Mechanism Of Turnover Research Articles

Comparative transcriptomic analysis of primary endometrial cancer and bone metastatic cancer: metastasis-associated genes and abnormal cell cycle regulation

Endometrial cancer (EC) is the most common tumor of the female reproductive system. Its incidence is rising worldwide. Bone metastasis (BMs) in EC is rarely reported, and is seen in only 0.8% of patients. Once bone metastasis develops, it often indicates a poor prognosis. Current research on the bone metastasis of primary tumors suggests that tumor cells primarily colonize bones through hematogenous metastasis and are stimulated to grow by the bone microenvironment. However, the biological mechanism of bone metastasis in EC remains unclear. In this study, we aim to determine the changes in gene expression profiles in EC bone metastasis and explore the transcriptomic differences between metastatic and primary lesions. We collected one primary EC case and two bone metastasis tumors for transcriptomic analysis. The analysis revealed that numerous genes are involved in regulating the cell cycle and proliferation. Analysis of differentially expressed genes (DEGs) revealed that these genes are involved in the regulation of post-translational modification, protein turnover, and signal transduction mechanisms. E2F1, MCM2, RFC2, and ICAM1 are involved in the metastasis and progression of EC with bone metastasis (ECBM). The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis indicates significant changes in the Hippo signaling pathway, which regulates cell proliferation, and in the cell adhesion signaling pathway. Numerous transcription factors, including SOX2, NUSAP1, and ACTA1, which promote tumor development, are involved in regulating the expression of cell cycle control genes. Survival curve analysis of high-expression cell cycle genes, including P27, P19, and CDK1, in ECBM showed that elevated levels of these genes are associated with poorer patient survival. Our research identified genes and key signaling pathways associated with bone metastasis. These findings provide a theoretical basis for the treatment of bone metastasis in EC.

Proteomic Analysis of Unicellular Cyanobacterium Crocosphaera subtropica ATCC 51142 under Extended Light or Dark Growth.

The daily light-dark cycle is a recurrent and predictable environmental phenomenon to which many organisms, including cyanobacteria, have evolved to adapt. Understanding how cyanobacteria alter their metabolic attributes in response to subjective light or dark growth may provide key features for developing strains with improved photosynthetic efficiency and applications in enhanced carbon sequestration and renewable energy. Here, we undertook a label-free proteomic approach to investigate the effect of extended light (LL) or extended dark (DD) conditions on the unicellular cyanobacterium Crocosphaera subtropica ATCC 51142. We quantified 2287 proteins, of which 603 proteins, were significantly different between the two growth conditions. These proteins represent several biological processes, including photosynthetic electron transport, carbon fixation, stress responses, translation, and protein degradation. One significant observation is the regulation of over two dozen proteases, including ATP-dependent Clp-proteases (endopeptidases) and metalloproteases, the majority of which were upregulated in LL compared to DD. This suggests that proteases play a crucial role in the regulation and maintenance of photosynthesis, especially the PSI and PSII components. The higher protease activity in LL indicates a need for more frequent degradation and repair of certain photosynthetic components, highlighting the dynamic nature of protein turnover and quality control mechanisms in response to prolonged light exposure. The results enhance our understanding of how Crocosphaera subtropica ATCC 51142 adjusts its molecular machinery in response to extended light or dark growth conditions.

Tripartite motif 25 inhibits protein aggregate degradation during PRRSV infection by suppressing p62-mediated autophagy.

Viral infection causes endoplasmic reticulum stress and protein metabolism disorder, influencing protein aggregates formation or degradation that originate from misfolded proteins. The mechanism by which host proteins are involved in the above process remains largely unknown. The present study found that porcine reproductive and respiratory syndrome virus (PRRSV) infection promoted the degradation of intracellular ubiquitinated protein aggregates via activating autophagy. The host cell E3 ligase tripartite motif-containing (TRIM)25 promoted the recruitment and aggregation of polyubiquitinated proteins and impeded their degradation caused by PRRSV. TRIM25 interacted with ubiquitinated aggregates and was part of the aggregates complex. Next, the present study investigated the mechanisms by which TRIM25 inhibited the degradation of protein aggregates, and it was found that TRIM25 interacted with both Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor E2-related factor 2 (Nrf2), facilitated the nuclear translocation of Nrf2 by targeting KEAP1 for K48-linked ubiquitination and proteasome degradation, and activated Nrf2-mediated p62 expression. Further studies indicated that TRIM25 interacted with p62 and promoted its K63-linked ubiquitination via its E3 ligase activity and thus caused impairment of its oligomerization, aggregation, and recruitment for the autophagic protein LC3, leading to the suppression of autophagy activation. Besides, TRIM25 also suppressed the p62-mediated recruitment of ubiquitinated aggregates. Activation of autophagy decreased the accumulation of protein aggregates caused by TRIM25 overexpression, and inhibition of autophagy decreased the degradation of protein aggregates caused by TRIM25 knockdown. The current results also showed that TRIM25 inhibited PRRSV replication by inhibiting the KEAP1-Nrf2-p62 axis-mediated autophagy. Taken together, the present findings showed that the PRRSV replication restriction factor TRIM25 inhibited the degradation of ubiquitinated protein aggregates during viral infection by suppressing p62-mediated autophagy.IMPORTANCESequestration of protein aggregates and their subsequent degradation prevents proteostasis imbalance and cytotoxicity. The mechanisms controlling the turnover of protein aggregates during viral infection are mostly unknown. The present study found that porcine reproductive and respiratory syndrome virus (PRRSV) infection promoted the autophagic degradation of ubiquitinated protein aggregates, whereas tripartite motif-containing (TRIM)25 reversed this process. It was also found that TRIM25 promoted the expression of p62 by activating the Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor E2-related factor 2 (Nrf2) pathway and simultaneously prevented the oligomerization of p62 by promoting its K63-linked ubiquitination, thus suppressing its recruitment of the autophagic adaptor protein LC3 and ubiquitinated aggregates, leading to the inhibition of PRRSV-induced autophagy activation and the autophagic degradation of protein aggregates. The present study identified a new mechanism of protein aggregate turnover during viral infection and provided new insights for understanding the pathogenic mechanism of PRRSV.

The NEDD4-binding protein N4BP1 degrades mRNA substrates through the coding sequence independent of nonsense-mediated decay

3'-Untranslated regions (3'UTRs) are recognized for their role in regulating mRNA turnover while the turnover of a specific group of mRNAs mediated by coding sequences (CDS) remains poorly understood. N4BP1 is a critical inflammatory regulator in vivo with a molecular mechanism that is not yet clearly defined. Our study reveals that N4BP1 efficiently degrades its mRNA targets via CDS rather than the 3'-UTR. This CDS-dependent mRNA turnover mechanism appears to be a general feature of N4BP1, as evidenced by testing multiple mRNA substrates, such as Fos-C, Fos-B, Jun-B and CXCL1. Detailed mapping of the motif identified a crucial 33nt (289-322) sequence near the 5'-end of Fos-C-CDS, where the presence of polyC is necessary for N4BP1-mediated degradation. Functional studies involving domain deletion and point mutations showed that both the KH and NYN domains are essential for N4BP1 to restrict mRNA substrates. The function of N4BP1 in mRNA turnover is not dependent on nonsense-mediated decay as it efficiently restricts mRNA substrates even in cells deficient in UPF1, UPF3A, and UPF3B. Additionally, the function of N4BP1 is not reliant on LUC7L3 despite its known association with this protein. Our findings suggest that N4BP1 acts as an endoribonuclease to degrade mRNA substrates primarily through coding sequences containing a C-rich motif.

Redundant pathways for removal of defective RNA polymerase II complexes at a promoter-proximal pause checkpoint.

The biological purpose of Integrator and RNA polymerase II (RNAPII) promoter-proximal pausing remains uncertain. Here, we show that loss of INTS6 in human cells results in increased interaction of RNAPII with proteins that can mediate its dissociation from the DNA template, including the CRL3ARMC5 E3 ligase, which ubiquitylates CTD serine5-phosphorylated RPB1 for degradation. ARMC5-dependent RNAPII ubiquitylation is activated by defects in factors acting at the promoter-proximal pause, including Integrator, DSIF, and capping enzyme. This ARMC5 checkpoint normally curtails a sizeable fraction of RNAPII transcription, and ARMC5 knockout cells produce more uncapped transcripts. When both the Integrator and CRL3ARMC5 turnover mechanisms are compromised, cell growth ceases and RNAPII with high pausing propensity disperses from the promoter-proximal pause site into the gene body. These data support a model in which CRL3ARMC5 functions alongside Integrator in a checkpoint mechanism that removes faulty RNAPII complexes at promoter-proximal pause sites to safeguard transcription integrity.

Effect of P Reduction on phoD-Harboring Bacteria Community in Solar Greenhouse Soil

Phosphorus (P) enrichment frequently occurs in the soil used in greenhouse vegetable production (GVP). Minimizing the application of P fertilizer represents a crucial approach to mitigating the accumulation of P in the soil and enhancing its utilization efficiency. However, the changes in bacterial communities and the turnover mechanism of soil P fractions related to soil P cycling after P fertilizer reduction are still unclear. To unravel these complexities, we devised three experimental treatments: conventional nitrogen (N), P, and potassium (K) fertilizer (N1P1K1); conventional N and K fertilizer without P (N1P0K1); and no fertilizer (N0P0K0). These experiments were conducted to elucidate the effects of P reduction on cucumber plant growth, soil P fractions, and the phoD-harboring bacterial community in the P-rich greenhouse soil. The results showed that there were no significant differences between the N1P1K1 and N1P0K1 treatments in terms of plant growth, yield, and P uptake, and the values for the N0P0K0 treatment were significantly lower than those for the N1P1K1 treatment. In a state of P depletion (N0P0K0, N1P0K1), the main P sources were Resin-Pi, NaHCO3-Pi, NaHCO3-Po, and NaOH-Pi. The contents of NaOH-Po and CHCl-Po in the N1P0K1 treatment increased significantly. Without P fertilizer, alkaline phosphatase (ALP) activity, phoD gene abundance, and bacterial community diversity were significantly increased. The abundance of Ensifer in the N0P0K0 and N1P0K1 treatments was 8 and 10.58 times that in the N1P1K1 treatment, respectively. Additionally, total phosphorus (TP) and available nitrogen (AN) were key factors affecting changes in the phoD bacterial community, while Shinella, Ensifer and Bradyrhizobium were the main factors driving the change in soil P fractions, and NaHCO3-Pi and NaOH-Pi were key factors affecting crop yield. Therefore, reducing the application of P fertilizer will increases the diversity of phoD-gene-harboring bacterial communities and promote organic P mineralization, thus maintaining the optimal crop yield.

Design and Experimental Optimization of an Automated Longline-Suspended Oyster Spat Insertion Device

To address the challenges of labor-intensive and costly manual oyster spat insertion in longline-suspended farming, an automated oyster spat insertion device was designed based on negative pressure suction and bundling fixation technologies. Using this device as the experimental platform, a three-factor, three-level Box–Behnken experiment was conducted, with fixation mechanism inclination, negative pressure suction cup span, and horizontal distance between turnover and fixation mechanisms as the experimental factors. The performance of the device was evaluated using the effective fixation rate and damage rate as the experimental indicators. The quadratic polynomial regression models were established to assess the impact of these factors on operational performance, while the response surface method was employed to analyze the interaction effects between factors. Parameter optimization and experimental validation were also performed. The results indicate that the factors affecting the effective fixation rate, in order of significance, are as follows: fixation mechanism inclination, horizontal distance between turnover and fixation mechanisms, and negative pressure suction cup span. For the damage rate, the order of significance is as follows: fixation mechanism inclination > negative pressure suction cup span < horizontal distance between turnover and fixation mechanisms. The optimization results show that when the fixation mechanism inclination is set at 43°, the negative pressure suction cup span at 27 mm, and the horizontal distance between turnover and fixation mechanisms at 179 mm, the effective fixation rate reaches 92.08%, and the damage rate is 4.71%. The relative errors between the measured and model-predicted values are less than 5%, indicating that the regression models are reliable. This research provides valuable insights for advancing the mechanization of the oyster farming industry and replacing manual labor with mechanized equipment.

Mechanisms and regulation of substrate degradation by the 26S proteasome.

The 26S proteasome is involved in degrading and regulating the majority of proteins in eukaryotic cells, which requires a sophisticated balance of specificity and promiscuity. In this Review, we discuss the principles that underly substrate recognition and ATP-dependent degradation by the proteasome. We focus on recent insights into the mechanisms of conventional ubiquitin-dependent and ubiquitin-independent protein turnover, and discuss the plethora of modulators for proteasome function, including substrate-delivering cofactors, ubiquitin ligases and deubiquitinases that enable the targeting of a highly diverse substrate pool. Furthermore, we summarize recent progress in our understanding of substrate processing upstream of the 26S proteasome by the p97 protein unfoldase. The advances in our knowledge of proteasome structure, function and regulation also inform new strategies for specific inhibition or harnessing the degradation capabilities of the proteasome for the treatment of human diseases, for instance, by using proteolysis targeting chimera molecules or molecular glues.

Effects of intermittent exposure to hypobaric hypoxia and cold on skeletal muscle regeneration: Mitochondrial dynamics, protein oxidation and turnover

Muscle injuries and the subsequent regeneration events compromise muscle homeostasis at morphological, functional and molecular levels. Among the molecular alterations, those derived from the mitochondrial function are especially relevant. We analysed the mitochondrial dynamics, the redox balance, the protein oxidation and the main protein repairing mechanisms after 9 days of injury in the rat gastrocnemius muscle. During the recovery rats were exposed to intermittent cold exposure (ICE), intermittent hypobaric hypoxia (IHH), and both simultaneous combined stimuli. Non-injured contralateral legs were also analysed to evaluate the specific effects of the three environmental exposures. Our results showed that ICE enhanced mitochondrial adaptation by improving the electron transport chain efficiency during muscle recovery, decreased the expression of regulatory subunit of proteasome and accumulated oxidized proteins. Exposure to IHH did not show mitochondrial compensation or increased protein turnover mechanisms; however, no accumulation of oxidized proteins was observed. Both ICE and IHH, when applied separately, elicited an increased expression of eNOS, which could have played an important role in accelerating muscle recovery. The combined effect of ICE and IHH led to a complex response that could potentially impede optimal mitochondrial function and enhanced the accumulation of protein oxidation. These findings underscore the nuanced role of environmental stressors in the muscle healing process and their implications for optimizing recovery strategies.

Aging-Associated Molecular Changes in Human Alveolar Type I Cells.

Human alveolar type I (AT1) cells are specialized epithelial cells that line the alveoli in the lungs where gas exchange occurs. The primary function of AT1 cells is not only to facilitate efficient gas exchange between the air and the blood in the lungs, but also to contribute to the structural integrity of the alveoli to maintain lung function and homeostasis. Aging has notable effects on the structure, function, and regenerative capacity of human AT1 cells. However, our understanding of the molecular mechanisms driving these age-related changes in AT1 cells remains limited. Leveraging a recent single-cell transcriptomics dataset we generated on healthy human lungs, we identified a series of significant molecular alterations in AT1 cells from aged lungs. Notably, the aged AT1 cells exhibited increased cellular senescence and chemokine gene expression, alongside diminished epithelial features such as decreases in cell junctions, endocytosis, and pulmonary matrisome gene expression. Gene set analyses also indicated that aged AT1 cells were resistant to apoptosis, a crucial mechanism for turnover and renewal of AT1 cells, thereby ensuring alveolar integrity and function. Further research on these alterations is imperative to fully elucidate the impact on AT1 cells and is indispensable for developing effective therapies to preserve lung function and promote healthy aging.

Spatiotemporal and vertical variability of water quality in lentic small water bodies: implications of varying rainfall and land use conditions.

Lentic small water bodies (LSWBs) deteriorate owing to anthropogenic activities, such as untreated domestic and agricultural waste disposal. Moreover, different turnover mechanisms occur during different seasons, contributing to nutrient enrichment and consequent degradation of LSWBs. However, understanding their spatial, temporal, and vertical variations during different seasons is understudied. In addition, studies on the variation in water quality under varying rainfall and land-use conditions are limited. Therefore, in this study, three LSWBs located in Northern India were studied during the pre-monsoon and monsoon seasons (December 2022 to October 2023). Total nitrogen (TN), chlorophyll-a (Chl-a), total phosphorus (TP), temperature, pH, dissolved oxygen (DO), total dissolved solids (TDS), chemical oxygen demand (COD),secchi disk depth (SDD), and water level (WL) were measured monthly. Sentinel-2 and CHIRPS pentad data were used for land use, land cover classification, and rainfall analysis. The spatial analysis indicates that the seasonal shift affects the water quality distribution, especially near the inlets and at the edges. The overall concentrations of TN and TP decreased during the monsoon season; however, they increased significantly at the inlets of the LSWBs. On the other hand, the Chl-a concentration shifted towards the edges due to the inflow during the monsoon. Temporal analysis also suggests that the arrival of the monsoon lowers pH, DO, and TDS. However, the concentrations of TN and TP increased because of agricultural runoff. Chl-a and COD show distinct variations due to the individual LSWBs' local conditions. Vertical variability analysis demonstrated pH, temperature, and TN stratification during the pre-monsoon period. However, during the monsoon, stratification is less significant due to intermixing. Redundancy analysis (RDA) showed that land use and rainfall patterns affected the water quality of LSWB 1, 2, and 3 by 53.49%, 81.62%, and 92.64%, respectively. This shows that land use, land cover, and rainfall changes affect the water quality of LSWBs. This study highlights the negative impact of runoff from agricultural land use as the main factor responsible for increased nutrient levels in the LSWBs.

Proteomic analysis of unicellular cyanobacterium Crocosphaera subtropica ATCC 51142 under extended light or dark growth.

The daily light-dark cycle is a recurrent and predictable environmental phenomenon to which many organisms, including cyanobacteria, have evolved to adapt. Understanding how cyanobacteria alter their metabolic attributes in response to subjective light or dark growth may provide key features for developing strains with improved photosynthetic efficiency and applications in enhanced carbon sequestration and renewable energy. Here, we undertook a label-free proteomic approach to investigate the effect of extended light (LL) or extended dark (DD) conditions on the unicellular cyanobacterium Crocosphaera subtropica ATCC 51142. We quantified 2287 proteins, of which 603 proteins were significantly different between the two growth conditions. These proteins represent several biological processes, including photosynthetic electron transport, carbon fixation, stress responses, translation, and protein degradation. One significant observation is the regulation of over two dozen proteases, including ATP dependent Clp-proteases (endopeptidases) and metalloproteases, the majority of which were upregulated in LL compared to DD. This suggests that proteases play a crucial role in the regulation and maintenance of photosynthesis, especially the PSI and PSII components. The higher protease activity in LL indicates a need for more frequent degradation and repair of certain photosynthetic components, highlighting the dynamic nature of protein turnover and quality control mechanisms in response to prolonged light exposure. The results enhance our understanding of how Crocosphaera subtropica ATCC51142 adjusts its molecular machinery in response to extended light or dark growth conditions.

Mass incarceration as a driver of the tuberculosis epidemic in Latin America and projected impacts of policy alternatives: A mathematical modeling study.

Tuberculosis incidence is increasing in Latin America, where the incarcerated population has nearly quadrupled since 1990. The full impact of incarceration on the tuberculosis epidemic, accounting for effects beyond prisons, has never been quantified. We calibrated dynamic compartmental transmission models to historical and contemporary data from Argentina, Brazil, Colombia, El Salvador, Mexico, and Peru, which comprise approximately 80% of the region's incarcerated population and tuberculosis burden. Using historical counterfactual scenarios, we estimated the transmission population attributable fraction (tPAF) for incarceration and the excess population-level burden attributable to increasing incarceration prevalence since 1990. We additionally projected the impact of alternative incarceration policies on future population tuberculosis incidence. Population tuberculosis incidence in 2019 was 29.4% (95% UI, 23.9-36.8) higher than expected without the rise in incarceration since 1990, corresponding to 34,393 (95% UI, 28,295-42,579) excess incident cases across countries. The incarceration tPAF in 2019 was 27.2% (95% UI, 20.9-35.8), exceeding estimates for other risk factors like HIV, alcohol use disorder, and undernutrition. Compared to a scenario where incarceration rates remain stable at current levels, a gradual 50% reduction in prison admissions and duration of incarceration by 2034 would reduce population tuberculosis incidence by over 10% in all countries except Mexico. The historical rise in incarceration in Latin America has resulted in a large excess tuberculosis burden that has been under-recognized to-date. International health agencies, ministries of justice, and national tuberculosis programs should collaborate to address this health crisis with comprehensive strategies, including decarceration. National Institutes of Health.

Distinct species turnover patterns shaped the richness of antibiotic resistance genes on eight different microplastic polymers

Elucidating the formation mechanism of plastisphere antibiotic resistance genes (ARGs) on different polymers is necessary to understand the ecological risks of plastisphere ARGs. Here, we explored the turnover and assembly mechanism of plastisphere ARGs on 8 different microplastic polymers (4 biodegradable (bMPs) and 4 non-biodegradable microplastics (nMPs)) by metagenomic sequencing. Our study revealed the presence of 479 ARGs with abundance ranging from 41.37 to 58.17 copies/16S rRNA gene in all plastispheres. These ARGs were predominantly multidrug resistance genes. The richness of plastisphere ARGs on different polymers had a significant correlation with the contribution of species turnover to plastisphere ARGs β diversity. Furthermore, polymer type was the most critical factor affecting the composition of plastisphere ARGs. More opportunistic pathogens carrying diverse ARGs on BMPs (PBAT, PBS, and PHA) with higher horizontal gene transfer potential may further magnify the ecological risks and human health threats. For example, the opportunistic pathogens Riemerella anatipestifer, Vibrio campbellii, and Vibrio cholerae are closely related to human production and life, which were the important potential hosts of many plastisphere ARGs and mobile genetic elements on BMPs. Thus, we emphasize the urgency of developing the formation mechanism of plastisphere ARGs and the necessity of controlling BMPs and ARG pollution, especially BMPs, with ever-increasing usage in daily life.

Differential amplification and contraction of satellite DNAs in the distinct lineages of the beetle Euchroma gigantea

Satellite DNA (satDNA) consists of tandem repeat sequences that typically evolve rapidly through evolutionary mechanisms, including unequal crossover, transposition events, and others. The evolutionary history of Euchroma gigantea is marked by complex chromosomal evolution between lineages, making this species an interesting model for understanding satDNA evolution at intraspecies level. Therefore, our aim was to comprehend the potential contribution of satDNAs to the greater chromosomal differentiation of evolutionary lineages in E. gigantea by investigating the differential patterns of amplification and contraction of the repeats. To achieve this, we employed de novo identification of satDNA using RepeatExplorer and TAREAN, allowing the satellitome characterization between lineages. A total of 26 satDNA families were identified, ranging from 18 to 1101 nucleotides in length, with most families being shared between individuals/lineages, as predicted by the library hypothesis, except for the satDNA EgiSat21-168 that was absent for Northeast Lineage. The total satDNA content of the individuals was less than 11.2%, and it appeared to increase in two directions following the chromosomal evolution model. Thirteen satDNAs exhibited different patterns of amplification, and nine ones were contracted among individuals. Additionally, most repeats showed a divergence of about 10% for these satDNAs, indicating satellitome differentiation for each lineage/individual. This scenario suggests that the expansion of the satellitome occurred differentially among individuals/lineages of E. gigantea, with the contribution of various DNA turnover mechanisms after geographical isolation, and that they could be involved with karyotype evolution.

Motif-VI loop acts as a nucleotide valve in the West Nile Virus NS3 Helicase.

The Orthoflavivirus NS3 helicase (NS3h) is crucial in virus replication, representing a potential drug target for pathogenesis. NS3h utilizes nucleotide triphosphate (ATP) for hydrolysis energy to translocate on single-stranded nucleic acids, which is an important step in the unwinding of double-stranded nucleic acids. Intermediate states along the ATP hydrolysis cycle and conformational changes between these states, represent important yet difficult-to-identify targets for potential inhibitors. Extensive molecular dynamics simulations of West Nile virus NS3h+ssRNA in the apo, ATP, ADP+Piand ADP bound states were used to model the conformational ensembles along this cycle. Energetic and structural clustering analyses depict a clear trend of differential enthalpic affinity of NS3h with ADP, demonstrating a probable mechanism of hydrolysis turnover regulated by the motif-VI loop (MVIL). Based on these results, MVIL mutants (D471L, D471Nand D471E) were found to have a substantial reduction in ATPase activity and RNA replication compared to the wild-type. Simulations of the mutants in the apo state indicate a shift in MVIL populations favoring either a closed or open 'valve' conformation, affecting ATP entry or stabilization, respectively. Combining our molecular modeling with experimental evidence highlights a conformation-dependent role for MVIL as a 'valve' for the ATP-pocket, presenting a promising target for antiviral development.

Decreasing Intracellular Entropy by Increasing Mitochondrial Efficiency and Reducing ROS Formation-The Effect on the Ageing Process and Age-Related Damage.

A hypothesis is presented to explain how the ageing process might be influenced by optimizing mitochondrial efficiency to reduce intracellular entropy. Research-based quantifications of entropy are scarce. Non-equilibrium metabolic reactions and compartmentalization were found to contribute most to lowering entropy in the cells. Like the cells, mitochondria are thermodynamically open systems exchanging matter and energy with their surroundings-the rest of the cell. Based on the calculations from cancer cells, glycolysis was reported to produce less entropy than mitochondrial oxidative phosphorylation. However, these estimations depended on the CO2 concentration so that at slightly increased CO2, it was oxidative phosphorylation that produced less entropy. Also, the thermodynamic efficiency of mitochondrial respiratory complexes varies depending on the respiratory state and oxidant/antioxidant balance. Therefore, in spite of long-standing theoretical and practical efforts, more measurements, also in isolated mitochondria, with intact and suboptimal respiration, are needed to resolve the issue. Entropy increases in ageing while mitochondrial efficiency of energy conversion, quality control, and turnover mechanisms deteriorate. Optimally functioning mitochondria are necessary to meet energy demands for cellular defence and repair processes to attenuate ageing. The intuitive approach of simply supplying more metabolic fuels (more nutrients) often has the opposite effect, namely a decrease in energy production in the case of nutrient overload. Excessive nutrient intake and obesity accelerate ageing, while calorie restriction without malnutrition can prolong life. Balanced nutrient intake adapted to needs/activity-based high ATP requirement increases mitochondrial respiratory efficiency and leads to multiple alterations in gene expression and metabolic adaptations. Therefore, rather than overfeeding, it is necessary to fine-tune energy production by optimizing mitochondrial function and reducing oxidative stress; the evidence is discussed in this paper.

Circadian control of histone turnover during cardiac development and growth

During postnatal cardiac hypertrophy, cardiomyocytes undergo mitotic exit, relying on DNA replication-independent mechanisms of histone turnover to maintain chromatin organization and gene transcription. In other tissues, circadian oscillations in nucleosome occupancy influence clock-controlled gene expression, suggesting a role for the circadian clock in temporal control of histone turnover and coordinated cardiomyocyte gene expression. To elucidate roles for the master circadian transcription factor, Bmal1, in histone turnover, chromatin organization, and myocyte-specific gene expression and cell growth in the neonatal period. Bmal1 knockdown in neonatal rat ventricular myocytes (NRVM) decreased myocyte size, total cellular protein synthesis, and transcription of the fetal hypertrophic gene Nppb following treatment with serum or the α-adrenergic agonist phenylephrine (PE). Depletion of Bmal1 decreased expression of clock-controlled genes Per2 and Tcap, as well as Sik1, a Bmal1 target upregulated in adult versus embryonic hearts. Bmal1 knockdown impaired Per2 and Sik1 promoter accessibility as measured by MNase-qPCR and impaired histone turnover as measured by metabolic labeling of acid-soluble chromatin fractions. Sik1 knockdown in turn decreased myocyte size, while simultaneously inhibiting Nppb transcription and activating Per2 transcription. Linking these changes to chromatin remodeling, depletion of the replication-independent histone variant H3.3a inhibited myocyte hypertrophy and prevented PE-induced changes in clock-controlled gene transcription. Bmal1 is required for neonatal myocyte growth, replication-independent histone turnover, and chromatin organization at the Sik1 promoter. Sik1 represents a novel clock-controlled gene that coordinates myocyte growth with hypertrophic and clock-controlled gene transcription. Replication-independent histone turnover is required for transcriptional remodeling of clock-controlled genes in cardiac myocytes in response to growth stimuli.

Key Technology Research and Equipment Development of Automatic Spool Feeding Device

To solve the problems of high labour intensity and low efficiency of artificial spool feeding, an automatic spool feeding device is developed. SolidWorks is used for overall structural scheme design and determination of design parameters. The kinematic equation of the chain conveyor line is established, a mathematical model is solved with MATLAB, and sprocket, and chain parameters are selected. The clamping mechanism and turnover mechanism are designed, theoretical analysis of the key structure is completed. Dynamic simulation of the chain conveyor line is carried out by ADAMS, and preliminary operational stability is determined by combining motion curves. The test prototype is developed for feeding tests and measurement of the operating parameters. The test results show that the efficiency of machine feeding is 13% higher than that of manual feeding, the average feeding time is 43% lower, the halt waiting time is 43% lower, and the operating parameters are by the theoretical design and the work is reliable. The research results can provide a reference for similar spool-feeding devices.

The Influence of Forest Litter Characteristics on Bacterial and Fungal Community Diversity in the Picea crassifolia Ecosystem on the Qinghai–Tibet Plateau

The biodiversity and activity of microorganisms are crucial for litter decomposition, but how litter traits at different stages of decomposition drive changes in microbial communities has yet to be thoroughly explored. In the typical alpine hilly area of the Qinghai–Tibet Plateau, three types of litter at different decomposition stages were selected under a natural Picea crassifolia (Picea crassifolia Kom.) forest: undecomposed (A-1), partially decomposed (A-2), and fully decomposed (A-3). By measuring physicochemical indicators, microbial diversity, and the composition of the litter at different decomposition stages, this study investigates the community changes and responses of bacteria to litter characteristic changes at different decomposition levels. The results show that with the increase in decomposition level, bacterial diversity increases, community structure changes, and network complexity gradually increases, while the changes in fungal communities are insignificant. Structural equation modeling indicates that the first principal component (PC1) of litter properties is significantly negatively correlated with bacterial diversity and positively correlated with bacterial community composition. There is no significant correlation between fungal diversity and community composition, indicating a closer relationship between bacteria and litter characteristics than fungi. In summary, with an increase in litter decomposition level, the diversity and network complexity of bacterial and fungal communities will significantly increase, which is related to the changes in various litter characteristics. This study provides a scientific basis for the regulatory mechanism of litter decomposition and turnover in the alpine hilly area of the Qinghai–Tibet Plateau, specifically in Picea crassifolia forests.