Cells need to sense their mechanical environment during the growth of developing tissues and maintenance of adult tissues. The concept of force-sensing mechanisms that act through cell-cell and ...cell-matrix adhesions is now well established and accepted. Additionally, it is widely believed that force sensing can be mediated through cilia. Yet, this hypothesis is still debated. By using primary cilia sensing as a paradigm, we describe the physical requirements for cilium-mediated mechanical sensing and discuss the different hypotheses of how this could work. We review the different mechanosensitive channels within the cilium, their potential mode of action and their biological implications. In addition, we describe the biological contexts in which cilia are acting - in particular, the left-right organizer - and discuss the challenges to discriminate between cilium-mediated chemosensitivity and mechanosensitivity. Throughout, we provide perspectives on how quantitative analysis and physics-based arguments might help to better understand the biological mechanisms by which cells use cilia to probe their mechanical environment.
Abstract Pulmonary arterial hypertension (PAH) is responsible for the premature death mainly because of progressive and severe heart failure. This disease is characterized by increased pulmonary ...vascular tone, inflammatory cell infiltration, vascular remodeling and occlusion of vessels with thrombi, frequently leading to right heart failure. Aiming to better comprehend the complexity of PAH and find novel therapeutic strategies or improve the existing ones, a variety of preclinical models have emerged. Although there is no ideal preclinical model of PAH currently available, animal models have been used to assist in the identification of the molecular pathways underlying PAH development and progression, and in the identification of novel therapeutics. Among preclinical models of PAH, monocrotaline (MCT) animal model offers the advantage of mimic several key aspects of human PAH, including vascular remodeling, proliferation of smooth muscle cells, endothelial dysfunction, upregulation of inflammatory cytokines, and right ventricle failure, requiring a single drug injection. This review summarizes the advantages and limitations of MCT animal model to the study of the molecular mechanisms underlying PAH pathogenesis, envisioning to improve the diagnosis and management of this complex disease.
The largest monkeypox virus (MPXV) outbreak described so far in non-endemic countries was identified in May 2022 (refs.
). In this study, shotgun metagenomics allowed the rapid reconstruction and ...phylogenomic characterization of the first MPXV outbreak genome sequences, showing that this MPXV belongs to clade 3 and that the outbreak most likely has a single origin. Although 2022 MPXV (lineage B.1) clustered with 2018-2019 cases linked to an endemic country, it segregates in a divergent phylogenetic branch, likely reflecting continuous accelerated evolution. An in-depth mutational analysis suggests the action of host APOBEC3 in viral evolution as well as signs of potential MPXV human adaptation in ongoing microevolution. Our findings also indicate that genome sequencing may provide resolution to track the spread and transmission of this presumably slow-evolving double-stranded DNA virus.
The impact of inhalable fine particulate matter (PM2.5, aerodynamic diameter <2.5 μm) on public health is of great concern worldwide. Knowledge on their harmful effects are mainly due to studies ...carried out with whole air particles, with the contribution of their different fractions remaining largely unknown. Herein, a set of urban PM2.5 samples were collected during daytime and nighttime periods in autumn and spring, aiming to address the seasonal and day-night variability of water-soluble organic matter (WSOM) composition. In vitro analysis of the oxidative and pro-inflammatory potential of WSOM samples was carried out in both acute (24 h) and chronic (3 weeks) exposure setups using Raw264.7 macrophages as cell model. Findings revealed that the structural composition of WSOM samples differs between seasons and in a day–night cycle. Cell exposure resulted in an increase in the transcription of the cytoprotective Hmox1 and pro-inflammatory genes Il1b and Nos2, leading to a moderate pro-inflammatory status. These macrophages showed an impaired capacity to subsequently respond to a strong pro-inflammatory stimulus such as bacterial lipopolysaccharide, which may implicate a compromised capacity to manage harmful pathogens. Further investigation on aerosol WSOM could help to constrain the mechanisms of WSOM-induced respiratory diseases and contribute to PM2.5 regulations.
The pattern of blood flow has long been thought to play a significant role in vascular morphogenesis, yet the flow-sensing mechanism that is involved at early embryonic stages, when flow forces are ...low, remains unclear. It has been proposed that endothelial cells use primary cilia to sense flow, but this has never been tested in vivo. Here we show, by noninvasive, high-resolution imaging of live zebrafish embryos, that endothelial cilia progressively deflect at the onset of blood flow and that the deflection angle correlates with calcium levels in endothelial cells. We demonstrate that alterations in shear stress, ciliogenesis, or expression of the calcium channel PKD2 impair the endothelial calcium level and both increase and perturb vascular morphogenesis. Altogether, these results demonstrate that endothelial cilia constitute a highly sensitive structure that permits the detection of low shear forces during vascular morphogenesis.
Display omitted
Display omitted
•Endothelial cilia are present during angiogenesis and deflected by low flow forces•Cilia deflection leads to endothelial calcium increase as flow forces increase•Endothelial cilia ultrastructure is unique, which makes it highly flexible•Cilia, flow, and PKD2 are necessary for early angiogenesis
Blood flow is a major mechanical stimulus that controls vascular development, yet the mechanodetection mechanisms that drive angiogenesis are poorly understood. Vermot and colleagues now show that primary cilia located at the endothelial cell surface regulate early angiogenesis. The authors demonstrate that cilia-mediated mechanodetection detects low flow forces through PKD2-mediated calcium fluxes.
Abstract
Traditional lab classes in microbiology are common in several educational institutions, which can provide a learning experience disconnected from the myriad of experiments performed in ...research laboratories. Attempting to promote an authentic learning opportunity of the functioning of a bacteriology research laboratory, we developed the “Real-Lab-Day,” a multimodal learning experience to develop competencies, abilities, critical analysis, and teamwork skills for undergraduate students. Students were divided into groups and assigned to research laboratories to be mentored by graduate students, to design and carry out scientific assays. Undergraduate students were introduced to methods such as cellular and molecular assays, flow cytometry, and fluorescence microscopy, as tools to address scientific questions about bacterial pathogenicity, bacterial resistance, and other topics. To consolidate their learning, students created and presented a poster in a rotational panel of peer learning. The perceived learning and interest in microbiology research were improved by the Real-Lab-Day experience, and >95% of the students approved the Real-Lab-Day as a teaching tool in microbiology. Students exposed to a research laboratory had a positive experience with the teaching method, and over 90% saw it as beneficial to improve their understanding of the scientific concepts discussed during lectures. Likewise, their interest in pursuing a career in microbiology was stimulated by the Real-Lab-Day experience. In conclusion, this educational initiative depicts an alternative methodology to connect students to the research and offers an opportunity to be in close contact with experts and graduate students, who gain teaching experience.
The “Real-Lab-Day” is a multimodal learning experience to develop competencies, abilities, critical analysis, and teamwork skills for undergraduate students.
Cancer-induced cardiac cachexia is an insidious syndrome with a dramatic impact on a patient’s quality of life and survival. Since exercise training provides several cardiovascular benefits in both ...physiological and pathological conditions (e.g., athletes and patients with heart failure, respectively), its use as a preventive and/or therapeutic tool for cancer-induced cardiac cachexia has been hypothesized. Existing evidence on the effects of exercise training in this particular setting is limited, but points towards a beneficial outcome. We report the current knowledge on cancer-induced cardiac cachexia and discuss the molecular pathways that may be modulated by exercise training in this setting, providing insights into possible future roads of study, namely in stem cell research and cardiac regeneration.
Cancer-induced cardiac cachexia is an insidious syndrome that may occur independently of cardiotoxic chemotherapy.
Exercise training modulates several molecular pathways involved in cardiac hypertrophy, regeneration, and metabolism, in both physiological and pathological conditions.
Preclinical data support the notion that exercise training prevents and reverts the cardiac remodeling suffered during cancer-induced cardiac cachexia, potentially by modulating tumoral activity, inflammation, metabolism, and fibrosis.
Exercise training presents itself as a promising therapy and/or adjuvant in cancer-induced cardiac cachexia.
Bacillus subtilis spores have been used as safe and heat-resistant antigen delivery vectors. Nonetheless, the oral administration of spores typically induces weak immune responses to the passenger ...antigens, which may be attributed to the fast transit through the gastrointestinal tract. To overcome this limitation, we have developed B. subtilis spores capable of binding to the gut epithelium by means of expressing bacterial adhesins on the spore surface. The resulting spores bound to in vitro intestinal cells, showed a longer transit through the mouse intestinal tract, and interacted with Peyer's patch cells. The adhesive spores increased the systemic and secreted antibody responses to the Streptococcus mutans P1 protein, used as a model antigen, following oral, intranasal, and sublingual administration. Additionally, P1-specific antibodies efficiently inhibited the adhesion of the oral pathogen Streptococcus mutans to abiotic surfaces. These results support the use of gut-colonizing B. subtilis spores as a new platform for the mucosal delivery of vaccine antigens.
Internal organs are asymmetrically positioned inside the body. Embryonic motile cilia play an essential role in this process by generating a directional fluid flow inside the vertebrate left-right ...organizer. Detailed characterization of how fluid flow dynamics modulates laterality is lacking. We used zebrafish genetics to experimentally generate a range of flow dynamics. By following the development of each embryo, we show that fluid flow in the left-right organizer is asymmetric and provides a good predictor of organ laterality. This was tested in mosaic organizers composed of motile and immotile cilia generated by dnah7 knockdowns. In parallel, we used simulations of fluid dynamics to analyze our experimental data. These revealed that fluid flow generated by 30 or more cilia predicts 90% situs solitus, similar to experimental observations. We conclude that cilia number, dorsal anterior motile cilia clustering, and left flow are critical to situs solitus via robust asymmetric charon expression.
•Fluid flow in zebrafish L-R organizer predicts charon expression and organ situs•Simulations establish a minimum of 30 cilia anteriorly clustered for situs solitus•Zebrafish Kupffer’s vesicle has both motile and immotile cilia•Cilia beat frequency analysis identifies two distinct populations of motile cilia
Cilia-generated directional fluid flow inside the vertebrate left-right organizer is involved in patterning asymmetric visceral organ placement. Sampaio et al. identify distinct cilia populations in the zebrafish embryonic left-right organizer and show that anterior clustering of motile cilia generates asymmetric early fluid flow, predicting organ laterality long before its formation.
As people age, their skeletal muscle (SkM) experiences a decline in mitochondrial functionality and density, which leads to decreased energy production and increased generation of reactive oxygen ...species. This cascade of events, in turn, might determine the loss of SkM mass, strength and quality. Even though the mitochondrial processes dysregulated by aging, such as oxidative phosphorylation, mitophagy, antioxidant defenses and mtDNA transcription, are the same in both sexes, mitochondria age differently in the SkM of men and women. Indeed, the onset and magnitude of the impairment of these processes seem to be influenced by sex-specific factors. Sexual hormones play a pivotal role in the regulation of SkM mass through both genomic and non-genomic mechanisms. However, the precise mechanisms by which these hormones regulate mitochondrial plasticity in SkM are not fully understood. Although the presence of estrogen receptors in mitochondria is recognized, it remains unclear whether androgen receptors affect mitochondrial function. This comprehensive review critically dissects the current knowledge on the interplay of sex in the aging of SkM, focusing on the role of sex hormones and the corresponding signaling pathways in shaping mitochondrial plasticity. Improved knowledge on the sex dimorphism of mitochondrial aging may lead to sex-tailored interventions that target mitochondrial health, which could be effective in slowing or preventing age-related muscle loss.
PDF
