Method, coupling the dynamics of tumour growth and the transport of oxygen, and incorporating cellular processes such as proliferation, differentiation, and apoptosis. In addition, our approach includes the simulation of the PSA dynamics, which allows to evaluate tumour growth through the PSA patient's levels. To obtain the model parameters, a multi-objective optimization process is performed to adjust the best parameters for two patients simultaneously. This framework is validated by means of data from four patients with several MRI follow-ups. The diagnosis MRI allows the model creation and initialization, while subsequent MRI-based data provide additional information to validate computational predictions. The model predicts prostate and tumour volumes growth, along with serum PSA levels. This work represents a preliminary step towards the creation of digital twins for PCa patients, providing personalized insights into tumour growth.

The development of red blood cell (RBC) storage lesion during hypothermic storage has long posed challenges for blood transfusion efficacy. These alterations are primarily driven by oxidative stress, concern both structural and biochemical aspects of RBCs, and affect their interactions with the recipient's tissues post-transfusion. Efforts to counteract these effects focus on improving the antioxidant capacity within stored RBCs, reducing oxygen exposure, and scavenging harmful molecules that accumulate during storage. Various supplements, such as ascorbic acid, N-acetylcysteine, polyphenolic compounds, and specific metabolites have shown the potential to improve RBC quality by reducing oxidative lesions and lysis phenomena, and enhancing antioxidant, energy, or proteostasis networks. Accordingly, anaerobic storage has emerged as a promising strategy, demonstrating improved RBC storability and recovery in both animal models and preliminary human studies. Finally, targeted scavenging of harmful storage-related phenotypes and molecules, like removal signals, oxidized proteins, and extracellular hemoglobin, while not so studied, also has the potential to benefit both the unit and the patient in need. Omics technologies have aided a lot in these endeavors by revealing biomarkers of superior storability and, thus, potential novel supplementation strategies. Nonetheless, while the so far examined storage modifications show significant promise, there are not many post-transfusion studies (either in vitro, in animal models, or humans) to evaluate RBC efficacy in the transfusion setting. Looking ahead, the future of blood storage and transfusion will likely depend on the optimization of these interventions to extend the shelf-life and quality of stored RBCs, as well as their therapeutic outcome.

Myocardial ischemia-reperfusion injury (MIRI) is a secondary injury caused by restoring blood flow after acute myocardial infarction, which may lead to serious arrhythmia and heart damage. In recent years, the role of potassium channels in MIRI has attracted much attention, especially the members of the two-pore domain potassium (K2P) channel family. K2P channel has unique structure and function, and the formation of its heterodimer increases its functional diversity. This paper reviews the structural characteristics, types, expression and physiological functions of K2P channel in the heart. In particular, we pay attention to whether members of the subfamily such as TWIK, TREK, TASK, TALK, THIK and TRESK participate in MIRI and their related mechanisms. Future research will help to reveal the molecular mechanism of K2P channel in MIRI and provide new strategies for the treatment of cardiovascular diseases.

Introduction: End-stage lung disease causes cardiac remodeling and induces electrocardiogram (ECG) changes. On the other way, whether lung transplantation (LTx) in end-stage lung disease patients are associated with ECG change is unknown. The object of this study was to investigate ECG changes before and after LTx in end-stage lung disease patients and whether these changes had clinical significance.

Method: This was a single-center retrospective cohort study of 280 end-stage lung disease patients who consecutively underwent LTx at a tertiary referral hospital. ECG findings before LTx and within 1 week and 1, 3, and 6 months after LTx were obtained and analyzed. To find clinical meaning, the ECG at 1 month after LTx was analyzed according to 1-year survival (survivor vs non-survivor groups). Survival data were estimated using the Kaplan-Meier method.

Results: Significant differences were observed in the PR interval, QRS duration, QT interval, QTc interval, and heart rate before LTx and 1 month after LTx; the PR interval, QRS duration, QTc interval, and heart rate were decreased. Particularly, the QTc interval was significantly decreased 1 month after LTx, whereas there was no significant change in the QTc interval from 1 to 6 months thereafter. The PR interval, QT interval, QTc interval, and heart rate were significantly different between the survivor and non-survivor groups. The serial changes in QTc interval before LTx and 1 and 3 months after LTx were also significantly different between the survivor and non-survivor groups (p = 0.040 after adjusting for age and body mass index). Upon dividing the patients based on the range of QTc interval change ≤ -8 ms, >-8-10 ms, >10-35 ms, >35 ms), the survival rate was significantly lower in the group whose QTc interval at 1 month after LTx decreased by > 35 m (p = 0.019).

Conclusion: LTx in patients with end-stage lung disease may induce ECG changes. Patients whose QTc interval at 1 month after LTx decreased by > 35 ms have a significantly higher 1-year mortality rate. Hence, these ECG changes may have clinical and prognostic significance.

The velvetbean caterpillar Anticarsia gemmatalis is one of the main soybean defoliators in Brazil. Currently, the main biopesticide used to control insect pests worldwide is the bacteria Bacillus thuringiensis (Bt), which produces entomopathogenic Crystal toxins (Cry) that act in the midgut of susceptible insects, leading them to death. The mode of action of Cry toxins in the midgut involves binding to specific receptors present on the brush border of epithelial cells such as aminopeptidase N (APN), alkaline phosphatase (ALP), cadherin, and others. Mutations in these receptors, among other factors, may be involved in the development of resistance; identification of functional Cry receptors in the midgut of A. gemmatalis is crucial to develop effective strategies to overcome this possible scenario. This study's goal is to characterize APNs of A. gemmatalis and identify a receptor for Cry1Ac in the midgut. The interaction of Bt spores with the midgut epithelium was observed in situ by immunohistochemistry and total aminopeptidase activity was estimated in brush border membrane vesicle (BBMV) samples, presenting higher activity in challenged individuals than in control ones. Ten APN sequences were found in a A. gemmatalis' transcriptome and subjected to different in silico analysis, such as phylogenetic tree, multiple sequence alignment and identification of signal peptide, activity domains and GPI-anchor signal. BBMV proteins from 5th instar larvae were submitted to a ligand blotting using activated Cry1Ac toxin and a commercial anti-Cry polyclonal antibody; corresponding bands of proteins that showed binding to Cry toxin were excised from the SDS-PAGE gel and subjected to mass spectrometry analysis, which resulted in the identification of seven of those APNs. Quantitative PCR was realized to compare expression levels between individuals subjected to sublethal infection with Bt spores and control ones, presenting up- and downregulations upon Bt infection. From these results, we can infer that aminopeptidases N in A. gemmatalis could be involved in the mode of action of Cry toxins in its larval stage.

The importance of fundamental basic research in the quest for much needed clinical treatments is a story that constantly must be retold. Funding of basic science in the USA by the National Institutes of Health and other agencies is provided under the assumption that fundamental research eventually will lead to improvements in healthcare worldwide. Understanding how basic research is connected to clinical developments is important, but just part of the story. Many basic science discoveries never see the light of day in a clinical setting because academic scientists are not interested in or do not have the inclination and/or support for entering the world of biotechnology. Even if the interest and inclination are there, often the unknowns about how to enter that world inhibit taking the initial step. Young investigators often ask me how I incorporated biotech opportunities into my otherwise purely academic research endeavors. Here I tell the story of the foundational basic science and early events of my career that led to forming the biotech companies responsible for the development of unique cardiac drugs, including mavacamten, a first in class human β-cardiac myosin inhibitor that is changing the lives of hypertrophic cardiomyopathy patients.

Traumatic spinal cord injury (SCI) results in the disruption of physiological systems below the level of the spinal lesion. Connexin hemichannels (CxHCs) are membrane-bound, non-selective pore proteins that are lost in mature myofibers but reappear de novo on the sarcolemma after peripheral denervation, chronic SCI, diabetes, and severe systemic stress such as sepsis. Cx43 and Cx45 have been implicated as the major CxHCs present in diseased muscle, and muscle-restricted knockout of these genes reduces muscle atrophy after denervation, likely by reducing excess calcium influx with resultant inflammasome activation. A muscle-restricted Cx43/45 conditional knockout (mKO) mouse model was developed and tested to check whether it would improve outcomes following either a complete spinal cord transection at the level of thoracic vertebrae-9 (T9) or a motor-incomplete T9 impact-contusion SCI. mKO had no effect on the body mass after complete T9 transection. There was reduced atrophy of the plantaris 15 days post-SCI that was not associated with molecular markers of inflammation, hypertrophic/atrophic protein signaling, or protein and mRNA expression related to mitochondrial integrity and function. mKO mice had faster and greater locomotor recovery across 28 days after a motor-incomplete contusion SCI with no differences in spared white matter; male mKO mice generally had greater muscle mass than genotype controls post-injury, but muscle sparing was not observed in female mKO mice post-injury. The data establish a new paradigm where muscle Cx43/45 may contribute to the tissue crosstalk that determines the neuromuscular function of sub-lesional musculature after motor-incomplete SCI in a sex-dependent manner. Our novel findings should promote investigation to develop innovative treatment strategies to improve the function and quality of life for persons with SCI.