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Flexible electronics have revolutionized the field by overcoming the rigid limitations of traditional devices, offering superior flexibility and adaptability. Conductive ink performance is crucial, directly impacting the stability of flexible electronics. While metal filler-based inks exhibit excellent conductivity, they often lack mechanical stability. To address this challenge, we present a novel conductive ink utilizing a ternary composite filler system: liquid metal and two micron-sized silver morphologies (particles and flakes). We systematically investigated the influence of filler type, mass ratio, and sintering process parameters on the composite ink's conductivity and mechanical stability. Our results demonstrate that flexible wires fabricated with the liquid metal/micron silver particle/micron silver flake composite filler exhibit remarkable conductivity and exceptional bending stability. Interestingly, increasing the liquid metal content results in a trade-off, compromising conductivity while enhancing mechanical performance. After enduring 5000 bending cycles, the resistance change in wires formulated with a 4:1 mass ratio of micron silver particles to flakes is only half that of wires with a 1:1 ratio. This study further investigates the mechanism governing resistance variations during flexible wire bending. Additionally, we observed a positive correlation between sintering temperature and pressure with the conductivity of flexible wires. The significance of the sintering parameters on conductivity follows a descending order: sintering temperature, sintering pressure, and sintering time. Finally, we demonstrate the practical application of this technology by integrating the composite ink-based flexible wires with conductive polymer-based strain sensors. This combination successfully achieved the detection of human movements, including finger and wrist bending.
Subject(s)
Electric Conductivity , Wearable Electronic Devices , Humans , Silver/chemistry , Motion , ElectronicsABSTRACT
Slide-ring hydrogels containing polyrotaxane structures have been widely developed, but current methods are more complex, in which modified cyclodextrins, capped polyrotaxanes, and multistep reactions are often needed. Here, a simple one-pot method dissolving the pseudopolyrotaxane (pPRX) in a mixture of acrylamide and boric acid to form a slide-ring hydrogel by UV light is used to construct a tough, puncture-resistant antibacterial polyrotaxane hydrogel. As a new dynamic ring cross-linking agent, boric acid effectively improves the mechanical properties of the hydrogel and involves the hydrogel with fracture toughness. The polyrotaxane hydrogel can withstand 1 MPa compression stress and maintain the morphology integrity, showing 197.5 mJ puncture energy under a sharp steel needle puncture. Meanwhile, its significant antibacterial properties endow the hydrogel with potential applications in the biomedical field.
Subject(s)
Anti-Bacterial Agents , Cyclodextrins , Escherichia coli , Hydrogels , Poloxamer , Rotaxanes , Rotaxanes/chemistry , Rotaxanes/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Hydrogels/chemistry , Hydrogels/pharmacology , Hydrogels/chemical synthesis , Poloxamer/chemistry , Escherichia coli/drug effects , Cyclodextrins/chemistry , Boric Acids/chemistry , Boric Acids/pharmacology , Microbial Sensitivity Tests , Staphylococcus aureus/drug effectsABSTRACT
BACKGROUND: This study investigated the relaxation effect of PGE2 on the ureter and its role in promoting calculi expulsion following calculi development. METHODS: By using immunofluorescence and Western blot, we were able to locate EP receptors in the ureter. In vitro experiments assessed the impact of PGE2, receptor antagonists, and agonists on ureteral relaxation rate. We constructed a model of ureteral calculi with flowable resin and collected ureteral tissue from postoperative side of the ureter after obstruction surgery. Western blot analysis was used to determine the protein expression levels of EP receptors and the PGE2 terminal synthase mPGES-1. Additionally, PGE2 was added to smooth muscle cells to observe downstream cAMP and PKA changes. RESULTS: The expression of EP2 and EP4 proteins in ureteral smooth muscle was verified by Western blot analysis. According to immunofluorescence, EP2 was primarily found on the cell membrane, while EP4 was found in the nucleus. In vitro, PGE2 induced concentration-dependent ureteral relaxation. Maximum diastolic rate was 70.94 ± 4.57% at a concentration of 30µM. EP2 antagonists hindered this effect, while EP4 antagonists did not. Obstructed ureters exhibited elevated mPGES-1 and EP2 protein expression (P < 0.01). Smooth muscle cells treated with PGE2 displayed increased cAMP and phosphorylated PKA. CONCLUSIONS: PGE2 binding to EP2 induces ureteral relaxation through the cAMP-PKA pathway. This will provide a new theoretical basis for the development of new therapeutic approaches for the use of PGE2 in the treatment of ureteral stones.
Subject(s)
Cyclic AMP-Dependent Protein Kinases , Cyclic AMP , Dinoprostone , Receptors, Prostaglandin E, EP2 Subtype , Ureter , Ureteral Calculi , Receptors, Prostaglandin E, EP2 Subtype/metabolism , Cyclic AMP/metabolism , Dinoprostone/metabolism , Dinoprostone/pharmacology , Cyclic AMP-Dependent Protein Kinases/metabolism , Animals , Ureter/metabolism , Signal Transduction/physiology , Male , Muscle Relaxation/drug effects , Muscle Relaxation/physiologyABSTRACT
Aortic aneurysm and dissection (AAD) are severe vascular diseases with high mortality rates. However, the causal relationship between serum uric acid levels and the occurrence of AAD remains a subject of controversy. To address this issue, we conducted a two-sample Mendelian randomization (MR) analysis to investigate whether there is a causal association between these factors. We obtained single-nucleotide polymorphisms (SNPs) data related to serum uric acid levels from the FinnGen study and data on AAD from the UK Biobank. Various two-sample MR methods, including inverse variance weighted (IVW) analysis, MR-Egger regression analysis, weighted median analysis, and contamination mixture method, were employed to assess the causal relationship between serum uric acid and the risk of AAD. Sensitivity analysis was conducted to evaluate the stability and reliability of the results. The findings revealed a positive association between serum uric acid levels and the risk of aortic aneurysm (AA) (odds ratio [OR] = 1.200, 95 % confidence interval [CI]: 1.020-1.400, P = 0.0239). However, no significant correlation was observed between serum uric acid levels and the occurrence of aortic dissection (AD) (OR = 0.893, 95 % CI = 0.602-1.326, P = 0.576). Our study, which employed MR analysis, identified a positive association between serum uric acid levels and the risk of AA. However, we did not observe a significant correlation with AD.
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MiR156 play important roles in regulation of plant growth and development, secondary metabolite synthesis, and other biological processes by targeting the SQUAMOSA promoter binding protein-like (SPL) family. Our previous sequencing data analysis suggested that Csn-miR156d may regulate flowering and anthocyanin accumulation by cleavage and degradation of the expression of the SPL in tea plant, but it remains to be elucidated. In this study, 5'RLM-RACE experiment, tobacco transient transformation, qRT-PCR, and antisense oligonucleotide (asODN) were used to verify that CsSPL1 is the target gene of Csn-miR156d. Stable transformation of Arabidopsis revealed that Csn-miR156d could delay flowering by negatively regulating the transcript levels of FT, AP1, FUL, and SOC1, while overexpression of CsSPL1 showed an opposite effect. Additionally, overexpression of Csn-miR156d in Arabidopsis could enhance the transcription of the anthocyanin biosynthesis-related structural genes DFR, ANS, F3H, UGT78D2, and LDOX, as well as regulatory genes PAP1, MYB113, GL3, MYB11, and MYB12, leading to anthocyanin accumulation. Moreover, asODN experiment revealed that Csn-miR156d could increase the anthocyanin content in tea plant. These results suggest that Csn-miR156d regulates flowering and anthocyanin accumulation in tea plant by suppressing the expression of CsSPL1. Our study provides new insights into the development and anthocyanin accumulation in tea plant and lays a theoretical foundation for further research on the molecular mechanism of miRNAs in regulating tea plant growth and secondary metabolism.
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OBJECTIVE: This study aimed to evaluate the efficacy and safety of neuroendoscopy for treating hypertensive putamen hemorrhage (HPH), compared with traditional craniotomy. METHODS: We retrospectively analyzed 81 consecutive patients with HPH treated with neuroendoscopy (n=36) or craniotomy (n=45) in the Department of Neurosurgery at the Anhui Provincial Hospital Affiliated to Anhui Medical University between January 2015 and December 2017. We compared the clinical and radiographic outcomes, excluded 14 patients who did not meet the inclusion criteria. Patient characteristics in emergency room were recorded. In addition, hospitalization days, total cost during hospitalization, operative time, blood loss, evacuation rate, rebreeding, intracranial infection, pulmonary infection, epilepsy, hemorrhage of digestive tract, venous thrombus, hypoproteinemia, aphasia, oculomotor paralysis, mortality, Modified Rankin Scale score 6 months after surgery, and Glasgow Outcome Scale score 6 months after surgery were compared between the 2 groups. RESULTS: Comparative analysis of preoperative patient data revealed no notable disparities. Neuroendoscopic surgery afford distinct benefits including reduced operative time, minimal patient blood loss, and enhanced efficacy in hematoma evacuation. However, the incidence of postoperative complications such as rebleeding, intracranial infections, pulmonary infections, postoperative epilepsy, hemorrhage of digestive tract, venous thrombus, hypoproteinemia, aphasia, and oculomotor paralysis did not significantly differ. In contrast, endoscopic techniques, relative to conventional craniotomy for hematoma evacuation, are characterized by less invasive incisions, a marked decrease in the duration of hospitalization, and a substantial reduction in associated healthcare costs. Furthermore, endoscopic techniques contribute to superior long-term recuperative outcomes in patients, without altering mortality rates. CONCLUSIONS: In comparison to the conventional method of craniotomy, the utilization of neuroendoscopy in the treatment of hypertensive putamen hemorrhage (HPH) may offer a more efficacious, minimally invasive, and cost-effective approach. This alternative approach has the potential to decrease the length of hospital stays and improve long-term neurologic outcomes, without altering mortality rates.
Subject(s)
Craniotomy , Postoperative Complications , Humans , Female , Male , Craniotomy/methods , Middle Aged , Retrospective Studies , Treatment Outcome , Aged , Putaminal Hemorrhage/surgery , Putaminal Hemorrhage/complications , Neuroendoscopy/methods , Length of Stay/statistics & numerical data , Operative Time , AdultABSTRACT
Micropillar array electrodes represent a promising avenue for enhancing detection sensitivity and response current. However, existing methods for depositing electrode materials on micropillar arrays often result in uneven distribution, with the thin sidewall layer being less conductive and prone to corrosion. In addressing this issue, this study introduces electroplating to enhance the copper layer on the sidewall of micropillar array electrodes. These electrodes, fabricated through standard microelectronics processes and electroplating, are proposed for non-enzymatic glucose detection, with the copper layer deposited via electroplating significantly enhancing sensitivity. Initially, the impact of cetyltrimethylammonium bromide (CTAB) concentration as an inhibitor on the surface morphology and sensitivity of the plated layer was investigated. It was discovered that CTAB could decrease surface roughness, hinder the development of large and coarse grains, generate small particles, and boost sensitivity. Compared to the uncoated electrode and plating without CTAB, sensitivity was elevated by a factor of 1.66 and 1.62, respectively. Subsequently, the alterations in plating morphology and detection performance within a range of 0.3 ASD to 3 ASD were examined. Sensitivity demonstrated a tendency to increase initially and then decrease. The electrode plated at 0.75 ASD achieved a maximum sensitivity of 3314 µA·mM-1·cm-2 and a detection limit of 15.9 µM. Furthermore, a potential mechanism explaining the impact of different morphology on detection performance due to CTAB and current density was discussed. It was believed that the presented effective strategy to enhance the sensitivity of micropillar array electrodes for glucose detection would promote the related biomedical detection applications.
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The island species-area relationship (ISAR) describes how species richness increases with increasing area of a given island or island-like habitat, such as freshwater lakes. While the ISAR is one of the most common phenomena observed in ecology, there is variation in both the form of the relationship and its underlying mechanisms. We compiled a global data set of benthic macroinvertebrates from 524 shallow freshwater lakes, ranging from 1 to 293,300 ha in area. We used individual-based rarefaction to determine the degree to which ISAR was influenced by mechanisms other than passive sampling (larger islands passively sample more individuals from the regional pool and, therefore, have more species than smaller islands), which would bias results away from expected relationships between rarefied species richness (and other measures that capture relative abundances) and lake area. We also examined how climate may alter the shape of the ISARs. We found that both rarefied species richness (the number of species standardized by area or number of individuals) and a measure of evenness emphasizing common species exhibit shallow slopes in relationships with lake area, suggesting that the expected ISARs in these lakes most likely result from passive sampling. While there was considerable variation among ISARs across the investigated lakes, we found an overall positive rarefied ISAR for lakes in warm (i.e. tropical/subtropical) regions (n = 195), and in contrast, an overall negative rarefied ISAR in cool (i.e. north temperate) lakes (n = 329). This suggested that mechanisms beyond passive sampling (e.g. colonization-extinction dynamics and/or heterogeneity) were more likely to operate in warm lakes. One possible reason for this difference is that the area-dependent intensity of fish predation, which can lead to flatter ISARs, is weaker in warmer relative to cooler lakes. Our study illustrates the importance of understanding both the pattern and potential processes underlying the ISARs of freshwater lakes in different climatic regions. Furthermore, it provides a baseline for understanding how further changes to the ecosystem (i.e. in lake area or climate) might influence biodiversity patterns.
Subject(s)
Biodiversity , Ecosystem , Animals , Lakes , Fishes , EcologyABSTRACT
Aim To explore the mechanism of hydroxy-a-sanshool in the treatment of diabetic cardiomyopathy ( DCM) based on label-free quantitative proteomics detection technique. Methods DCM model was established by high fat diet and intraperitoneal injection of streptozotocin ( STZ) . They were divided into control group ( CON group ) , diabetic cardiomyopathy group (DCM group) and hydroxy-a-sanshool treatment group ( DCM + SAN group) . The cardiac function of mice was evaluated by echocardiography, the myocardial morphology was observed by pathology staining, the protective mechanism of hydroxy-a-sanshool on diabetic cardiomyopathy was speculated by proteomic technique , and the expression level of cAMP/PKA signaling pathway and key proteins were verified by Western blotting. Results Cardiac ultrasound and pathology staining showed that hydroxy-a-sanshool had protective effect on the heart of DCM mice. Label-free quantitative proteomic analysis was carried out between DCM + SAN group and DCM group, and 160 differential pro-teins were identified by proteomics, in which 127 proteins were up-regulated and 33 proteins were down regulated ; GO secondary functional annotations showed the biological process, molecular function and cellular component; KEGG enrichment analysis showed that cAMP signaling pathway was the most abundant; protein interaction network showed that PKA as the central node interacted with many proteins in the cAMP signaling pathway. Western blot showed that the relative expression of с AMP, PKA protein in DCM group was significantly lower than that in CON group ( P < 0. 05 ) , while the relative expression of cAMP, PKA protein in DCM + SAN group was significantly higher than that in DCM group ( P < 0. 05 ) . Conclusions Hydroxy-a-sanshool has protective effect on heart function of mice with diabetes, which plays a role through cAMP signaling pathway.
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Eutrophication and cyanobacterial blooms have severely affected many freshwater ecosystems. We studied the effects of filter-feeding fish and bivalves on algal populations using a mesocosm experiment and long-term monitoring data from Lake Taihu (China). The mesocosm study, comprised of a two-way factorial design with the clam Corbicula fluminea and the fish Aristichthys nobilis at three biomass levels, resulted in lower chlorophyll a (Chl a) in high fish treatments, but no significant differences in the low and medium fish treatments. Chl a also decreased with an increase in clam biomass in the high fish treatments. Moreover, filter-feeding fish resulted in a decrease in algal sizes (e.g., the colony size of Microcystis aeruginosa was inversely related to fish biomass) which likely increased the filter-feeding efficiency of bivalves. Biomass of filter-feeding fish was found to be a key factor driving the synergistic effects of filter-feeding fish and bivalves in waters dominated by Microcystis colonies. Long-term monitoring revealed increasing trends in Chl a concentration, total fish catch per unit effort (TF-CPUE), and filter-feeding fish (FF-CPUE), and slightly decreasing trends in bivalve biomass and nitrogen to phosphorus ratios (N:P) from 2006 to 2016. Bivalve biomass and N:P were negatively correlated with Chl a, while FF-CPUE was not significantly related to Chl a. The current filter-feeding fish biomass in Lake Taihu is estimated to be too low to drive synergistic algal control effects together with bivalves. Furthermore, the lack of filter feeders in Lake Taihu may lead to top-down control by predators that cannot counteract the bottom-up effects of nutrients on phytoplankton. Collectively, these long-term monitoring and experimental data support the combined use filter-feeding fish and bivalves for managing cyanobacteria blooms in Lake Taihu.
Subject(s)
Bivalvia , Cyanobacteria , Microcystis , Animals , Lakes/microbiology , Chlorophyll A , Ecosystem , Phosphorus/analysis , Eutrophication , China , Fishes , Environmental Monitoring/methodsABSTRACT
Biomanipulation has been widely used in the ecological restoration of eutrophic lakes for decades. However, biomanipulation is prone to failure if external nutrient loads are not reduced. In order to explore the importance of filter-feeding fish and bivalves on algal control, an outdoor mesocosm experiment was conducted using different nutrient concentrations. Four treatments simulating daily loads of nutrients in Lake Taihu were studied: current, two times, and three times average daily loads of nutrients with both fish (Aristichthys nobilis) and Asian clam (Corbicula fluminea) and as a control current daily loads without fish or bivalves. Results showed that stocking of filter-feeding fish and bivalves (80 g m-3 bighead carp; 200 g cm-2 clams) at two times daily nutrient loads could effectively control water column Chl a concentrations and phytoplankton biomass. At higher nutrient concentrations (TN ≥ 260 µg L-1 d-1; TP ≥ 10 µg L-1 d-1), top-down control of filter-feeding fish and bivalves was less effective and bottom-up effects resulted in significant increases of Chl a concentration. Thus, as phytoplankton biomass in freshwater ecosystems is determined by both the top-down effects of predators and the bottom-up effects of nutrients, external loadings should be controlled when filter-feeding fish and bivalves are used for algal control to ensure the efficacy of biomanipulation.
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OBJECTIVE: To compare the prognosis of patients with spontaneous basal ganglia intracerebral hematoma treated by endoscopic evacuation, craniotomy, or puncture aspiration. METHODS: This retrospective observational study included information from patients with basal ganglia hematoma who received craniotomy, endoscopic evacuation, or puncture aspiration in the Department of Neurosurgery of the First Affiliated Hospital of USTC between January 2016 and May 2021. Patients were grouped according to their treatment method for comparison. RESULTS: From a total of 184 patients, 62 cases (51 males, aged 54.44 ± 9.92 years) received craniotomy, 64 cases (45 males, aged 53.97 ± 11.87 years) received endoscopic evacuation, and 58 cases (43 males, aged 54.25 ± 10.35 years) received puncture aspiration. No significant difference was found in baseline characteristics among three surgical procedures. Patients in the endoscopy group had the shortest hospital stay (15.16 ± 4.89 days vs. 17.88 ± 5.97 and 20.77 ± 6.96 days), lowest infectious meningitis [1(1.6 %) vs. 2(3.4%) and 8(12.9%)] and pulmonary infection [3(4.7%) vs. 5(8.6%) and 13(21.0%)] rates, and highest hematoma removal rate (90.39 ± 5.22% vs. 35.87 ± 6.23 and 84.76 ± 4.91%) and Glasgow outcome scale 6 months after surgery (4.41 ± 0.53 vs. 3.74 ± 1.09 and 3.81 ± 1.03). The occurrence of gastrointestinal bleeding, epilepsy, and mortality were similar (all p > 0.05) among the groups. CONCLUSION: Patients with spontaneous basal ganglia intracerebral hematoma who received endoscopic evacuation might have better prognosis than those treated with craniotomy or puncture aspiration. In future, endoscopic surgery could become the most common method for treating spontaneous basal ganglia hemorrhages.
Subject(s)
Basal Ganglia Hemorrhage , Endoscopy , Male , Humans , Treatment Outcome , Endoscopy/methods , Craniotomy/methods , Cerebral Hemorrhage/surgery , Punctures , Basal Ganglia Hemorrhage/diagnostic imaging , Basal Ganglia Hemorrhage/surgery , Basal Ganglia/diagnostic imaging , Basal Ganglia/surgery , Retrospective Studies , Hematoma/surgeryABSTRACT
The development of nanohybrid with high electrocatalytic activity is of great significance for electrochemical sensing applications. In this work, we develop a novel and facile method to prepare a high-performance flexible nanohybrid paper electrode, based on nitrogen-doped carbon (NC) wrapped Bi nanoparticles (Bi-NPs) assembly derived from Bi-MOF, which are decorated on a flexible and freestanding graphene paper (GP) electrode. The as-obtained Bi-NPs encapsulated by an NC layer are uniform, and the active sites are increased by introducing a nitrogen source while preparing Bi-MOF. Owing to the synergistic effect between the high conductivity of GP electrode and the highly efficient electrocatalytic activity of Bi-NPs, the NC wrapped Bi-NPs (Bi-NPs@NC) modified GP (Bi-NPs@NC/GP) electrode possesses high electrochemically active area, rapid electron-transfer capability, and good electrochemical stability. To demonstrate its outstanding functionality, the Bi-NPs@NC/GP electrode has been integrated into a handheld electrochemical sensor for detecting heavy metal ions. The result shows that Zn2+, Cd2+, and Pb2+ can be detected with extremely low detection limits, wide linear range, high sensitivity, as well as good selectivity. Furthermore, it demonstrates outstanding electrochemical sensing performance in the simultaneous detection of Zn2+, Cd2+, and Pb2+. Finally, the proposed electrochemical sensor has achieved excellent repeatability, reproducibility, stability, and reliability in measuring real water samples, which will have great potential in advanced applications in environmental systems.
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Directional hydraulic fracturing (DHF) is more and more widely used in coal mines in China for hard roof and coal burst control. The key to this technology is to determine the crack initiation pressure that affected by the shape of the artificial notch and the stress state around the fracturing hole. Reasonable and simple formula for fracturing pressure calculation is essential since the fracturing pump used in coal mines is usually limited by the harsh conditions and hardly replaced once selected. Based on the superposition principle, the simplified 2D model of DHF was established as the elliptical hole with the internal pressure and solved by using the complex functions method. The analytical solution of tangential stress on the inner surface was obtained meanwhile the corresponding criterion of fracturing pressure can be set up. Considering the characteristics of DHF in coal mines, we further got a simplified formula that controlled by the ratio of major to minor axis of the ellipse-like notch, the ratio of the minimum to the maximum principal stress, as well as the tensile strength of the rock. The formula also gave a guide to the design of the notch that major diameter should be at least twice the minor diameter, and the optimal solution for the ratio is to 2ï½4 and recommended 4, which can resist the initiation pressure to a large extent affected by the in-situ stress. Once the pressure of the fracturing fluid is high enough to satisfy the equation cracks would arise at the tips of the notch along the major axis which belongs to mode â crack and would grow unsteadily and rapidly. A PFC simulation model was used to verify the analysis, the results of which are very consistent with the theoretical solutions.
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OBJECTIVE: Hip subluxation is a common complication in children with spinal cord injury. This study aimed to investigate the incidence and influencing factors of hip subluxation and discuss prevention strategies. METHODS: Medical records of children with spinal cord injury were reviewed. The inclusion criteria were as follows: (1) the patient was younger than 18 years old when injured; (2) absence of traumatic or congenital pathological changes of the hip at the time of injury. The migration percentage and acetabular index were selected to evaluate hip stability and acetabulum development. Influencing factors of sex, age, injury duration, severity, level, and spasticity were analyzed. RESULTS: A total of 146 children were enrolled. Twenty-eight children presented with hip subluxation and were significantly younger at the time of injury than those with normal hips (P = 0.002). The incidence of hip subluxation increased with the prolonged injury duration. Injury before age 6, complete injury, and flaccid lower extremities were significant influencing factors (P = 0.003, 0.004, and 0.015, respectively). The risk of hip subluxation decreased by 18% for every year older in injury age (P = 0.031) and decreased by 85% in children with spasticity (P = 0.018) than those without. However, the risk of hip subluxation in children with injury duration longer than 1 year was 7.1 times higher than those with shorter injury duration (P < 0.001). CONCLUSIONS: The incidence of hip subluxation in children with spinal cord injury increased with the injury duration. Younger children had immature hip development. Due to complete injury and flaccid muscle, lack of protection around the hip may lead to subluxation. Follow-up and prevention of hip subluxation need the joint effort of medical staff and families.
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Intraguild predation (IGP) can have a significant impact on phytoplankton biomass, but its effects on their diversity and assemblage composition are not well understood. In this study, we constructed an IGP model based on the common three-trophic food chain of "fish (or shrimp)-large branchiopods (Daphnia)-phytoplankton", and investigated the effects of IGP on phytoplankton assemblage composition and diversity in outdoor mesocosms using environmental DNA high-throughput sequencing. Our results indicated that the alpha diversities (number of amplicon sequence variants and Faith's phylogenetic diversity) of phytoplankton and the relative abundance of Chlorophyceae increased with the addition of Pelteobagrus fulvidraco, while similar trends were found in alpha diversities but with a decrease in the relative abundance of Chlorophyceae in the Exopalaemon modestus treatment. When both predators were added to the community, the strength of collective cascading effects on phytoplankton alpha diversities and assemblage composition were weaker than the sum of the individual predator effects. Network analysis further showed that this IGP effect also decreased the strength of collective cascading effects in reducing the complexity and stability of the phytoplankton assemblages. These findings contribute to a better understanding of the mechanisms underlying the impacts of IGP on lake biodiversity, and provide further knowledge relevant to lake management and conservation.
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Selective CDK2 inhibitors have the potential to provide effective therapeutics for CDK2-dependent cancers and for combating drug resistance due to high cyclin E1 (CCNE1) expression intrinsically or CCNE1 amplification induced by treatment of CDK4/6 inhibitors. Generative models that take advantage of deep learning are being increasingly integrated into early drug discovery for hit identification and lead optimization. Here we report the discovery of a highly potent and selective macrocyclic CDK2 inhibitor QR-6401 (23) accelerated by the application of generative models and structure-based drug design (SBDD). QR-6401 (23) demonstrated robust antitumor efficacy in an OVCAR3 ovarian cancer xenograft model via oral administration.
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Fatty acids (FAs) are critical nutrients that regulate an organism's health and development in mammal. Long-chain fatty acids (LCFAs) can be divided into saturated and unsaturated fatty acids, depending on whether the carbon chain contains at least 1 double bond. The fatty acids that are required for humans and animals are obtained primarily from dietary sources, and LCFAs are absorbed from outside of cells in mammals. LCFAs enter cells through several mechanisms, including passive diffusion and protein-mediated translocation across the plasma membrane, the latter in which FA translocase (FAT/CD36), plasma membrane FA-binding protein (FABPpm), FA transport protein (FATP), and caveolin-1 are believed to have important functions. The LCFAs that are taken up by cells bind to FA-binding proteins (FABPs) and are transported to the specific organelles, where they are activated into acyl-CoA to target specific metabolic pathways. LCFA-CoAs can be esterified to phospholipids, triacylglycerol, cholesteryl ester, and other specialized lipids. Non-esterified free fatty acids are preferentially stored as triacylglycerol molecules. The main pathway by which fatty acids are catabolized is ß-oxidation, which occurs in mitochondria and peroxisomes. stearoyl-CoA desaturase (SCD)-dependent and Fatty acid desaturases (FADS)-dependent fatty acid desaturation pathways coexist in cells and provide metabolic plasticity. The process of fatty acid elongation occurs by cycling through condensation, reduction, dehydration, and reduction. Extracellular LCFA can be mediated by membrane protein G protein-coupled receptor 40 (GPR40) or G protein-coupled receptor 120 (GPR120) to activate mammalian target of rapamycin complex 1 (mTORC1) signaling, and intracellular LCFA's sensor remains to be determined. The crystal structures of a phosphatidic acid phosphatase and a membrane-bound fatty acid elongase-condensing enzyme and other LCFA-related proteins provide important insights into the mechanism of utilization, increasing our understanding of the cellular uptake, metabolism and sensing of LCFAs.
Subject(s)
Fatty Acids , Mitochondria , Animals , Humans , Biological Transport , Cell Membrane , Membrane Proteins , Protein TransportABSTRACT
The mutant KRAS was considered as an "undruggable" target for decades, especially KRASG12D. It is a great challenge to develop the inhibitors for KRASG12D which lacks the thiol group for covalently binding ligands. The discovery of MRTX1133 solved the dilemma. Interestingly, MRTX1133 can bind to both the inactive and active states of KRASG12D. The binding mechanism of MRTX1133 with KRASG12D, especially how MRTX1133 could bind the active state KRASG12D without triggering the active function of KRASG12D, has not been fully understood. Here, we used a combination of all-atom molecular dynamics simulations and Markov state model (MSM) to understand the inhibition mechanism of MRTX1133 and its analogs. The stationary probabilities derived from MSM show that MRTX1133 and its analogs can stabilize the inactive or active states of KRASG12D into different conformations. More remarkably, by scrutinizing the conformational differences, MRTX1133 and its analogs were hydrogen bonded to Gly60 to stabilize the switch II region and left switch I region in a dynamically inactive conformation, thus achieving an inhibitory effect. Our simulation and analysis provide detailed inhibition mechanism of KRASG12D induced by MRTX1133 and its analogs. This study will provide guidance for future design of novel small molecule inhibitors of KRASG12D.
Subject(s)
Molecular Dynamics Simulation , Proto-Oncogene Proteins p21(ras) , Proto-Oncogene Proteins p21(ras)/genetics , Fungal Proteins , Sulfhydryl CompoundsABSTRACT
In this work, we report the development of a new type of highly active and stable Bi-based electrode material, i.e., BiCu metal-organic frames (MOF) derived carbon film (CF) encapsulating BiCu alloy nanoparticles (BiCu-ANPs) for electrochemical sensing. The integration of Bi with Cu to form BiCu-ANPs can improve their electrocatalytic activity as well as the acid resistance. Meanwhile, the carbon film that encapsulates BiCu-ANPs not only guarantees the BiCu-ANPs with high electrical conductivity and fast electrochemical kinetics but also effectively alleviates the volume change during the adsorption and desorption of heavy metal (HM) ions. Therefore, the as-obtained CF encapsulating BiCu-ANPs (BiCu-ANPs@CF) exhibits fully exposed active sites, facile charge transfer, high stability and conductivity, which gives rise to enhanced sensitivity and stability for the electrochemical detection of HM ions. When integrated into a potable electrochemical sensing system for simultaneous detection of Pb2+, Cd2+ and Zn2+, the BiCu-ANPs@CF modified electrode exhibits low detection limit (i.e., 0.081 ppb for Pb2+, 0.95 ppb for Cd2+, 35 ppb for Zn2+), wide detection range (i.e., 0.5-700 ppb for Pb2+, 5-900 ppb for Cd2+, 150-600 ppb for Zn2+) and good anti-interference. Finally, the system has been used for on-site detection of multiplexed HM ions in human biological liquids and environmental water with a good spiked recovery rate, which demanstrates its promise application in the future for on-site monitoring of human health and pollutants in water quality.