BACKGROUND: Myocardial fibrosis is an important pathological feature of dilated cardiomyopathy (DCM). The roles of SOCS2 in fibrosis of different organs are controversial. Herein, we investigated the function and potential mechanism of SOCS2 in myocardial fibrosis.
METHODS: Bioinformatics, immunohistochemistry (IHC), immunofluorescence (IF), western blot (WB), real-time fluorescence quantitative PCR (qPCR), rat primary myocardial fibroblasts (rCFs) culture, doxorubicin (DOX) induced mouse dilated cardiomyopathy (DCM) model, and in vivo adeno-associated virus (AAV) infection were used to explore the role of SOCS2 in DCM.
RESULTS: Bioinformatics analysis showed that SOCS2 was positively correlated with fibrosis related factors. SOCS2 was significantly upregulated in patients and mice with DCM. In vivo experiments showed that targeted inhibition of cardiac SOCS2 could improve mouse cardiac function and alleviate myocardial fibrosis. Further research demonstrated that SOCS2 promoted the transformation of myofibroblasts. Knockdown of SOCS2 reduced the nuclear localization of β-catenin, which inhibited the fibrogenic effect of Wnt/β-catenin pathway. In addition, bioinformatics analysis suggested that lymphoid enhancer binding factor 1 (LEF1) was significantly positively correlated with SOCS2. Finally, dual luciferase assays demonstrated that LEF1 could bind to the promoter region of SOCS2, thereby mediating its transcriptional activation.
CONCLUSIONS: SOCS2 could activate the Wnt/β-catenin by regulating the nuclear translocation of β-catenin, which induces the transcriptional activation of SOCS2. Overall, these results indicated a positive feedback activation phenomenon between SOCS2, β-catenin and LEF1 in DCM. These results suggested that inhibition of SOCS2 could effectively alleviate the progression of myocardial fibrosis and improve cardiac function.

The characteristics of lake dissolved organic matter (DOM) pool and lake ecosystem interact, and studying the responses between sediment DOM characteristics and lake ecosystem changes may shed light on the inherent connection between ecosystem evolution and carbon biogeochemical cycles. Lakes in cold and arid regions are sensitive to changes and accumulate large amounts of carbon as DOM, which may provide a window into more explicit relationships between ecosystem evolution and changes in sediment DOM characteristics in time dimension. However, considerable blind spots exist in the responses between the sediment DOM and ecosystem evolution on time scale and the underlying mechanisms. In this study, multiple approaches were combined to investigate the relationship between the variation trend of sediment DOM characteristics and the evolution of fragile lake ecosystems across three different lake ecosystems in cold and arid regions of China. A strong positive relationship between sediment DOM stabilities, especially humification, and ecosystem degradation was found, consistent for the three lakes. Ultra-high-resolution mass spectrometry and structural equation modeling revealed that the changes of ecosystems affected sediment DOM stability through direct pathways (0.24), such as the contents of terrestrial DOM in lake DOM pool, and indirect pathways, including algae-mediated (0.43) and salinity-mediated pathways (0.22), which all increased the contents of refractory DOM in the lake DOM pool and sediments. Based on the fact that DOM stability changes could act on the ecosystem in turn, a possible positive feedback mechanism between ecosystem degradation and increased DOM stability was further inferred. These results suggested that the continuous increased stability of sediment DOM in may implies ecosystem degradation of lakes in the cold and arid regions. This study provides a new perspective for recognizing ecosystem evolution through sediment DOM and improves the understanding of the interaction of lake ecosystem evolution and the biogeochemical cycle of DOM.

Stability is the most pressing challenge hindering the commercialization of perovskite solar cells (PSCs), and previous efforts focused more on enhancing the resistance of PSCs to external stimulus. Here, we found that the indium tin oxide (ITO) will deteriorate the photovoltaic performance of PSCs through positive feedback cycles. Specifically, the perovskite degradation products will cross the electron transport layer to chemically etch the electrode ITO to generate In3+, which will migrate upwards into the perovskite film. Then, the reaction that corrodes ITO consumes the decomposition products of perovskite and shifts the balance of the perovskite decomposition reaction, further promoting the degradation and thus falling into a positive feedback cycle. Moreover, the In3+ in the perovskite film was found to accumulate at the upper surface, which would lead to n-type doping of perovskite film to form the energy barrier for interface carrier extraction. Subsequently, the chelating molecule ethylenediaminetetraacetic acid disodium salt (EDTA-2Na) was introduced onto ITO to firmly chelate the In3+ and prevent it from migrating upward, thus breaking this internal positive feedback cycle and significantly enhancing the efficiency and stability of PSCs. This work provides new perspectives for understanding the mechanism of photovoltaic performance loss and ionic transport in PSCs.

Interacting molecules create regulatory architectures that can persist despite turnover of molecules. Although epigenetic changes occur within the context of such architectures, there is limited understanding of how they can influence the heritability of changes. Here, I develop criteria for the heritability of regulatory architectures and use quantitative simulations of interacting regulators parsed as entities, their sensors, and the sensed properties to analyze how architectures influence heritable epigenetic changes. Information contained in regulatory architectures grows rapidly with the number of interacting molecules and its transmission requires positive feedback loops. While these architectures can recover after many epigenetic perturbations, some resulting changes can become permanently heritable. Architectures that are otherwise unstable can become heritable through periodic interactions with external regulators, which suggests that mortal somatic lineages with cells that reproducibly interact with the immortal germ lineage could make a wider variety of architectures heritable. Differential inhibition of the positive feedback loops that transmit regulatory architectures across generations can explain the gene-specific differences in heritable RNA silencing observed in the nematode Caenorhabditis elegans. More broadly, these results provide a foundation for analyzing the inheritance of epigenetic changes within the context of the regulatory architectures implemented using diverse molecules in different living systems.

Heme, found in hemoproteins, is a valuable source of iron, an essential mineral. The need for an alternative hemoprotein source has emerged due to the inherent risks of large-scale livestock farming and animal proteins. Corynebacterium glutamicum, regarded for Qualified Presumption of Safety or Generally Recognized as Safe, can biosynthesize hemoproteins. C. glutamicum single-cell protein (SCP) can be a valuable alternative hemoprotein for supplying heme iron without adversely affecting blood fat levels. We constructed the chemostat culture system to increase hemoprotein content in C. glutamicum SCP. Through adaptive evolution, hemoprotein levels could be naturally increased to address oxidative stress resulting from enhanced growth rate. In addition, we used several specific plasmids containing growth-accelerating genes and the hemA promoter to expedite the evolutionary process. Following chemostat culture for 15 days, the plasmid in selected descendants was cured. The evolved strains showed improved specific growth rates from 0.59 h-1 to 0.62 h-1, 20% enhanced resistance to oxidative stress, and increased heme concentration from 12.95 µg/g-DCW to 14.22-15.24 µg/g-DCW. Notably, the putative peptidyl-tRNA hydrolase-based evolved strain manifested the most significant increase (30%) of hemoproteins. This is the first report presenting the potential of a growth-acceleration-targeted evolution (GATE) strategy for developing non-GMO industrial strains with increased bio-product productivity.

Complement provides powerful, fast responses in the human circulation to SARS-CoV-2 (COVID-19 virus) infection of the lower respiratory tract. COVID-19 effects were investigated in a revised human in silico Mass Action model of complement\'s alternative pathway (AP) responses. Bursts of newly circulating virions increased the fission of Complement protein C3 into C3a and C3b via stimulation of the lectin pathway or inhibited complement factor H. Viral reproduction sub-models incorporated smoothly exponential or step-wise exponential growth. Starting complement protein concentrations were drawn randomly from published normal male or female ranges and each infection model run for 10 days. C3 and factor B (FB) syntheses driven by Lectin Pathway stimulation led to declining plasma C3 and increasing FB concentrations. The C3-convertase concentration, a driver of viral elimination, could match viral growth over three orders of magnitude but near-complete exhaustion of circulating C3 was more prevalent with step-wise than with \'smooth\' increases in viral stimulation. C3 exhaustion could be prolonged. Type 2 Diabetes and hypertension led to greatly increased peak C3-convertase concentrations, as did short-term variability of COVID-19 viraemia, pulmonary capillary clotting and secondary acidosis. Positive feedback in the AP greatly extends its response range at the expense of stability.

In this study, we investigate the temperature-dependent electrical characteristics of bistable silicon resistors (biristors) at temperatures ranging from 275 to 400 K. The proposed biristor exhibits low latch voltages owing to the surface accumulation layer transistor concept. Moreover, the biristor was abruptly turned on and off by positive and negative feedback phenomena, respectively. As the temperature increased from 275 to 400 K, the latch-up voltage decreased from 2.131 to 1.696 V, while the latch-down voltage increased from 1.486 to 1.637 V. Mechanisms of temperature-dependent change in latch voltage were analyzed using energy band diagrams. This temperature-dependent analysis on silicon biristor can serve as blueprint for the contribution of stable operation.

Construction site managers play a critical role in occupational safety in the construction industry. This study aimed to develop and test a method for training construction site managers in positive feedback and active listening by incorporating the behavioral training components of behavior analysis, goal setting, practice with behavior feedback, homework, and maintenance planning into individualized behavior-based safety-leadership training (IBST), and to assess the effect of IBST on construction site managers\' safety-leadership behaviors and performance.
In a naturalistic randomized controlled trial, construction site managers were randomly assigned to an experimental group (n = 16) or a control group (n = 19). The experimental-group managers received IBST, while the control-group managers received no training. Paired sample t-tests on pre- to post-training (i.e., six weeks after the final training session) were performed separately for the experimental- and control-group managers.
The safety-leadership behaviors of the experimental-group managers improved in terms of favorable feedback (d = 0.99, p <.01), safety-specific feedback (d = 0.89, p =.02), behavior-specific feedback (d = 0.66, p =.02), antecedent listening (d = 0.68, p =.02), and consequential listening (d = 0.78, p =.01). In addition, safety-leadership performance improved in terms of transformational leadership (d = 0.78, p =.01) and contingent-reward leadership (d = 0.64, p =.02). No significant change was found for the control-group managers.
The results indicate that behavior analysis, goal setting, practice with behavior feedback, homework, and maintenance planning are effective behavioral training components of safety-leadership training. Positive feedback and active listening were also found to be important behavioral requisites for transformational and contingent-reward leadership.
IBST can be used to develop occupational safety in the construction industry by improving construction site managers\' safety-leadership behaviors and performance.

Autoimmune myocarditis, which falls within the broad spectrum of myocarditis, is characterized by an excessive inflammatory response in the heart, and can progress into dilated cardiomyopathy and irreversible heart failure in all possibility. However, effective clinical therapeutics are limited due to its complex inflammatory reactions. Empagliflozin (EMPA) has been previously demonstrated to possess anti-inflammatory properties. This study aimed to determine the improvement effects of EMPA on cardiac dysfunction under the condition of autoimmune myocarditis, and to further investigate the potential mechanisms. In vivo, all male Balb/c mice were randomly divided into four groups: control, experimental autoimmune myocarditis (EAM), EAM+EMPA and EMPA. In vitro, the effects of EMPA on IL-18-stimulated H9C2 cells were explored and the underlying molecular mechanisms were further determined. EMPA treatment significantly inhibited the development of autoimmune myocarditis, and mice treated with EMPA exhibited improved cardiac function compared with that in the EAM group, potentially through modulating pyroptosis of myocardium. Specifically, the NF-κB pathway was activated in the hearts of the EAM mice, which further activated NLRP3 inflammasome-dependent pyroptosis. EMPA treatment significantly inhibited such activation, thus alleviating inflammatory reactions in the context of EAM. Moreover, in vitro, we also observed that EMPA significantly inhibited pyroptosis of IL-18-stimulated H9C2 cells, and reduced nuclear translocation of NF-κB and degradation of activated IκBα. This work provides the first direct evidence that EMPA can inhibit myocardial inflammation and improve cardiac function in EAM mice, partly attributed to the drug-induced suppression of cardiomyocyte pyroptosis via disrupting the NF-κB pathway.

Abrupt and rapid changes in human societies are among the most exciting population phenomena. Human populations tend to show rapid expansions from low to high population density along with increased social complexity in just a few generations. Such demographic transitions appear as a remarkable feature of Homo sapiens population dynamics, most likely fuelled by the ability to accumulate cultural/technological innovations that actively modify their environment. We are especially interested in establishing if the demographic transitions of pre-historic populations show the same dynamic signature of the Industrial Revolution transition (a positive relationship between population growth rates and size). Our results show that population growth patterns across different pre-historic societies were similar to those observed during the Industrial Revolution in developed western societies. These features, which appear to have been operating during most of our recent demographic history from hunter-gatherers to modern industrial societies, imply that the dynamics of cooperation underlay sudden population transitions in human societies. This article is part of the theme issue \'Evolution and sustainability: gathering the strands for an Anthropocene synthesis\'.