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Ma, T.

Publications and source records attributed to Ma, T..

At least 55 records · Page 3Linked to original sources

Mechanics limit ecological diversity and promote heterogeneity in confined bacterial communities

Multi-species bacterial populations often inhabit confined and densely packed environments where spatial competition determines the ecological diversity of the community. However, the role of mechanical interactions in shaping the ecology is still poorly understood. Here we study a model system consisting of two populations of non-motile E. coli bacteria competing within open, monolayer micro-channels. The competitive dynamics is observed to be bi-phasic: after seeding, either one strain rapidly fixates or both strains orient into spatially stratified, stable communities. We find that mechanical interactions with other cells and local spatial constraints influence the resulting community ecology in unexpected ways, severely limiting the overall diversity of the communities while simultaneously allowing for the establishment of stable, heterogeneous populations of bacteria displaying disparate growth rates. Surprisingly, the populations have a high probability of coexisting even when one strain has a significant growth advantage. A more coccus morphology is shown to provide a selective advantage, but agent based simulations indicate this is due to hydrodynamic and adhesion effects within the microchannel and not from breaking of the nematic ordering. Our observations are qualitatively reproduced by a simple Polya urn model, which suggests the generality of our findings for confined population dynamics and highlights the importance of early colonization conditions on the resulting diversity and ecology of bacterial communities. These results provide fundamental insights into the determinants of community diversity in dense confined ecosystems where spatial exclusion is central to competition as in organized biofilms or intestinal crypts.

biophysics↗

Broad H3K4me3 Domain Is Associated with Spatial Coherence during Mammalian Embryonic Development

It is well known that the chromatin states play a major role in cell-fate decision and cell-identity maintenance; however, the spatial variation of chromatin states in situ remains poorly characterized. Here, by leveraging recently available spatial-CUT&Tag data, we systematically characterized the global spatial organization of the H3K4me3 profiles in a mouse embryo. Our analysis identified a subset of genes with spatially coherent H3K4me3 patterns, which together delineate the tissue boundaries. The spatially coherent genes are strongly enriched with tissue-specific transcriptional regulators. Remarkably, their corresponding genomic loci are marked by broad H3K4me3 domains, which is distinct from the typical H3K4me3 signature. Spatial transition across tissue boundaries is associated with continuous shortening of the broad H3K4me3 domains as well as expansion of H3K27me3 domains. Our analysis reveals a strong connection between the genomic and spatial variation of chromatin states, which may play an important role in embryonic development.

systems biology↗

Pharmacologically inducing regenerative cardiac cells by small molecule drugs

Adult mammals, unlike some lower organisms, lack the ability to regenerate damaged hearts through cardiomyocytes (CMs) dedifferentiation into cells with regenerative capacity. Developing conditions to induce such naturally unavailable cells with potential to proliferate and differentiate into CMs, i.e., regenerative cardiac cells (RCCs), in mammals will provide new insights and tools for heart regeneration research. In this study, we demonstrate that a two-compound combination, CHIR99021 and A-485 (2C), effectively induces RCCs from human embryonic stem cell (hESC)-derived TNNT2+ CMs in vitro, as evidenced by lineage tracing experiments. Functional analysis shows that these RCCs express a broad spectrum of cardiogenesis genes and have the potential to differentiate into functional CMs, endothelial cells (ECs), and smooth muscle cells (SMCs). Importantly, similar results were observed in neonatal rat CMs both in vitro and in vivo. Remarkably, administering 2C in adult mouse hearts significantly enhances survival and improves heart function post-myocardial infarction. Mechanistically, CHIR99021 is crucial for the transcriptional and epigenetic activation of genes essential for RCC development, while A-485 primarily suppresses H3K27Ac and particularly H3K9Ac in CMs. Their synergistic effect enhances these modifications on RCC genes, facilitating the transition from CMs to RCCs. Therefore, our findings demonstrate the feasibility and reveal the mechanisms of pharmacological induction of RCCs from endogenous CMs, which could offer a promising regenerative strategy to repair injured hearts.

cell biology↗

Transdifferentiation of fibroblasts into muscle cells to constitute cultured meat with tunable intramuscular fat deposition

Current studies on cultured meat mainly focused on the muscle tissue reconstruction in vitro, but lack the formation of intramuscular fat which is a crucial factor in determining taste, texture and nutritional contents. Therefore, incorporating fat into cultured meat is of superior value. In this study, we employed the myogenic/lipogenic transdifferentiation of chicken fibroblasts in 3D to produce muscle mass and deposit fat into the same cells without the co-culture or mixture of different cells or fat substances. The immortalized chicken embryonic fibroblasts were implanted into the hydrogel scaffold and the cell proliferation and myogenic transdifferentiation were conducted in 3D to produce the whole-cut meat mimics. Compare to 2D, cells grown in 3D matrix showed elevated myogenesis and collagen production. We further induced fat deposition in the transdifferentiated muscle cells and the triglyceride content could be manipulated to match and exceed the levels of chicken meat. The gene expression analysis indicated that both lineage-specific and multi-functional signalings could contribute to the generation of muscle/fat matrix. Overall, we were able to precisely modulate muscle, fat, and extracellular matrix contents according to balanced or specialized meat preferences. These findings provide new avenues for customized cultured meat production with desired intramuscular fat contents that can be tailored to meet the diverse demands of consumers. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC="FIGDIR/small/564179v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1697f5dorg.highwire.dtl.DTLVardef@128e4a1org.highwire.dtl.DTLVardef@1ba31b4org.highwire.dtl.DTLVardef@11559ba_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

cell biology↗

Loss of finger control complexity and intrusion of flexor biases are dissociable in finger individuation impairment after stroke

The ability to control each finger independently is an essential component of human hand dexterity. A common observation of hand function impairment after stroke is the loss of this finger individuation ability, often referred to as enslavement, i.e., the unwanted coactivation of non-intended fingers in individuated finger movements. In the previous literature, this impairment has been attributed to several factors, such as the loss of corticospinal drive, an intrusion of flexor synergy due to upregulations of the subcortical pathways, and/or biomechanical constraints. These factors may or may not be mutually exclusive and are often difficult to tease apart. It has also been suggested, based on a prevailing impression, that the intrusion of flexor synergy appears to be an exaggerated pattern of the involuntary coactivations of task-irrelevant fingers seen in a healthy hand, often referred to as a flexor bias. Most previous studies, however, were based on assessments of enslavement in a single dimension (i.e., finger flexion/extension) that coincide with the flexor bias, making it difficult to tease apart the other aforementioned factors. Here, we set out to closely examine the nature of individuated finger control and finger coactivation patterns in all dimensions. Using a novel measurement device and a 3D finger-individuation paradigm, we aim to tease apart the contributions of lower biomechanical, subcortical constraints, and top-down cortical control to these patterns in both healthy and stroke hands. For the first time, we assessed all five fingers full capacity for individuation. Our results show that these patterns in the healthy and paretic hands present distinctly different shapes and magnitudes that are not influenced by biomechanical constraints. Those in the healthy hand presented larger angular distances that were dependent on top-down task goals, whereas those in the paretic hand presented larger Euclidean distances that arise from two dissociable factors: a loss of complexity in finger control and the dominance of an intrusion of flexor bias. These results suggest that finger individuation impairment after stroke is due to two dissociable factors: the loss of finger control complexity present in the healthy hand reflecting a top-down neural control strategy and an intrusion of flexor bias likely due to an upregulation of subcortical pathways. Our device and paradigm are demonstrated to be a promising tool to assess all aspects of the dexterous capacity of the hand.

neuroscience↗

The 3' exonuclease TOE1 selectively processes snRNAs through recognition of Sm complex assembly and 5' cap trimethylation

Competing exonucleases that promote 3 end maturation or degradation direct quality control of small non-coding RNAs, but how these enzymes distinguish normal from aberrant RNAs is poorly understood. The Pontocerebellar Hypoplasia 7 (PCH7)-associated 3 exonuclease TOE1 promotes maturation of canonical small nuclear RNAs (snRNAs). Here, we demonstrate that TOE1 achieves specificity towards canonical snRNAs by recognizing Sm complex assembly and cap trimethylation, two features that distinguish snRNAs undergoing correct biogenesis from other small non-coding RNAs. Indeed, disruption of Sm complex assembly via snRNA mutations or protein depletions obstructs snRNA processing by TOE1, and in vitro snRNA processing by TOE1 is stimulated by a trimethylated cap. An unstable snRNA variant that normally fails to undergo maturation becomes fully processed by TOE1 when its degenerate Sm binding motif is converted into a canonical one. Our findings uncover the molecular basis for how TOE1 distinguishes snRNAs from other small non-coding RNAs and explain how TOE1 promotes maturation specifically of canonical snRNAs undergoing proper processing.

molecular biology↗

PSTPIP2 ameliorates aristolochic acid nephropathy by suppressing interleukin-19-mediated neutrophil extracellular trap formation

Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by herbal medicines. Previously, we found that proline-serine-threonine phosphatase interacting protein 2 (PSTPIP2) and neutrophil extracellular traps (NETs) play important roles in kidney injury and immune defense, respectively; however, the mechanism of AAN regulation by PSTPIP2 and NETs remains unclear. We found that renal tubular epithelial cell (RTEC) apoptosis, neutrophil infiltration, and inflammatory factor and NET production were increased in a mouse model of AAN, while PSTPIP2 expression was low. Conditional knock-in of PSTPIP2 in mouse kidneys inhibited cell apoptosis, reduced neutrophil infiltration, suppressed the production of inflammatory factors and NETs, and ameliorated renal dysfunction. In contrast, restoring normal PSTPIP2 expression promoted kidney injury. In vivo, the use of Ly6G-neutralizing antibody to remove neutrophils and peptidyl arginine deiminase 4 (PAD4) inhibitors to prevent NET formation reduced apoptosis, thereby alleviating kidney injury. In vitro, damaged RTECs released interleukin-19 (IL-19) via the PSTPIP2/nuclear factor (NF)-{kappa}B pathway and induced NET formation via the IL-20R{beta} receptor. Concurrently, NETs promoted the apoptosis of damaged RTECs. PSTPIP2 affected NET formation by regulating IL-19 expression via inhibition of NF-{kappa}B pathway activation in RTECs, inhibiting their apoptosis and reducing kidney damage.

pharmacology and toxicology↗

The super-pangenome of Populus unveil genomic facets for adaptation and diversification in widespread forest trees

Understanding the underlying mechanisms between genome evolution and phenotypic and adaptive innovations is a key goal of evolutionary studies. Poplars are the worlds most widely distributed and cultivated trees, with extensive phenotypic diversity and environmental adaptability. Here we report a genus-level super-pangenome of 19 Populus genomes. After integrating pan-genomes with transcriptomes, methylomes and chromatin accessibility mapping, we reveal that the evolutionary fate of pan-genes and duplicated genes are largely associated with local genomic landscapes of regulatory and epigenetic architectures. Further comparative genomic analyses enabled to identify 142,202 structural variations (SVs) across species, which overlap with substantial genes and play key roles in both phenotypic and adaptive divergence. We experimentally validated a [~]180 bp presence/absence variant located in the promoter of the CUC2 gene, which contributed critically to leaf serration divergence between species. Together, this first super-pangenome resource in forest trees will not only accelerate molecular functional studies and genetic breeding of this globally important tree genus, but also lays a foundation for our understanding of tree biology.

evolutionary biology↗

Post-acute immunological and behavioral sequelae in mice after Omicron infection

Progress in understanding long COVID and developing effective therapeutics is hampered in part by the lack of suitable animal models. Here we used ACE2-transgenic mice recovered from Omicron (BA.1) infection to test for pulmonary and behavioral post-acute sequelae. Through in-depth phenotyping by CyTOF, we demonstrate that naive mice experiencing a first Omicron infection exhibit profound immune perturbations in the lung after resolving acute infection. This is not observed if mice were first vaccinated with spike-encoding mRNA. The protective effects of vaccination against post-acute sequelae were associated with a highly polyfunctional SARS-CoV-2-specific T cell response that was recalled upon BA.1 breakthrough infection but not seen with BA.1 infection alone. Without vaccination, the chemokine receptor CXCR4 was uniquely upregulated on multiple pulmonary immune subsets in the BA.1 convalescent mice, a process previously connected to severe COVID-19. Taking advantage of recent developments in machine learning and computer vision, we demonstrate that BA.1 convalescent mice exhibited spontaneous behavioral changes, emotional alterations, and cognitive-related deficits in context habituation. Collectively, our data identify immunological and behavioral post-acute sequelae after Omicron infection and uncover a protective effect of vaccination against post-acute pulmonary immune perturbations.

microbiology↗

Nfe2l1-mediated proteasome function controls muscle energy metabolism in obesity

Muscle function is an important denominator of energy metabolism and metabolic health. Adapting the myocyte proteome to energetic challenges, in response to diet or fasting, is facilitated by programs of proteostasis, but the adaptive role of the ubiquitin-proteasome system (UPS) in muscle remains unclear. Here, we show that myocyte Nuclear factor erythroid derived 2,-like 1 (Nfe2l1, also known as Nrf1) is a key regulator of skeletal muscle proteostasis and function. In mice and humans, Nfe2l1 is highly expressed in skeletal myocytes, and its loss diminishes proteasomal activity and leads to hyperubiquitylation. Mice lacking myocyte Nfe2l1 display muscle fiber type switching and insulin resistance when fed a high-fed diet. Nfe2l1 protects myocytes from ferroptosis, which is enhanced in the presence of excess lipids. In conclusion, we define a new adaptive role for the Nfe2l1-ubiquitin proteasome system in the control of skeletal muscle function and energy metabolism.

physiology↗

Stray cats and dogs carrying zoonotic Enterocytozoon bieneusi genotype D in China: a public health concern

Enterocytozoon bieneusi is reported to be a common microsporidian of humans and animals in various countries. However, scarce information on E. bieneusi has been recorded in cats (Felis catus) and dogs (Canis familiaris) in China. As such, we undertook molecular epidemiological investigation of E. bieneusi in cats and dogs in Shanghai, China. A total of 359 genomic DNAs were extracted from individual faecal samples from cats (n = 59) and dogs (n = 300), and then tested using a nested PCR-based sequencing approach employing internal transcribed spacer (ITS) of nuclear ribosomal DNA as the genetic marker. Enterocytozoon bieneusi was detected in 34 of all 359 (9.5%) faecal samples from cats (32.2%; 19/59) and dogs (5.0%; 15/300), including 24 stray cats and dogs (22.6%; 24/106), as well as ten household/raised cats and dogs (4.0%; 10/253). Correlation analyses revealed that E. bieneusi positive rates were significantly associated with stray cats and dogs (P < 0.05). The analysis of ITS sequence data revealed the presentation of five known genotypes CD7, CHN-HD2, D, PtEb IX and Type IV and two novel genotypes D-like1 and PtEb IX-like1. Zoonotic genotype D was the predominant type with percentage of 61.8 (21/34). Phylogenetic analysis of ITS sequence data sets showed that genotypes D, D-like1 and Type IV clustered within Group 1, showing zoonotic potential. The others were assigned into Group 10 with host specificity. These findings suggested that cats and dogs in Shanghai harbor zoonotic genotype D of E. bieneusi and may have a significant risk for zoonotic transmission. Further insight into the epidemiology of E. bieneusi in animals, water and the environment from other areas in China will be important to have an informed position on the public health significance of microsporidiosis caused by this microbe.

genetics↗

An axis-referenced morphometric model reshaping the hippocampus following its longitudinal organization

The anterior-posterior gradient of the human hippocampus on coronal slices is commonly referred to as the long axis, which exhibits morphological heterogeneity related to aging and neurodegeneration. However, the actual longitudinal organization follows a laminar architecture along a longitudinal trajectory that terminates not in the absolute anterior tip of the hippocampus, but rather traces the folding uncus. This study proposes an axis-referenced morphometric model (ARMM) to reshape the hippocampus based on its anatomical nature. An atlas of the hippocampus derived from large samples of 7T ex-vivo MRI and histology serves as the prototype of the model. We set up an orthogonal curvilinear coordinate system within the hippocampus, where the internal coordinate lines correspond naturally to longitudinal and transversal axes of the hippocampus through conformal mapping, providing reference when measuring structural features like thickness, width, length, etc. The inverse mapping allows the hippocampal grey matter to unfold onto a two-dimensional rectangle, facilitating point-wise morphological correspondence across individuals. To evaluate the ARMM, we perform a detailed shape representation of the hippocampus from 7T-MRI and compare it with three state-of-the-art shape models. The results show that the ARMM performs best in metrics measuring shape similarity between the reshaped hippocampus and the ground truth, particularly in head folds (Dice=0.9934). Moreover, our examination of ARMM on longitudinal 7T images revealed its ability to capture subtle structural variations due to neurodegeneration. The ARMM offers a unique anatomically motivated morphometric model of hippocampus, and sheds light on discovering new image markers for diseases associated with hippocampal damage. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/531443v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1e39698org.highwire.dtl.DTLVardef@b4119forg.highwire.dtl.DTLVardef@1f0f6b3org.highwire.dtl.DTLVardef@d4a25d_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

Dopamine promotes Klebsiella quasivariicola proliferation and inflammatory response in the presence of macrophages

Klebsiella quasivariicola was a novel strain of Klebsiella species and had potential pathogenicity. Our previously studies showed dopamine, one of the most commonly used rescue drugs for critically ill patients, had clear effects on the growth of K. quasivariicola in culture medium, however, its effects on host immune system were ignored. Therefore, in consideration of the host immunity, the interactions of K. quasivariicola, dopamine and macrophages were explored. In this study, RAW264.7 cells and C57/BL6 mice were infected with K. quasivariicola, and the bacterial growth in macrophage, the production of inflammatory cytokines and the pathological changes of mice lung were detected, in the absence or presence of dopamine. Our results showed dopamine inhibited the K. quasivariicola growth in medium, but promoted the bacterial growth when K. quasivariicola was co-cultured with macrophages; The expression of proinflammatory cytokines in K. quasivariicola infected RAW 264.7 were increased, while a sharp rise was observed with the addition of dopamine; Infection of K. quasivariicola to mice induced an inflammatory response and lung injury, which were exacerbated by dopamine administration. It can be concluded that dopamine administration resulted in a significantly increase of K. quasivariicola burdens in the presence of macrophage, consequently, aggravated the inflammatory response and inflammatory injury. ImportanceDopamine is one of the most commonly used rescue drugs for critically ill patients. Here we indicated K. quasivariicola was a potential pathogen of pulmonary infection, and dopamine significantly increased the proliferation of K. quasivariicola when exposed to macrophage, subsequently result in severe inflammatory response and inflammatory injury. We also proposed an in vitro model of microbes-drugs-host immune cells that could better mimic in vivo environment and more suitable for the studies of inhibitor screening. This fundamental work had contributed to the present understanding of the crosstalk between pathogen, dopamine and host immune cells. Furthermore, our data showed dopamine was one of the risk factors for patients with K. quasivariicola infection, which provided a basis for clinical precision medicine.

microbiology↗

Spatial exclusion leads to tug-of-war ecological dynamics between competing species within microchannels

Competition is ubiquitous in microbial communities, shaping both their spatial and temporal structure and composition. Many classic minimal models, such as the Moran model, have been employed in ecology and evolutionary biology to understand the role of fixation and invasion in the maintenance of a population. Informed by recent experimental studies of cellular competition in confined spaces, we extend the Moran model to explicitly incorporate spatial exclusion through mechanical interactions among cells within a one-dimensional, open microchannel. The results of our spatial exclusion model differ significantly from those of its classical counterpart. The fixation/extinction probability of a species sharply depends on the species initial relative abundance, and the mean time to fixation is greatly accelerated, scaling logarithmically, rather than algebraically, with the system size. In non-neutral cases, spatial exclusion tends to attenuate the effects of fitness differences on the probability of fixation, and the fixation times increase as the relative fitness differences between species increase. Successful fixation by invasive species, whether through mutation or immigration, are also less probable on average than in the Moran model. Surprisingly, in the spatial exclusion model, successful fixations occur on average more rapidly in longer channels. The mean time to fixation heuristically arises from the boundary between populations performing either quasi-neutral diffusion, near a semi-stable fixed point, or quasi-deterministic avalanche dynamics away from the fixed point. These results, which can be tested in microfluidic monolayer devices, have implications for the maintenance of species diversity in dense bacterial ecosystems where spatial exclusion is central to the competition, such as in organized biofilms or intestinal crypts. The results may be broadly applied to any system displaying tug-of-war type dynamics with a region of quasi-neutral diffusion centered around regions of deterministic population collapse. Author summaryCompetition for territory between different species has far reaching consequences for the diversity and fate of bacterial communities. In this study, we theoretically and computationally study the competitive dynamics of two bacterial populations competing for space in confined environments. The model we develop extends classical models that have served as paradigms for understanding competitive dynamics but did not explicitly include spatial exclusion. We find that spatial effects drastically change the probability of one species successfully outcompeting the other and accelerates the mean time it takes for a species to exclude the other from the environment. In comparison to the predictions of population models that neglect spatial exclusion, species with higher selective advantages are less heavily favoured to outcompete their rival species. Moreover, spatial exclusion influences the success of an invasive species taking over a densely populated community. Compared to classical well-mixed models, there is a reduction in the effectiveness of an invaders fitness advantage at improving the chances of taking over the population. Our results show that spatial exclusion has rich and unexpected repercussions on species dominance and the long-time composition of populations. These must be considered when trying to understand complex bacterial ecosystems such as biofilms and intestinal flora.

ecology↗

Phylogenomics reveals patterns of ancient hybridization and differential diversification contributing to phylogenetic conflict in Populus L. and Salix L.

Despite the economic, ecological, and scientific importance of the genera Populus L. (poplars, cottonwoods, and aspens) and Salix L. Salicaceae (willows), we know little about the sources of differences in species diversity between the genera and of the phylogenetic conflict that often confounds estimating phylogenetic trees. Salix subgenera and sections, in particular, have been difficult to classify, with one recent attempt termed a spectacular failure due to a speculated radiation of the subgenera Vetrix and Chamaetia. Here we use targeted sequence capture to understand the evolutionary history of this portion of the Salicaceae plant family. Our phylogenetic hypothesis was based on 787 gene regions and identified extensive phylogenetic conflict among genes. Our analysis supported some previously described subgeneric relationships and confirmed polyphyly of others. Using an fbranch analysis we identified several cases of hybridization in deep branches of the phylogeny, which likely contributed to discordance among gene trees. In addition, we identified a rapid increase in diversification rate near the origination of the Vetrix-Chamaetia clade in Salix. This region of the tree coincided with several nodes that lacked strong statistical support, indicating a possible increase in incomplete lineage sorting due to rapid diversification. The extraordinary level of both recent and ancient hybridization in both Populus and Salix have played important roles in the diversification and diversity in these two genera. Supplementary data files will be provided by request to matt.olson@ttu.edu

evolutionary biology↗

Effects of cardiac function alterations on the risk of postoperative thrombotic complications in patients receiving endovascular aortic repair

Chronic heart disease (CHD) is a common comorbidity of patients receiving endovascular aneurysm repair (EVAR) for abdominal aortic aneurysms (AAA). The ventricular systolic function determines the hemodynamic environments in aorta, and thus regulating the formation of postoperative thrombus. However, the explicit relationship between ventricular systolic function and EVAR complication of thrombotic events is unknown. Here, we proposed a three-dimensional numerical model coupled with the lumped-elements heart model, which is capable of simulating thrombus formation in diverse systolic functions. The computational results demonstrate that thrombus tended to form on the interior side of the aorta arch and iliac branches, which is consistent with the four patients post-operative imaging follow-up. In addition, we found that the thrombus formation has negative correlations with the maximum ventricular contractile force (r=-0.2814{+/-}0.1012) and positive correlations with the minimum ventricular contractile force (r=0.238{+/-}0.074), whereas the effect of heart rate (r=-0.0148{+/-}0.1211) on thrombus formation is not significant. In conclusion, changes in ventricular systolic function may alter the risk of thrombotic events after EVAR repair, which could provide insight into the selection of adjuvant therapy strategies for AAA patients with CHD.

bioengineering↗

Coupling of perinuclear actin cap and nuclear mechanics regulates flow-induced YAP spatiotemporal nucleocytoplasmic transport

Mechanical forces, including flow shear stress, regulate fundamental cellular process by modulating the nucleocytoplasmic transport of transcription factors, such as Yes-associated Protein (YAP). However, the mechanical mechanism how flow induces the nucleocytoplasmic transport remains largely unclear. Here we found that unidirectional flow applied to endothelial cells induces biphasic YAP nucleocytoplasmic transport with initial nuclear import, followed by nuclear export as perinuclear actin cap forms and nuclear stiffening in a dose and timing-dependent manner. In contrast, pathological oscillatory flow induces slight actin cap formation and nuclear softening, sustaining YAP nuclear localization. To explain the disparately spatiotemporal distribution of YAP, we developed a three-dimensional mechanochemical model considering coupling processes of flow sensing, cytoskeleton organization, nucleus mechanotransduction, and YAP spatiotemporal transport. We discovered that actin cap formation and nuclear stiffness alteration under flow synergically regulate nuclear deformation, hence governing YAP transport. Furthermore, we expanded our single cell model to a collective vertex framework and found that actin cap irregularities in individual cells under flow shear stress potentially induce topological defects and spatially heterogeneous YAP distribution in cellular monolayers. Our work unveils the unified mechanism of flow-induced nucleocytoplasmic transport, offering a universal linkage between transcriptional regulation and mechanical stimulation.

bioengineering↗

HSPB1 facilitates chemoresistance through inhibiting ferroptotic cancer cell death and regulating NF-κB signaling pathway in breast cancer

Chemoresistance is one of the major causes of therapeutic failure and poor prognosis for breast cancer patients, especially for triple-negative breast cancer patients. However, the underlying mechanism remains elusive. Here, we identified novel functional roles of heat shock protein beta-1 (HSPB1), regulating the chemoresistance and ferroptotic cell death in breast cancer. Based on TCGA and GEO databases, HSPB1 expression was upregulated in breast cancer tissues and associated with poor prognosis of breast cancer patients, which was considered as an independent prognostic factor for breast cancer. Functional assays revealed that HSPB1 could promote cancer growth and metastasis in vitro and in vivo. Furthermore, HSPB1 facilitated doxorubicin resistance through protecting breast cancer cells from drug-induced ferroptosis. Mechanistically, HSPB1 could bind with Ik{beta}- and promote its ubiquitination-mediated degradation, leading to increased nuclear translocation and activation of NF-{kappa}B signaling. In addition, HSPB1 overexpression led to enhanced secretion of IL6, which further facilitated breast cancer progression. These findings revealed that HSPB1 upregulation might be a key driver to progression and chemoresistance through regulating ferroptosis in breast cancer, while targeting HSPB1 could be an effective strategy against breast cancer.

cancer biology↗