Reconciling carbon quality with availability predicts temperature sensitivity of global soil carbon mineralization.

Soil organic carbon (SOC) mineralization is a key component of the global carbon cycle. Its temperature sensitivity Q10 (which is defined as the factor of change in mineralization with a 10 °C temperature increase) is crucial for understanding the carbon cycle-climate change feedback but remains uncertain. Here, we demonstrate the universal control of carbon quality-availability tradeoffs on Q10. When carbon availability is not limited, Q10 is controlled by carbon quality; otherwise, substrate availability controls Q10. A model driven by such quality-availability tradeoffs explains 97% of the spatiotemporal variability of Q10 in incubations of soils across the globe and predicts a global Q10 of 2.1 ± 0.4 (mean ± one SD) with higher Q10 in northern high-latitude regions. We further reveal that global Q10 is predominantly governed by the mineralization of high-quality carbon. The work provides a foundation for predicting SOC dynamics under climate and land use changes which may alter soil carbon quality and availability.

Myc suppresses male-male courtship in Drosophila.

Despite strong natural selection on species, same-sex sexual attraction is widespread across animals, yet the underlying mechanisms remain elusive. Here, we report that the proto-oncogene Myc is required in dopaminergic neurons to inhibit Drosophila male-male courtship. Loss of Myc, either by mutation or neuro-specific knockdown, induced males' courtship propensity toward other males. Our genetic screen identified DOPA decarboxylase (Ddc) as a downstream target of Myc. While loss of Ddc abrogated Myc depletion-induced male-male courtship, Ddc overexpression sufficed to trigger such behavior. Furthermore, Myc-depleted males exhibited elevated dopamine level in a Ddc-dependent manner, and their male-male courtship was blocked by depleting the dopamine receptor DopR1. Moreover, Myc directly inhibits Ddc transcription by binding to a target site in the Ddc promoter, and deletion of this site by genome editing was sufficient to trigger male-male courtship. Finally, drug-mediated Myc depletion in adult neurons by GeneSwitch technique sufficed to elicit male-male courtship. Thus, this study uncovered a novel function of Myc in preventing Drosophila male-male courtship, and supports the crucial roles of genetic factors in inter-male sexual behavior.

A coherent FOXO3-SNAI2 feed-forward loop in autophagy.

SignificanceUnderstanding autophagy regulation is instrumental in developing therapeutic interventions for autophagy-associated disease. Here, we identified SNAI2 as a regulator of autophagy from a genome-wide screen in HeLa cells. Upon energy stress, SNAI2 is transcriptionally activated by FOXO3 and interacts with FOXO3 to form a feed-forward regulatory loop to reinforce the expression of autophagy genes. Of note, SNAI2-increased FOXO3-DNA binding abrogates CRM1-dependent FOXO3 nuclear export, illuminating a pivotal role of DNA in the nuclear retention of nucleocytoplasmic shuttling proteins. Moreover, a dFoxO-Snail feed-forward loop regulates both autophagy and cell size in Drosophila, suggesting this evolutionarily conserved regulatory loop is engaged in more physiological activities.

Bip-Yorkie interaction determines oncogenic and tumor-suppressive roles of Ire1/Xbp1s activation.

Unfolded protein response (UPR) is the mechanism by which cells control endoplasmic reticulum (ER) protein homeostasis. ER proteostasis is essential to adapt to cell proliferation and regeneration in development and tumorigenesis, but mechanisms linking UPR, growth control, and cancer progression remain unclear. Here, we report that the Ire1/Xbp1s pathway has surprisingly oncogenic and tumor-suppressive roles in a context-dependent manner. Activation of Ire1/Xbp1s up-regulates their downstream target Bip, which sequesters Yorkie (Yki), a Hippo pathway transducer, in the cytoplasm to restrict Yki transcriptional output. This regulation provides an endogenous defensive mechanism in organ size control, intestinal homeostasis, and regeneration. Unexpectedly, Xbp1 ablation promotes tumor overgrowth but suppresses invasiveness in a Drosophila cancer model. Mechanistically, hyperactivated Ire1/Xbp1s signaling in turn induces JNK-dependent developmental and oncogenic cell migration and epithelial-mesenchymal transition (EMT) via repression of Yki. In humans, a negative correlation between XBP1 and YAP (Yki ortholog) target gene expression specifically exists in triple-negative breast cancers (TNBCs), and those with high XBP1 or HSPA5 (Bip ortholog) expression have better clinical outcomes. In human TNBC cell lines and xenograft models, ectopic XBP1s or HSPA5 expression alleviates tumor growth but aggravates cell migration and invasion. These findings uncover a conserved crosstalk between the Ire1/Xbp1s and Hippo signaling pathways under physiological settings, as well as a crucial role of Bip-Yki interaction in tumorigenesis that is shared from Drosophila to humans.

The CoFeNC@NC Catalyst with Numerous Surface Cracks Bidirectionally Catalyzes the Conversion of Polysulfides to Accelerate the Reaction Kinetics of Lithium-Sulfur Batteries.

More and more attention has been paid to lithium-sulfur (Li─S) batteries due to their high energy density and low cost. However, the intractable "shuttle effect" and the low conductivity of S and its reaction product, Li2 S, compromise battery performance. To address the inherent challenges, a hollow composite catalyst as a separator coating material is designed, in which CoFe alloy is embedded in a carbon skeleton (CoFeNC@NC). In the hybrid structure, the carbon layer can endow the batteries with high electrical conductivity, while the CoFe alloy can effectively bidirectionally catalyze the conversion between lithium polysulfides (LiPSs) and Li2 S, accelerating the reaction kinetics and reducing the dissolution of LiPSs. Furthermore, the distinctive hollow structure with a cracked surface can facilitate the exposure of a more accessible catalytically active site and enhance Li+ diffusion. Benefiting from the synergistic effects, Li─S batteries with a CoFeNC@NC catalyst achieve a high sulfur utilization (1250.8 mAh g-1 at 0.2 C), superior rate performance (756 mAh g-1 at 2 C), and excellent cycling stability (an ultralow capacity fading of 0.054% per cycle at 1 C for 1000 cycles). Even at a sulfur loading of 5.3 mg cm-2 , a high area capacity of 4.05 mAh cm-2 can still be achieved after 100 cycles, demonstrating its potential practicality.

NAD + salvage governs mitochondrial metabolism, invigorating natural killer cell antitumor immunity.

BACKGROUND AND AIMS: Natural killer (NK) cells are key players in tumor immunosurveillance, and metabolic adaptation manipulates their fate and functional state. The nicotinamide adenine dinucleotide (NAD + ) has emerged as a vital factor to link cellular metabolism and signaling transduction. Here, we identified NAD + metabolism as a central hub to determine the homeostasis and function of NK cells. APPROACH AND RESULTS: NAD + level was elevated in activated NK cells. NAD + supplementation not only enhanced cytokine production and cytotoxicity but also improved the proliferation and viability of NK cells. Intriguingly, the salvage pathway was involved in maintaining NAD + homeostasis in activated NK cells. Genetic ablation or pharmacological blockade of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD + salvage pathway, markedly destroyed the viability and function of NK cells. Mechanistically, NAD + salvage dictated the mitochondrial homeostasis and oxidative phosphorylation activity to support the optimal function of NK cells. However, in human HCC tissues, NAMPT expression and NAD + level were significantly down-regulated in tumor-infiltrating NK cells, which negatively correlated with patient survival. And lactate accumulation in the tumor microenvironment was at least partially responsible for the transcriptional repression of NAMPT in NK cells. Further, deficiency of Nampt in NK cells accelerated the growth of HCC and melanoma. Supplementation of the NAD + precursor nicotinamide mononucleotide (NMN) significantly improved NK antitumor response in both mouse and human cell-derived xenografts. CONCLUSIONS: These findings reveal NAD + salvage as an essential factor for NK-cell homeostasis and function, suggesting a potential strategy for invigorating NK cell-based immunotherapy.

Global pattern of organic carbon pools in forest soils.

Understanding the mechanisms of soil organic carbon (SOC) sequestration in forests is vital to ecosystem carbon budgeting and helps gain insight in the functioning and sustainable management of world forests. An explicit knowledge of the mechanisms driving global SOC sequestration in forests is still lacking because of the complex interplays between climate, soil, and forest type in influencing SOC pool size and stability. Based on a synthesis of 1179 observations from 292 studies across global forests, we quantified the relative importance of climate, soil property, and forest type on total SOC content and the specific contents of physical (particulate vs. mineral-associated SOC) and chemical (labile vs. recalcitrant SOC) pools in upper 10 cm mineral soils, as well as SOC stock in the O horizons. The variability in the total SOC content of the mineral soils was better explained by climate (47%-60%) and soil factors (26%-50%) than by NPP (10%-20%). The total SOC content and contents of particulate (POC) and recalcitrant SOC (ROC) of the mineral soils all decreased with increasing mean annual temperature because SOC decomposition overrides the C replenishment under warmer climate. The content of mineral-associated organic carbon (MAOC) was influenced by temperature, which directly affected microbial activity. Additionally, the presence of clay and iron oxides physically protected SOC by forming MAOC. The SOC stock in the O horizons was larger in the temperate zone and Mediterranean regions than in the boreal and sub/tropical zones. Mixed forests had 64% larger SOC pools than either broadleaf or coniferous forests, because of (i) higher productivity and (ii) litter input from different tree species resulting in diversification of molecular composition of SOC and microbial community. While climate, soil, and forest type jointly determine the formation and stability of SOC, climate predominantly controls the global patterns of SOC pools in forest ecosystems.

Mechanistic insights and implications of FOXO-SNAI interplay.

Autophagy promotes both health and disease, depending on tissue types and genetic contexts, yet the regulatory mechanism remain incompletely understood. Our recent publication has uncovered a coherent FOXO-SNAI feed-forward loop in autophagy, which is evolutionarily conserved from Drosophila to human. In addition, it's revealed that DNA binding plays a critical role in intracellular localization of nucleocytoplasmic shuttling proteins. Based on these findings, herein we further integrate mechanistic insights of FOXO-SNAI regulatory interplay in autophagy and unravel the potential link of FOXO-induced autophagy with SNAI in diseases. Besides, the generality of DNA-retention mechanism on transcription factor nuclear localization is illustrated with wide-ranging discussion, and more functions potentially regulated by FOXO-SNAI feedforward loop are provided. Elucidation of these unsolved paradigms will expand the understanding of FOXO-SNAI interplay and facilitate the development of new therapeutics targeting FOXO-SNAI axis in diseases.

Insights into the solvation chemistry in liquid electrolytes for lithium-based rechargeable batteries.

Lithium-based rechargeable batteries have dominated the energy storage field and attracted considerable research interest due to their excellent electrochemical performance. As indispensable and ubiquitous components, electrolytes play a pivotal role in not only transporting lithium ions, but also expanding the electrochemical stable potential window, suppressing the side reactions, and manipulating the redox mechanism, all of which are closely associated with the behavior of solvation chemistry in electrolytes. Thus, comprehensively understanding the solvation chemistry in electrolytes is of significant importance. Here we critically reviewed the development of electrolytes in various lithium-based rechargeable batteries including lithium-metal batteries (LMBs), nonaqueous lithium-ion batteries (LIBs), lithium-sulfur batteries (LSBs), lithium-oxygen batteries (LOBs), and aqueous lithium-ion batteries (ALIBs), and emphasized the effects of interactions between cations, anions, and solvents on solvation chemistry, and functions of solvation chemistry in different types of electrolytes (strong solvating electrolytes, moderate solvating electrolytes, and weak solvating electrolytes) on the electrochemical performance and redox mechanism in the abovementioned rechargeable batteries. Specifically, the significant effects of solvation chemistry on the stability of electrode-electrolyte interphases, suppression of lithium dendrites in LMBs, inhibition of the co-intercalation of solvents in LIBs, improvement of anodic stability at high cut-off voltages in LMBs, LIBs and ALIBs, regulation of redox pathways in LSBs and LOBs, and inhibition of hydrogen/oxygen evolution reactions in LOBs are thoroughly summarized. Finally, the review concludes with a prospective outlook, where practical issues of electrolytes, advanced in situ/operando techniques to illustrate the mechanism of solvation chemistry, and advanced theoretical calculation and simulation techniques such as "material knowledge informed machine learning" and "artificial intelligence (AI) + big data" driven strategies for high-performance electrolytes have been proposed.

Vegetation restoration in an alpine meadow: Insights from soil microbial communities and resource limitation across soil depth.

Aboveground vegetation restoration shapes the soil microbial community structure and affects microbial resource acquisition. However, the changes in soil microbial resource limitation in subsoil during vegetation restoration are still unclear. In this study, the microbial community structure and resource limitation in an alpine meadow soil profile that had undergone natural restoration for short-term (4-year) and long-term (10-year) restoration in response to vegetation restoration were explored through high-throughput sequencing analysis and extracellular enzyme stoichiometry (EES). There was no significant difference in microbial composition and α diversity between short- and long-term restoration soils. Soil microorganisms in this alpine meadow were mainly limited by phosphorus. Carbon limitation of soil microorganisms was significantly decreased in each layer (0-15, 15-30, 30-45, 45-60, and 60-80 cm corresponding to L1, L2, L3, L4, and L5, respectively) of long-term restoration soils when compared to that of the short-term restoration soil layers, while phosphorus limitation of microorganisms in subsoil (60-80 cm) was significantly increased by 17.38%. Soil nutrients, pH, moisture content, and microbial composition are the main drivers of microbial resource limitation in restoration, and their effects on microbial resource limitation were different in short- and long-term restoration. Meanwhile, key microbial taxa have a significant impact on microbial resource limitation, especially in short-term restoration soils. This study suggested that vegetation restoration significantly affected soil microbial resource limitation, and could alleviate microbial resource limitations by adding nutrients, thus accelerating the process of vegetation restoration in alpine ecosystems.

An Exploration of Dissolution Tests for Inhalation Aerosols.

This study aimed to establish a feasible dissolution method for inhalation aerosols. A method of collecting fine particles was investigated to capture aerosol particles less than 4 µm in diameter for dissolution tests. This dose collection method enabled the aerosol particles to be uniformly distributed on the glass fiber filter, thus considerably reducing particle agglomeration. Budesonide was used as a model drug. The aerodynamic particle size distribution (APSD) of the meter-dose inhaler (MDI) was compared by replacing actuators with different orifice sizes. Dissolution tests were conducted on fine particle doses collected using various actuators, and the dissolution profiles were modeled. The fine particle dose decreased with an increasing orifice size of the actuator. Actuators with different orifice sizes would affect the dissolution behavior of inhaled drugs. This finding was supported by similarity factor f2 analysis, suggesting the dissolution method has a discriminative capacity. The results of various model fits showed that the dissolution profiles produced by the different actuators could be fitted well using the Weibull mathematical model. The method employed in this study could offer a potential avenue for exploring the relationship between the orifice size of the actuator and the dissolution behavior of inhaled corticosteroids. This dissolution method was simple, reproducible, and suitable for determining the dissolution of inhalation aerosols.

A field incubation approach to evaluate the depth dependence of soil biogeochemical responses to climate change.

Soil biogeochemical processes may present depth-dependent responses to climate change, due to vertical environmental gradients (e.g., thermal and moisture regimes, and the quantity and quality of soil organic matter) along soil profile. However, it is a grand challenge to distinguish such depth dependence under field conditions. Here we present an innovative, cost-effective and simple approach of field incubation of intact soil cores to explore such depth dependence. The approach adopts field incubation of two sets of intact soil cores: one incubated right-side up (i.e., non-inverted), and another upside down (i.e., inverted). This inversion keeps soil intact but changes the depth of the soil layer of same depth origin. Combining reciprocal translocation experiments to generate natural climate shift, we applied this incubation approach along a 2200 m elevational mountainous transect in southeast Tibetan Plateau. We measured soil respiration (Rs) from non-inverted and inverted cores of 1 m deep, respectively, which were exchanged among and incubated at different elevations. The results indicated that Rs responds significantly (p < .05) to translocation-induced climate shifts, but this response is depth-independent. As the incubation proceeds, Rs from both non-inverted and inverted cores become more sensitive to climate shifts, indicating higher vulnerability of persistent soil organic matter (SOM) to climate change than labile components, if labile substrates are assumed to be depleted with the proceeding of incubation. These results show in situ evidence that whole-profile SOM mineralization is sensitive to climate change regardless of the depth location. Together with measurements of vertical physiochemical conditions, the inversion experiment can serve as an experimental platform to elucidate the depth dependence of the response of soil biogeochemical processes to climate change.

Climate Warming-Driven Changes in the Molecular Composition of Soil Dissolved Organic Matter Across Depth: A Case Study on the Tibetan Plateau.

Dissolved organic matter (DOM) is critical for soil carbon sequestration in terrestrial ecosystems. DOM molecular composition varies with soil depth. However, the spatial heterogeneity of depth-dependent DOM in response to climate warming remains unclear, especially in alpine ecosystems. In this study, the DOM of alpine meadow soil samples was characterized comprehensively by using spectroscopy and mass spectrometry, and open-top chambers (OTCs) were employed to simulate warming. It was found that climate warming had the greatest impact on the upper layer (0-30 cm), followed by the lower layer (60-80 cm), while the middle layer (30-60 cm) was the most stable among the three soil layers. The reasons for the obvious changes in DOM in the upper and lower layers of soil were further explained based on biotic and abiotic factors. Specifically, soil nutrients (NH4+-N, NO3--N, TC, and TP) affected the molecular composition of DOM in layer L1 (0-15 cm), while pH affected layer L5 (60-80 cm). Gemmatimonadetes, Proteobacteria, and Actinobacteria played important roles in the composition of DOM in the L5 layer (60-80 cm), while the dominant fungal groups affecting the DOM composition increased in the L1 layer (0-15 cm) under warming. In summary, this research has contributed to a deeper understanding of depth-dependent changes in DOM molecular composition in alpine ecosystems.

PVA Electrospun Fibers Coated with PPy Nanoparticles for Wearable Strain Sensors.

Current conductive polymers win wide applications in smart strain-stress sensors, bioinspired actuators, and wearable electronics. This work investigates a novel strain sensor by using conductive polypyrrole (PPy) nanoparticles coated polyvinyl alcohol (PVA) fibers as matrix. The flexible, water-resistant PVA fibers are initially prepared by combined electrospinning and annealing techniques, and then are coated with PPy nanoparticles through in situ polymerization. The resultant PPy@PVA fibers exhibit stable, favorable electrical conductivities due to the uniform point-to-point connections among PPy nanoparticles, e.g. after three-time' polymerizations, the PPy@PVA3 fiber film presents a sheet resistance of ≈840 Ω sq-1 and a bulk conductivity of ≈32.1 mS cm-1 . Cyclic sensing tests reveal that, PPy@PVA sensors show linear relationships between the relative resistance variations and the applied strains, e.g. the linear deviation of PPy@PVA3 is only 0.9 % within 33 % strain. After long-term stretching/releasing cycles, the PPy@PVA sensor exhibits stable, durable, and reversible sensing behaviors, no evident "drift" is observed over 1,000 cycles (5,000 seconds).

Spatial distribution and functional analysis define the action pathway of Tim-3/Tim-3 ligands in tumor development.

The spatial organization of immune cells within the tumor microenvironment (TME) largely determines the anti-tumor immunity and also highly predicts tumor progression and therapeutic response. Tim-3 is a well-accepted immune checkpoint and plays multifaceted immunoregulatory roles via interaction with distinct Tim-3 ligands (Tim-3L), showing great potential as an immunotherapy target. However, the cell sociology mediated by Tim-3/Tim-3L and their contribution to tumor development remains elusive. Here, we analyzed the spatial distribution of Tim-3/Tim-3L in TME using multiplex fluorescence staining and revealed that despite the increased Tim-3 expression in various tumor-infiltrated lymphocytes, Tim-3+CD4+ cells were more accumulated in parenchymal/tumor region compared with stromal region and exhibited more close association with patient survival. Strikingly, CD4 T cells surrounding Tim-3L+ cells expressed higher Tim-3 than other cells in cancerous tissues. In vivo studies confirmed that depletion of CD4 T cells completely abrogated the inhibition of tumor growth and metastasis, as well as the functional improvement of CD8 T and NK, mediated by Tim-3 blockade, which was further validated in peripheral lymphocytes from patients with hepatocellular carcinoma. In conclusion, our findings unravel the importance of CD4 T cells in Tim-3/Tim-3L-mediated immunosuppression and provide new thoughts for Tim-3 targeted cancer immunotherapy.

Rox8 promotes microRNA-dependent yki messenger RNA decay.

The Hippo pathway is an evolutionarily conserved regulator of organ growth and tumorigenesis. In Drosophila, oncogenic RasV12 cooperates with loss-of-cell polarity to promote Hippo pathway-dependent tumor growth. To identify additional factors that modulate this signaling, we performed a genetic screen utilizing the Drosophila RasV12/lgl-/- in vivo tumor model and identified Rox8, a RNA-binding protein (RBP), as a positive regulator of the Hippo pathway. We found that Rox8 overexpression suppresses whereas Rox8 depletion potentiates Hippo-dependent tissue overgrowth, accompanied by altered Yki protein level and target gene expression. Mechanistically, Rox8 directly binds to a target site located in the yki 3' UTR, recruits and stabilizes the targeting of miR-8-loaded RISC, which accelerates the decay of yki messenger RNA (mRNA). Moreover, TIAR, the human ortholog of Rox8, is able to promote the degradation of yki mRNA when introduced into Drosophila and destabilizes YAP mRNA in human cells. Thus, our study provides in vivo evidence that the Hippo pathway is posttranscriptionally regulated by the collaborative action of RBP and microRNA (miRNA), which may provide an approach for modulating Hippo pathway-mediated tumorigenesis.

Comparison the treatment of anterior inferior tibiofibular ligament anatomical repair and syndesmosis screw fixation for syndesmotic injuries in ankle fracture.

BACKGROUND: The fixation method of syndesmotic injuries in ankle fractures remains controversial. The goal of the study was to compare radiographic and clinical outcomes between anterior inferior tibiofibular ligament (AITFL) anatomical repair with syndesmosis screw fixation in syndesmotic injuries. METHODS: We analyzed 62 patients who were treated with AITFL anatomical repair or syndesmosis screw fixation for syndesmotic injuries in an advanced teaching hospital between March 2016 and March 2019. Fixation was performed with AITFL anatomical repair in 30 patients (AAR group) and syndesmosis screw in 32 patients (SS group). Radiographic evaluations were the differences in mean anterior and posterior (A difference and P difference) tibiofibular distance between injured and uninjured ankle computed tomography (CT) scan at 6 months postoperatively. Clinical evaluation of patients was done using the American Orthopaedic Foot & Ankle Society (AOFAS) Ankle Hindfoot Score, the Olerud-Molander Ankle (OMA) score and visual analogue scale (VAS) score at 1, 3, 6 months and 1, 2 years postoperatively. RESULTS: The A difference and P difference on CT was no differences (1.6 ± 0.8 mm, 1.3 ± 0.7 mm vs. 1.5 ± 0.7 mm, 1.2 ± 0.7 mm) between the two groups (All of P > 0.05). The AAR group had higher mean AOFAS score (65.6 ± 5.9, 82.3 ± 4.2, 87.6 ± 5.6 vs. 61.8 ± 5.2, 79.1 ± 4.0, 83.8 ± 4.9; P = 0.008, 0.003, 0.007) and higher mean OMA score (45.7 ± 8.7, 79.2 ± 6.5, 84.1 ± 5.3 vs. 40.4 ± 7.3, 74.8 ± 6.3, 80.3 ± 5.8; P = 0.012, 0.009, 0.010)) at 1, 3 and 6 months postoperatively. The AAR group had lower mean VAS scores (2.6 ± 1.2, 1.7 ± 0.7 vs. 3.4 ± 1.2, 2.2 ± 1.1; P = 0.018, 0.038) at 1 and 3 months postoperatively. CONCLUSIONS: The results of this study suggest that the AITFL anatomical repair technique could effectively improve ankle function during daily activity. Therefore, AITFL anatomical repair technique is expected to become a better fixation method for syndesmotic injuries.

A Novel Fiber-Optic Ice Sensor to Identify Ice Types Based on Total Reflection.

To address the issues of not accurately identifying ice types and thickness in current fiber-optic ice sensors, in this paper, we design a novel fiber-optic ice sensor based on the reflected light intensity modulation method and total reflection principle. The performance of the fiber-optic ice sensor was simulated by ray tracing. The low-temperature icing tests validated the performance of the fiber-optic ice sensor. It is shown that the ice sensor can detect different ice types and the thickness from 0.5 to 5 mm at temperatures of -5 °C, -20 °C, and -40 °C. The maximum measurement error is 0.283 mm. The proposed ice sensor provides promising applications in aircraft and wind turbine icing detection.

Zanubrutinib Ameliorates Cardiac Fibrosis and Inflammation Induced by Chronic Sympathetic Activation.

(1) Background: Heart failure (HF) is the final stage of multiple cardiac diseases, which have now become a severe public health problem worldwide. ß-Adrenergic receptor (ß-AR) overactivation is a major pathological factor associated with multiple cardiac diseases and mediates cardiac fibrosis and inflammation. Previous research has demonstrated that Bruton's tyrosine kinase (BTK) mediated cardiac fibrosis by TGF-ß related signal pathways, indicating that BTK was a potential drug target for cardiac fibrosis. Zanubrutinib, a second-generation BTK inhibitor, has shown anti-fibrosis effects in previous research. However, it is unclear whether Zanubrutinib can alleviate cardiac fibrosis induced by ß-AR overactivation; (2) Methods: In vivo: Male C57BL/6J mice were treated with or without the ß-AR agonist isoproterenol (ISO) to establish a cardiac fibrosis animal model; (3) Results: In vivo: Results showed that the BTK inhibitor Zanubrutinib (ZB) had a great effect on cardiac fibrosis and inflammation induced by ß-AR. In vitro: Results showed that ZB alleviated ß-AR-induced cardiac fibroblast activation and macrophage pro-inflammatory cytokine production. Further mechanism studies demonstrated that ZB inhibited ß-AR-induced cardiac fibrosis and inflammation by the BTK, STAT3, NF-κB, and PI3K/Akt signal pathways both in vivo and in vitro; (4) Conclusions: our research provides evidence that ZB ameliorates ß-AR-induced cardiac fibrosis and inflammation.

ParaCopasi: A package for parallel biochemical simulation and analysis.

Biochemical simuflation and analysis play a significant role in systems biology research. Numerous software tools have been developed to serve this area. Using these tools for completing tasks, for example, stochastic simulation, parameter fitting and optimization, usually requires sufficient computational power to make the duration of completion acceptable. COPASI is one of the most powerful tools for quantitative simulation and analysis targeted at biological systems. It supports systems biology markup language and covers multiple categories of tasks. This work develops an open source package ParaCopasi for parallel COPASI tasks and investigates its performance regarding accelerations. ParaCopasi can be installed on platforms equipped with multicore CPU to exploit the cores, scaling from desktop computers to large scale high-performance computing clusters. More cores bring more performance. The results show that the parallel efficiency has a positive correlation with the total workload. The parallel efficiency reaches a level of at least 95% for both homogeneous and heterogenous tasks when computational workload is adequate. An example is illustrated by applicating this package in parameter estimation to calibrate a biochemical kinetics model.