Explore the vast range of titles available.

Cardiac maturation lays the foundation for postnatal heart development and disease, yet little is known about the contributions of the microenvironment to cardiomyocyte maturation. By integrating single-cell RNA-sequencing data of mouse hearts at multiple postnatal stages, we construct cellular interactomes and regulatory signaling networks. Here we report switching of fibroblast subtypes from a neonatal to adult state and this drives cardiomyocyte maturation. Molecular and functional maturation of neonatal mouse cardiomyocytes and human embryonic stem cell-derived cardiomyocytes are considerably enhanced upon co-culture with corresponding adult cardiac fibroblasts. Further, single-cell analysis of in vivo and in vitro cardiomyocyte maturation trajectories identify highly conserved signaling pathways, pharmacological targeting of which substantially delays cardiomyocyte maturation in postnatal hearts, and markedly enhances cardiomyocyte proliferation and improves cardiac function in infarcted hearts. Together, we identify cardiac fibroblasts as a key constituent in the microenvironment promoting cardiomyocyte maturation, providing insights into how the manipulation of cardiomyocyte maturity may impact on disease development and regeneration. How cardiomyocytes mature and what regulates this is unclear. Here, the authors use single-cell analysis to examine how the population of murine cardiac fibroblasts changes during development and affects maturation of cardiomyocytes.

Exercise has an effect on the reduction of myocardial fibrosis in diabetic rats as previously reported, in which oxidative stress and the TGF-β1/Smad signaling pathway may play key roles. There is little direct experimental evidence that exercise alleviates myocardial fibrosis in type 2 diabetes mellitus (T2DM). Here we established a type 2 diabetic model by using streptozotocin and a high-fat diet. Rats were divided into groups of normal control (NC), T2DM and T2DM plus exercise (T2DME). The T2DME group received further treadmill training at moderate intensity for 8 weeks. Histological and biochemical methods were used to detect the benefits of exercise to T2DM. Results showed that the weight of rats in the T2DM group dropped dramatically, along with significant increases in blood glucose, myocardial fibrosis and oxidative stress, associated with upregulated expression of factors of myocardial fibrosis, except Smad7. Exercise largely reversed T2DM-induced alterations in factors of myocardial fibrosis, including suppressing expression of MMP-2, CTGF, TGF-β1, p-Smad2 and p-Smad3, and increased expression of TIMP–1 and Smad7. Therefore, exercise might be considered an alternative therapeutic remedy for diabetic cardiomyopathy.

Cell-cell communication via gap junctions regulates a wide range of physiological processes by enabling the direct intercellular electrical and chemical coupling. However, the in vivo distribution and function of gap junctions remain poorly understood, partly due to the lack of non-invasive tools with both cell-type specificity and high spatiotemporal resolution. Here, we developed PARIS (pairing actuators and receivers to optically isolate gap junctions), a new fully genetically encoded tool for measuring the cell-specific gap junctional coupling (GJC). PARIS successfully enabled monitoring of GJC in several cultured cell lines under physiologically relevant conditions and in distinct genetically defined neurons in Drosophila brain, with ~10 s temporal resolution and sub-cellular spatial resolution. These results demonstrate that PARIS is a robust, highly sensitive tool for mapping functional gap junctions and study their regulation in both health and disease. For the tissues and organs of our bodies to work properly, the cells within them need to communicate with each other. One important part of cellular communication is the movement of signals – usually small molecules or ions – directly from one cell to another. This happens via structures called gap junctions, a type of sealed ‘channel’ that connects two cells. Gap junctions are found throughout the body, but investigating their precise roles in health and disease has been difficult. This is due to problems with the tools available to detect and monitor gap junctions. Some are simply harmful to cells, while others cannot be restricted to specific cell populations within a tissue. This lack of specificity makes it difficult to study gap junctions in the brain, where it is important to understand the connectivity patterns between distinct types of nerve cells. Wu et al. wanted to develop a new, non-harmful method to track gap junctions in distinct groups of cells within living tissues. To do this, Wu et al. devised PARIS, a two-part, genetically encoded system. The first part comprises a light-sensitive molecular ‘pump’, which can only be turned on by shining a laser onto the cell of interest. When the pump is active, it transports hydrogen ions out of the cell. The second part of the system is a fluorescent sensor, present inside ‘receiving’ cells, which responds to the outcoming hydrogen ions (small enough to pass through gap junctions). If an illuminated ‘signaling’ cell is connected via gap junctions to cells containing the fluorescent sensor, they will light up within seconds, but other cells not connected through gap junctions will not. The researchers first tested PARIS in cultured human and rat cells that had been genetically engineered to produce both components of the system. The experiments confirmed that PARIS could both detect networks of gap junctions in healthy cells and reveal when these networks had been disrupted, for instance by drugs or genetic mutations. Experiments using fruit flies demonstrated that PARIS was stable in living tissue and could also map the gap junctions connecting specific groups of nerve cells. PARIS is a valuable addition to the toolbox available to study cell communication. In the future, it could help increase our understanding of diseases characterized by defective gap junctions, such as seizures, cardiac irregularities, and even some cancers.

The Endoplasmic/sarcoplasmic reticulum (ER/SR) is central to calcium (Ca 2+ ) signaling, yet current genetically encoded Ca 2+ indicators (GECIs) cannot detect elementary Ca 2+ release events from ER/SR, particularly in muscle cells. Here, we report NEMOer, a set of organellar GECIs, to efficiently capture ER Ca 2+ dynamics with increased sensitivity and responsiveness. NEMOer indicators exhibit dynamic ranges an order of magnitude larger than G-CEPIA1er, enabling 2.7-fold more sensitive detection of Ca 2+ transients in both non-excitable and excitable cells. The ratiometric version further allows super-resolution monitoring of local ER Ca 2+ homeostasis and dynamics. Notably, NEMOer-f enabled the inaugural detection of Ca 2+ blinks, elementary Ca 2+ releasing signals from the SR of cardiomyocytes, as well as in vivo spontaneous SR Ca 2+ releases in zebrafish. In summary, the highly dynamic NEMOer sensors expand the repertoire of organellar Ca 2+ sensors that allow real-time monitoring of intricate Ca 2+ dynamics and homeostasis in live cells with high spatiotemporal resolution. The endoplasmic/sarcoplasmic reticulum (ER/SR) plays a crucial role in calcium signaling, but there are few methods capable of efficiently capturing ER/SR Ca 2+ dynamics. Here authors develop a set of genetically encoded indicators enabling ratiometric super-resolution imaging and detection of elementary Ca 2+ release in cardiomyocytes.

Ziziphus spinosa (Bunge) H.H. Hu ex F.H. Chen is a woody plant species of the family Rhamnaceae (order Rhamnales) that possesses high nutritional and medicinal value. Predicting the effects of climate change on the distribution of Z. spinosa is of great significance for the investigation, protection, and exploitation of this germplasm resource. For this study, optimized maximum entropy models were employed to predict the distribution patterns and changes of its present (1970–2000) and future (2050s, 2070s, and 2090s) potential suitable regions in China under multiple climate scenarios (SSP1‐2.6, SSP2‐4.5, SSP3‐7.0 & SSP5‐8.5). The results revealed that the total area of the present potential suitable region for Z. spinosa is 162.60 × 104 km2, which accounts for 16.94% of China's territory. Within this area, the regions having low, medium, and high suitability were 80.14 × 104 km2, 81.50 × 104 km2, and 0.96 × 104 km2, respectively, with the high suitability regions being distributed primarily in Shanxi, Hebei, and Beijing Provinces. Except for SSP‐1‐2.6‐2070s, SSP‐5‐8.5‐2070s, and SSP‐5‐8.5‐2090s, the suitable areas for Z. spinosa in the future increased to different degrees. Meanwhile, considering the distribution of Z. spinosa during different periods and under different climate scenarios, our study predicted that the low impact areas of Z. spinosa were mainly restricted to Shanxi, Shaanxi, Ningxia, Gansu, Liaoning, Inner Mongolia, and Jilin Provinces. The results of core distributional shifts showed that, except for SSP1‐2.6, the center of the potential suitable region of Z. spinosa exhibited a trend of gradually shifting to the northwest. Predicting the effects of climate change on the distribution of Ziziphus spinosa is of great significance for the investigation, protection, and exploitation of this germplasm resource. For this study, optimized maximum entropy models were employed to predict the distribution patterns and changes of its present (1970–2000) and future (2050s, 2070s, and 2090s) potential suitable regions in China under multiple climate scenarios (SSP1‐2.6, SSP2‐4.5, SSP3‐7.0, and SSP5‐8.5).

The mitochondrion is essential for energy metabolism and production of reactive oxygen species （ROS）. In intact cells, respiratory mitochondria exhibit spontaneous ＂superoxide flashes＂, the quantal ROS-producing events consequential to transient mitochondrial permeability transition （tMPT）. Here we perform the first in vivo imaging of mitochondrial superoxide flashes and tMPT activity in living mice expressing the superoxide biosensor mt-cpYFP, and demonstrate their coupling to whole-body glucose metabolism. Robust tMPT/superoxide flash activity occurred in skeletal muscle and sciatic nerve of anesthetized transgenic mice. In skeletal muscle, imaging tMPT/superoxide flashes revealed labyrinthine three-dimensional networks of mitochondria that operate synchronously. The tMPT/ superoxide flash activity surged in response to systemic glucose challenge or insulin stimulation, in an apparently frequency-modulated manner and involving also a shift in the gating mode of tMPT. Thus, in vivo imaging of tMPT- dependent mitochondrial ROS signals and the discovery of the metabolism-tMPT-superoxide flash coupling mark important technological and conceptual advances for the study of mitochondrial function and ROS signaling in health and disease.

The differentiation of pluripotent stem cells (PSCs) into diverse functional cell types provides a promising solution to support drug discovery, disease modeling, and regenerative medicine. However, functional cell differentiation is currently limited by the substantial line-to-line and batch-to-batch variabilities, which severely impede the progress of scientific research and the manufacturing of cell products. For instance, PSC-to-cardiomyocyte (CM) differentiation is vulnerable to inappropriate doses of CHIR99021 (CHIR) that are applied in the initial stage of mesoderm differentiation. Here, by harnessing live-cell bright-field imaging and machine learning (ML), we realize real-time cell recognition in the entire differentiation process, e.g., CMs, cardiac progenitor cells (CPCs), PSC clones, and even misdifferentiated cells. This enables non-invasive prediction of differentiation efficiency, purification of ML-recognized CMs and CPCs for reducing cell contamination, early assessment of the CHIR dose for correcting the misdifferentiation trajectory, and evaluation of initial PSC colonies for controlling the start point of differentiation, all of which provide a more invulnerable differentiation method with resistance to variability. Moreover, with the established ML models as a readout for the chemical screen, we identify a CDK8 inhibitor that can further improve the cell resistance to the overdose of CHIR. Together, this study indicates that artificial intelligence is able to guide and iteratively optimize PSC differentiation to achieve consistently high efficiency across cell lines and batches, providing a better understanding and rational modulation of the differentiation process for functional cell manufacturing in biomedical applications.

Calstabin2 is a component of the cardiac ryanodine receptor (RyR2) macromolecular complex, which modulates Ca 2+ release from the sarcoplasmic reticulum in cardiomyocytes. Previous reports implied that genetic deletion of Calstabin2 leads to phenotypes related to cardiac aging. However, the mechanistic role of Calstabin2 in the process of cardiac aging remains unclear. To assess whether Calstabin2 is involved in age-related heart dysfunction, we studied Calstabin2 knockout (KO) and control wild-type (WT) mice. We found a significant association between deletion of Calstabin2 and cardiac aging. Indeed, aged Calstabin2 KO mice exhibited a markedly impaired cardiac function compared with WT littermates. Calstabin2 deletion resulted also in increased levels of cell cycle inhibitors p16 and p19, augmented cardiac fibrosis, cell death and shorter telomeres. Eventually, we demonstrated that Calstabin2 deletion resulted in AKT phosphorylation, augmented mTOR activity and impaired autophagy in the heart. Taken together, our results identify Calstabin2 as a key modulator of cardiac aging and indicate that the activation of the AKT/mTOR pathway plays a mechanistic role in such a process.

Coptis chinensis Franch. (Ranales: Ranunculaceae) is a perennial species with high medicinal value. Predicting the potentially geographical distribution patterns of C. chinensis against the background of climate change can facilitate its protection and sustainable utilization. This study employed the optimized maximum entropy model to predict the distribution patterns and changes in potentially suitable C. chinensis’ regions in China under multiple climate change scenarios (SSP1-2.6, SSP2-4.5, SSP3-7.0 and SSP5-8.5) across different time periods (1970–2000, 2050s, 2070s, and 2090s). The results revealed that the currently potentially suitable regions of C. chinensis span an area of 120.47 × 104 km2, which accounts for 12.54% of China’s territory. Among these areas, the low, moderate, and highly suitable regions are 80.10 × 104 km2, 37.16 × 104 km2, and 3.21 × 104 km2, respectively. The highly suitable regions are primarily distributed in Chongqing, Guizhou, Zhejiang, Hubei, and Hunan Provinces. Over time, the potentially suitable regions of C. chinensis are predicted to shrink. Furthermore, our study revealed that the relatively low impact areas of C. chinensis were mainly distributed in Yunnan, Guizhou, Hubei, Chongqing, and other Provinces. Centroid transfer analysis indicated that except for SSP1-2.6, the center of the potentially suitable region of C. chinensis showed a trend of gradual transfer to the northwest and high-altitude areas.

Bletilla striata (Thunb. ex A. Murray) Rchb. f., a species of the perennial herb Orchidaceae, has potent anti-inflammatory and antiviral biological activities. MADS-box transcription factors play critical roles in the various developmental processes of plants. Although this gene family has been extensively investigated in many species, it has not been analyzed for B. striata. In total, 45 MADS-box genes were identified from B. striata in this study, which were classified into five subfamilies (Mδ, MIKC, Mα, Mβ, and Mγ). Meanwhile, the highly correlated protein domains, motif compositions, and exon–intron structures of BsMADSs were investigated according to local B. striata databases. Chromosome distribution and synteny analyses revealed that segmental duplication and homologous exchange were the main BsMADSs expansion mechanisms. Further, RT-qPCR analysis revealed that BsMADSs had different expression patterns in response to various stress treatments. Our results provide a potential theoretical basis for further investigation of the functions of MADS genes during the growth of B. striata.