In vertebrate hearts, the ventricular trabecular myocardium develops as a sponge-like network of cardiomyocytes that is critical for contraction and conduction, ventricular septation, papillary ...muscle formation and wall thickening through the process of compaction
. Defective trabeculation leads to embryonic lethality
or non-compaction cardiomyopathy (NCC)
. There are divergent views on when and how trabeculation is initiated in different species. In zebrafish, trabecular cardiomyocytes extrude from compact myocardium
, whereas in chicks, chamber wall thickening occurs before overt trabeculation
. In mice, the onset of trabeculation has not been described, but is proposed to begin at embryonic day 9.0, when cardiomyocytes form radially oriented ribs
. Endocardium-myocardium communication is essential for trabeculation, and numerous signalling pathways have been identified, including Notch
and Neuregulin (NRG)
. Late disruption of the Notch pathway causes NCC
. Whereas it has been shown that mutations in the extracellular matrix (ECM) genes Has2 and Vcan prevent the formation of trabeculae in mice
and the matrix metalloprotease ADAMTS1 promotes trabecular termination
, the pathways involved in ECM dynamics and the molecular regulation of trabeculation during its early phases remain unexplored. Here we present a model of trabeculation in mice that integrates dynamic endocardial and myocardial cell behaviours and ECM remodelling, and reveal new epistatic relationships between the involved signalling pathways. NOTCH1 signalling promotes ECM degradation during the formation of endocardial projections that are critical for individualization of trabecular units, whereas NRG1 promotes myocardial ECM synthesis, which is necessary for trabecular rearrangement and growth. These systems interconnect through NRG1 control of Vegfa, but act antagonistically to establish trabecular architecture. These insights enabled the prediction of persistent ECM and cardiomyocyte growth in a mouse NCC model, providing new insights into the pathophysiology of congenital heart disease.
Bone morphogenetic protein 10 (BMP10) is a cardiac peptide growth factor belonging to the transforming growth factor β superfamily that critically controls cardiovascular development, growth, and ...maturation. It has been shown that BMP10 elicits its intracellular signaling through a receptor complex of activin receptor-like kinase 1 with morphogenetic protein receptor type II or activin receptor type 2A. Previously, we generated and characterized a transgenic mouse line expressing BMP10 from the α-myosin heavy chain gene promoter and found that these mice have normal cardiac hypertrophic responses to both physiological and pathological stimuli. In this study, we report that these transgenic mice exhibit significantly reduced levels of cardiomyocyte apoptosis and cardiac fibrosis in response to a prolonged administration of the β-adrenoreceptor agonist isoproterenol. We further confirmed this cardioprotective function with a newly generated conditional Bmp10 transgenic mouse line, in which Bmp10 was activated in adult hearts by tamoxifen. Moreover, the intraperitoneal administration of recombinant human BMP10 was found to effectively protect hearts from injury, suggesting potential therapeutic utility of using BMP10 to prevent heart failure. Gene profiling and biochemical analyses indicated that BMP10 activates the SMAD-mediated canonical pathway and, unexpectedly, also the signal transducer and activator of transcription 3 (STAT3)–mediated signaling pathway both in vivo and in vitro. Additional findings further supported the notion that BMP10's cardioprotective function likely is due to its dual activation of SMAD- and STAT3-regulated signaling pathways, promoting cardiomyocyte survival and suppressing cardiac fibrosis.
Abstract
Complex oxide heterointerfaces and van der Waals heterostructures present two versatile but intrinsically different platforms for exploring emergent quantum phenomena and designing new ...functionalities. The rich opportunity offered by the synergy between these two classes of materials, however, is yet to be charted. Here, we report an unconventional nonlinear optical filtering effect resulting from the interfacial polar alignment between monolayer MoS
2
and a neighboring ferroelectric oxide thin film. The second harmonic generation response at the heterointerface is either substantially enhanced or almost entirely quenched by an underlying ferroelectric domain wall depending on its chirality, and can be further tailored by the polar domains. Unlike the extensively studied coupling mechanisms driven by charge, spin, and lattice, the interfacial tailoring effect is solely mediated by the polar symmetry, as well explained via our density functional theory calculations, pointing to a new material strategy for the functional design of nanoscale reconfigurable optical applications.
CRISPR-Cas9 gene-editing technology has facilitated the generation of knockout mice, providing an alternative to cumbersome and time-consuming traditional embryonic stem cell-based methods. An ...earlier study reported up to 16% efficiency in generating conditional knockout (cKO or floxed) alleles by microinjection of 2 single guide RNAs (sgRNA) and 2 single-stranded oligonucleotides as donors (referred herein as "two-donor floxing" method).
We re-evaluate the two-donor method from a consortium of 20 laboratories across the world. The dataset constitutes 56 genetic loci, 17,887 zygotes, and 1718 live-born mice, of which only 15 (0.87%) mice contain cKO alleles. We subject the dataset to statistical analyses and a machine learning algorithm, which reveals that none of the factors analyzed was predictive for the success of this method. We test some of the newer methods that use one-donor DNA on 18 loci for which the two-donor approach failed to produce cKO alleles. We find that the one-donor methods are 10- to 20-fold more efficient than the two-donor approach.
We propose that the two-donor method lacks efficiency because it relies on two simultaneous recombination events in cis, an outcome that is dwarfed by pervasive accompanying undesired editing events. The methods that use one-donor DNA are fairly efficient as they rely on only one recombination event, and the probability of correct insertion of the donor cassette without unanticipated mutational events is much higher. Therefore, one-donor methods offer higher efficiencies for the routine generation of cKO animal models.
Acid rain not only has serious harm to the environment, but also has the same threat to plants, but the invasive plant
Alternanthera philoxeroides
still grows well compared to the native plant
...Alternanthera sessilis
under acid rain stress. However, the underlying mechanism of resistance to the acid rain environment in invasive
Alternanthera philoxeroides
remains unclear. In the current study, we comparatively analyzed the plant physiological characteristics, soil physicochemical properties, and rhizosphere microbial communities of invasive
A
.
philoxeroides
and native
A
.
sessilis
under different pH condition. The simulated acid rain had a significant inhibitory effect on the morphological and physiological traits of
A
.
philoxeroides
and
A
.
sessilis
and reduced the soil nutrient content. However,
A
.
philoxeroides
was more tolerant of acid rain. Compared with CK, simulated acid rain treatment at pH 2.5 significantly increased the Chao1, ACE, and Shannon indexes of
A
.
philoxeroides
microorganisms. Under simulated acid rain treatment at pH 2.5, the fungal flora Chao1, ACE and Shannon index were significantly higher than those of CK by 14.5%, 12.4%, and 30.4%, respectively. The dominant bacterial phyla of soil bacteria were Proteobacteria, Actinobacteria, Bacteroidota, Actinobacteria, Firmicutes, Myxococcota, Chloroflexi, Patescibacteria, Gemmatimonadota, Verrucomicrobiota, and Armatimonadota. The dominant fungi were Ascomycota, Basidiomycota, Rozellomycota, and Olpidiomycota. The bacterial and fungal diversity and structure of
A
.
philoxeroides
and
A
.
sessilis
showed the greatest difference between the pH 2.5 treatment and CK. Redundancy analysis showed that electrical conductivity (EC) and total phosphorus (TP) were the main factors changing the bacterial communities, and available phosphorus (AP), organic matter (OM), EC, and pH were the main factors changing the fungal communities. This study contributes to the microbial community structure of the invasive plant
A
.
philoxeroides
and provides a theoretical basis for studying the invasion mechanism of invasive plants under acid rain.
Many important signaling pathways rely on multiple ligands. It is unclear if this is a mechanism of safeguard via redundancy or if it serves other functional purposes. In this study, we report unique ...insight into this question by studying the activin receptor-like kinase 1 (ALK1) pathway. Despite its functional importance in vascular development, the physiological ligand or ligands for ALK1 remain to be determined. Using conventional knockout and specific antibodies against bone morphogenetic protein 9 (BMP9) or BMP10, we showed that BMP9 and BMP10 are the physiological, functionally equivalent ligands of ALK1 in vascular development. Timing of expression dictates the in vivo requisite role of each ligand, and concurrent expression results in redundancy. We generated mice (Bmp10 ⁹/⁹) in which the coding sequence of Bmp9 replaces that of Bmp10 . Surprisingly, analysis of Bmp10 ⁹/⁹ mice demonstrated that BMP10 has an exclusive function in cardiac development, which cannot be substituted by BMP9. Our study reveals context-dependent significance in having multiple ligands in a signaling pathway.
Sheep exhibit a distinct estrous cycle that includes four different phases: proestrus, estrus, late estrus, and luteal phase. As the estrous cycle repeats, follicular development regularly ...alternates. We thus investigated ovarian transcriptome data from each of the four phases using weighted gene co-expression network analysis (WGCNA) to identify modules, pathways, and genes essential to follicle growth and development. We clustered mRNA and long non-coding RNA (lncRNA) into different modules by WGCNA, and calculated correlation coefficients between genes and Stages of the estrous cycle. Co-expression of the black module (cor = 0.81,
<0.001) and the yellow module (cor = 0.61,
<0.04) was found to be critical for follicle growth and development. A total of 2066 genes comprising the black and yellow modules was used for functional enrichment. The results reveal that these genes are mainly enriched in Cell cycle, PI3K-Akt signaling pathway, Oocyte meiosis, Apoptosis, and other important signaling pathways. We also identified seven hub genes (
, and
) that may play a role in follicle development. Our study may provide several important new markers allowing in depth exploration of the genetic basis for multiparous reproduction in sheep.
Granulosa cells (GCs) are essential for follicular development, and long non-coding RNAs (LncRNAs) are known to support the maintenance of this process and hormone synthesis in mammals. Nevertheless, ...the regulatory roles of these lncRNAs within sheep follicular GCs remain largely unexplored. This study delved into the influence of a
, on the proliferation and steroid hormone synthesis of sheep ovarian GCs and the associated target genes
. Cell Counting Kit-8 (CCK-8) gain-of-function experiments indicated that overexpression of
significantly boosted GCs proliferation, along with estrogen (E
) and progesterone (P
) levels. Further mechanistic scrutiny revealed that
is primarily localized within the cytoplasm of ovarian granulosa cells and engages in molecular interplay with
. This interaction results in the upregulation of
protein expression. Moreover, it was discerned that increased
levels contribute to augmented proliferation of follicular granulosa cells and the secretion of E
and P
. Experiments involving co-transfection elucidated that the concurrent overexpression of
and
acted synergistically to potentiate these effects. These findings provide insights into the molecular underpinnings of fecundity in ovine species and may inform future strategies for enhancing reproductive outcomes.
A deep-learning model was proposed for predicting the remaining time to automatic scram during abnormal conditions of nuclear power plants (NPPs) based on long short-term memory (LSTM) and dropout. ...The proposed model was trained by simulated condition data of abnormal conditions; the input of the model was the deviation of the monitoring parameters from the normal operating state, and the output was the remaining time from the current moment to the upcoming reactor trip. The predicted remaining time to the reactor trip decreases with the development of abnormal conditions; thus, the output of the proposed model generates a predicted countdown to the reactor trip. The proposed prediction model showed better prediction performance than the Elman neural network model in the experiments but encountered an overfitting problem for testing data containing noise. Therefore, dropout was applied to further improve the generalization ability of the prediction model based on LSTM. The proposed automatic scram prediction model can provide NPP operators with an alert to the automatic scram during abnormal conditions.
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