Advanced biology最新文献

Skeletal muscle trauma such as fracture or crush injury can result in a life-threatening condition called acute compartment syndrome (ACS), which involves elevated compartmental pressure within a closed osteo-fascial compartment, leading to collapse of the microvasculature and resulting in necrosis of the tissue due to ischemia. Diagnosis of ACS is complex and controversial due to the lack of standardized objective methods, which results in high rates of misdiagnosis/late diagnosis, leading to permanent neuro-muscular damage. ACS pathophysiology is poorly understood at a cellular level due to the lack of physiologically relevant models. In this context, microfluidics organ-on-chip systems (OOCs) provide an exciting opportunity to investigate the cellular mechanisms of microvascular dysfunction that leads to ACS. In this article, the state-of-the-art OOCs designs and strategies used to investigate microvasculature dysfunction mechanisms is reviewed. The differential effects of hemodynamic shear stress on endothelial cell characteristics such as morphology, permeability, and inflammation, all of which are altered during microvascular dysfunction is highlighted. The article then critically reviews the importance of microfluidics to investigate closely related microvascular pathologies that cause ACS. The article concludes by discussing potential biomarkers of ACS with a special emphasis on glycocalyx and providing a future perspective.

Axons have intrinsically poor regenerative capacity in the mature central nervous system (CNS), leading to permanent neurological impairments in individuals. There is growing evidence that exercise is a powerful physiological intervention that can obviously enhance cell rejuvenate capacity, but its molecular mechanisms that mediate the axonal regenerative benefits remain largely unclear. Using the eye as the CNS model, here it is first indicated that placing mice in an exercise stimulation environment induced DNA methylation patterns and transcriptomes of retinal ganglion cell, promoted axon regeneration after injury, and reversed vision loss in aged mice. These beneficial effects are dependent on the DNA demethylases TET3-mediated epigenetic effects, which increased the expression of genes associated with the regenerative growth programs, such as STAT3, Wnt5a, Klf6. Exercise training also shows with the improved mitochondrial and metabolic dysfunction in retinas and optic nerves via TET3. Collectively, these results suggested that the increased regenerative capacity induced by enhancing physical activity is mediated through epigenetic reprogramming in mouse model of optic nerve injury and in aged mouse. Understanding the molecular mechanism underlying exercise-dependent neuronal plasticity led to the identification of novel targets for ameliorating pathologies associated with etiologically diverse diseases.

When low muscle mass and impaired strength and physical function coexist with excess adiposity, it is termed sarcopenic obesity (SO). Handgrip strength (HGS) is a predictor of disability and mortality. Asymmetry in HGS, particularly ≥ 10% strength differences between hands, may indicate neuromuscular dysfunction observable prior to declines in maximal strength are detectedand therefore could be incorporated to identify those at risk of physical limitations and SO. This study compares HGS values and asymmetry in older adults with excess adiposity and evaluates their relationships with physical function. Baseline data from two previous pilot weight loss studies in 85 older adults with body mass index values ≥ 30 kg m⁻² are included with measures of body composition, walking speed, and chair stand ability. Sixty-three participants met the criteria for SO. HGS correlated to gait speed (r = 0.22), distance walked (r = 0.40), chair stand time for 5 repetitions (r = 0.42) and during 30 s (r = 0.31). HGS asymmetry is only correlated to gait speed (r = 0.31) and there are no differences in physical function between those with and without asymmetry. Maximal HGS tests should continue to be used to screen for functional decline and disability.

For monogenic genetic diseases, in utero gene therapy (IUGT) shows the potential for early prevention against irreversible and lethal pathological changes. Moreover, animal models have also demonstrated the effectiveness of IUGT in the treatment of coagulation disorders, hemoglobinopathies, neurogenetic disorders, and metabolic and pulmonary diseases. For major alpha thalassemia and severe osteogenesis imperfecta, in utero stem cell transplantation has entered the phase I clinical trial stage. Within the realm of the inner ear, genetic hearing loss significantly hampers speech, cognitive, and intellectual development in children. Nowadays, gene therapies offer substantial promise for deafness, with the success of clinical trials in autosomal recessive deafness 9 using AAV-OTOF gene therapy. However, the majority of genetic mutations that cause deafness affect the development of cochlear structures before the birth of fetuses. Thus, gene therapy before alterations in cochlear structure leading to hearing loss has promising applications. In this review, addressing advances in various fields of IUGT, the progress, and application of IUGT in the treatment of genetic hearing loss are focused, in particular its implementation methods and unique advantages.

Gene-Environment Interactions

Gene-environment interactions on PhenoAgeAccel (age-adjusted PhenoAge) were searched through variance quantitative trait loci (vQTLs) analyses of 111,996 Taiwan Biobank participants. A total of 4 nearly independent vQTLs were identified with p < 5E-8. Further studies showed that smoking exacerbated the vQTLs' aging effects, while higher educational attainment attenuated these effects. More details can be found in article number 2400149 by Wan-Yu Lin.

Aging and regeneration are opposite cellular processes. Aging refers to progressive dysfunction in most cells and tissues, and regeneration refers to the replacement of damaged or dysfunctional cells or tissues with existing adult or somatic stem cells. Various studies have shown that aging is accompanied by decreased regenerative abilities, indicating a link between them. The performance of any cellular process needs to be supported by the energy that is majorly produced by mitochondria. Thus, mitochondria may be a link between aging and regeneration. It should be interesting to discuss how mitochondria behave during aging and regeneration. The changes of mitochondria in aging and regeneration discussed in this review can provide a timely and necessary study of the causal roles of mitochondrial homeostasis in longevity and health.

Mesenchymal–epithelial transition (MET) is essential for tissue and organ development and is thought to contribute to cancer by enabling the establishment of metastatic lesions. Despite its importance in both health and disease, there is a lack of in vitro platforms to study MET and little is known about the regulation of MET by mechanical cues. Here, hyaluronic acid-based hydrogels with dynamic and tunable stiffnesses mimicking that of normal and tumorigenic mammary tissue are synthesized. The platform is then utilized to examine the response of mammary epithelial cells and breast cancer cells to dynamic modulation of matrix stiffness. Gradual softening of the hydrogels reduces proliferation and increases apoptosis of breast cancer cells. Moreover, breast cancer cells exhibit temporal changes in cell morphology, cytoskeletal organization, and gene expression that are consistent with mesenchymal–epithelial plasticity as the stiffness of the matrix is reduced. A reduction in matrix stiffness attenuates the expression of integrin-linked kinase, and inhibition of integrin-linked kinase impacts proliferation, apoptosis, and gene expression in cells cultured on stiff and dynamic hydrogels. Overall, these findings reveal intermediate epithelial/mesenchymal states as cells move along a matrix stiffness-mediated MET trajectory and suggest an important role for matrix mechanics in regulating mesenchymal–epithelial plasticity.

Mycobacterium tuberculosis (M. tb) is a significant intracellular pathogen responsible for numerous infectious disease-related deaths worldwide. It uses ESX-1 T7SS to damage phagosomes and to enter the cytosol of host cells after phagocytosis. During infection, M. tb and host mitochondria release dsDNA, which activates the CGAS-STING1 pathway. This pathway leads to the production of type I interferons and proinflammatory cytokines and activates autophagy, which targets and degrades bacteria within autophagosomes. However, the role of type I IFNs in immunity against M. tb is controversial. While previous research has suggested a protective role, recent findings from cgas-sting1 knockout mouse studies have contradicted this. Additionally, a study using knockout mice and non-human primate models uncovered a new mechanism by which neutrophils recruited to lung infections form neutrophil extracellular traps. Activating plasmacytoid dendritic cells causes them to produce type I IFNs, which interfere with the function of interstitial macrophages and increase the likelihood of tuberculosis. Notably, M. tb uses its virulence proteins to disrupt the CGAS-STING1 signaling pathway leading to enhanced pathogenesis. Investigating the CGAS-STING1 pathway can help develop new ways to fight tuberculosis.

As 3D culture technology advances, new avenues have opened for the development of physiological human cancer models. These preclinical models provide efficient ways to translate basic cancer research into clinical tumor therapies. Recently, cancer organoids have emerged as a model to dissect the more complex tumor microenvironment. Incorporating cancer organoids into preclinical programs have the potential to increase the success rate of oncology drug development and recapitulate the most efficacious treatment regimens for cancer patients. In this review, four main types of cancer organoids are introduced, their applications, advantages, limitations, and prospects are discussed, as well as the recent application of single-cell RNA-sequencing (scRNA-seq) in exploring cancer organoids to advance this field.