Targeting autophagy with natural products as a potential therapeutic approach for diabetic microangiopathy.

As the quality of life improves, the incidence of diabetes mellitus and its microvascular complications (DMC) continues to increase, posing a threat to people's health and wellbeing. Given the limitations of existing treatment, there is an urgent need for novel approaches to prevent and treat DMC. Autophagy, a pivotal mechanism governing metabolic regulation in organisms, facilitates the removal of dysfunctional proteins and organelles, thereby sustaining cellular homeostasis and energy generation. Anomalous states in pancreatic ß-cells, podocytes, Müller cells, cardiomyocytes, and Schwann cells in DMC are closely linked to autophagic dysregulation. Natural products have the property of being multi-targeted and can affect autophagy and hence DMC progression in terms of nutrient perception, oxidative stress, endoplasmic reticulum stress, inflammation, and apoptosis. This review consolidates recent advancements in understanding DMC pathogenesis via autophagy and proposes novel perspectives on treating DMC by either stimulating or inhibiting autophagy using natural products.

Enhancing Retinal Fundus Image Quality Assessment With Swin-Transformer-Based Learning Across Multiple Color-Spaces.

Purpose: The assessment of retinal image (RI) quality holds significant importance in both clinical trials and large datasets, because suboptimal images can potentially conceal early signs of diseases, thereby resulting in inaccurate medical diagnoses. This study aims to develop an automatic method for Retinal Image Quality Assessment (RIQA) that incorporates visual explanations, aiming to comprehensively evaluate the quality of retinal fundus images (RIs). Methods: We developed an automatic RIQA system, named Swin-MCSFNet, utilizing 28,792 RIs from the EyeQ dataset, as well as 2000 images from the EyePACS dataset and an additional 1,000 images from the OIA-ODIR dataset. After preprocessing, including cropping black regions, data augmentation, and normalization, a Swin-MCSFNet classifier based on the Swin-Transformer for multiple color-space fusion was proposed to grade the quality of RIs. The generalizability of Swin-MCSFNet was validated across multiple data centers. Additionally, for enhanced interpretability, a Score-CAM-generated heatmap was applied to provide visual explanations. Results: Experimental results reveal that the proposed Swin-MCSFNet achieves promising performance, yielding a micro-receiver operating characteristic (ROC) of 0.93 and ROC scores of 0.96, 0.81, and 0.96 for the "Good," "Usable," and "Reject" categories, respectively. These scores underscore the accuracy of RIQA based on Swin-MCSF in distinguishing among the three categories. Furthermore, heatmaps generated across different RIQA classification scores and various color spaces suggest that regions in the retinal images from multiple color spaces contribute significantly to the decision-making process of the Swin-MCSFNet classifier. Conclusions: Our study demonstrates that the proposed Swin-MCSFNet outperforms other methods in experiments conducted on multiple datasets, as evidenced by the superior performance metrics and insightful Score-CAM heatmaps. Translational Relevance: This study constructs a new retinal image quality evaluation system, which will contribute to the subsequent research of retinal images.

An EEG Signature of MCH Neuron Activities Predicts Cocaine Seeking.

Background: Identifying biomarkers that predict substance use disorder (SUD) propensity may better strategize anti-addiction treatment. The melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH) critically mediates interactions between sleep and substance use; however, their activities are largely obscured in surface electroencephalogram (EEG) measures, hindering the development of biomarkers. Methods: Surface EEG signals and real-time Ca2+ activities of LH MCH neurons (Ca2+MCH) were simultaneously recorded in male and female adult rats. Mathematical modeling and machine learning were then applied to predict Ca2+MCH using EEG derivatives. The robustness of the predictions was tested across sex and treatment conditions. Finally, features extracted from the EEG-predicted Ca2+MCH either before or after cocaine experience were used to predict future drug-seeking behaviors. Results: An EEG waveform derivative - a modified theta-to-delta ratio (EEG Ratio) - accurately tracks real-time Ca2+MCH in rats. The prediction was robust during rapid eye movement sleep (REMS), persisted through REMS manipulations, wakefulness, circadian phases, and was consistent across sex. Moreover, cocaine self-administration and long-term withdrawal altered EEG Ratio suggesting shortening and circadian redistribution of synchronous MCH neuron activities. In addition, features of EEG Ratio indicative of prolonged synchronous MCH neuron activities predicted lower subsequent cocaine seeking. EEG Ratio also exhibited advantages over conventional REMS measures for the predictions. Conclusions: The identified EEG Ratio may serve as a non-invasive measure for assessing MCH neuron activities in vivo and evaluating REMS; it may also serve as a potential biomarker predicting drug use propensity.

No causal association between serum vitamin D levels and diabetes retinopathy: A Mendelian randomization analysis.

BACKGROUND AND AIM: Diabetes retinopathy (DR) is a common microvascular complication of diabetes, and it is the main cause of global vision loss. The current observational research results show that the causal relationship between Vitamin D and DR is still controversial. Therefore, we conducted a Mendelian randomization study to determine the potential causal relationship between serum 25-hydroxyvitamin D 25(OH)D and DR. METHODS AND RESULTS: In this study, we selected aggregated data on serum 25(OH)D levels (GWAS ID: ebi-a-GCST90000615) and DR (GWAS ID: finn-b-DM_RETINOPATHY) from a large-scale GWAS database. Then use MR analysis to evaluate the possible causal relationship between them. We mainly use inverse variance weighted (IVW), supplemented by MR Egger and weighted median methods. Sensitivity analysis is also used to ensure the stability of the results, such as Cochran's Q-test, MR-PRESSO, MR-Egger interception test, and retention method. The MR analysis results showed that there was no significant causal relationship between 25(OH)D and DR (OR = 1.0128, 95%CI=(0.9593,1.0693), P = 0.6447); Similarly, there was no significant causal relationship between DR and serum 25 (OH) D levels (OR = 0.9900, 95% CI=(0.9758,1.0045), P = 0.1771). CONCLUSION: Our study found no significant causal relationship between serum 25(OH)D levels and DR, and vice versa. A larger sample size randomized controlled trial is needed to further reveal its potential causal relationship.

Ultrathin Parylene C-based sensitivity-gain nanoplasmonic sensor integrated on VCSEL for Aß42 detection.

As Alzheimer's disease prevalence continues to rise, there is an increasing demand for efficient on-chip biosensors capable of early biomarker detection. This study presents a novel biosensor chip leveraging vertical cavity surface emitting laser (VCSEL) technology, with Parylene C serving as the antibody coupling layer and utilizing a streamlined one-step antibody modification method. Integration of Parylene C enhances chip sensitivity from 34.28 µW/RIU to 40.32 µW/RIU. Moreover, post-testing removal of Parylene C enables chip reusability without significant alteration of results. The sensor demonstrates effective detection of Aß42, an Alzheimer's biomarker, exhibiting a linear range of 1-200 ng/mL and a detection limit of 0.26 ng/mL. These findings underscore the reusability and reliability of the ultrathin Parylene C-based VCSEL biosensor chip, highlighting its potential for point-of-care Alzheimer's disease diagnosis.

Ubiquitin ligase MDM2 mediates endothelial inflammation in Kawasaki disease vasculitis development.

Background: Kawasaki disease (KD) often complicates coronary artery lesions (CALs). Despite the established significance of STAT3 signaling during the acute phase of KD and signal transducer and activator of transcription 3 (STAT3) signaling being closely related to CALs, it remains unknown whether and how STAT3 was regulated by ubiquitination during KD pathogenesis. Methods: Bioinformatics and immunoprecipitation assays were conducted, and an E3 ligase, murine double minute 2 (MDM2) was identified as the ubiquitin ligase of STAT3. The blood samples from KD patients before and after intravenous immunoglobulin (IVIG) treatment were utilized to analyze the expression level of MDM2. Human coronary artery endothelial cells (HCAECs) and a mouse model were used to study the mechanisms of MDM2-STAT3 signaling during KD pathogenesis. Results: The MDM2 expression level decreased while the STAT3 level and vascular endothelial growth factor A (VEGFA) level increased in KD patients with CALs and the KD mouse model. Mechanistically, MDM2 colocalized with STAT3 in HCAECs and the coronary vessels of the KD mouse model. Knocking down MDM2 caused an increased level of STAT3 protein in HCAECs, whereas MDM2 overexpression upregulated the ubiquitination level of STAT3 protein, hence leading to significantly decreased turnover of STAT3 and VEGFA. Conclusions: MDM2 functions as a negative regulator of STAT3 signaling by promoting its ubiquitination during KD pathogenesis, thus providing a potential intervention target for KD therapy.

Association between Glycosylated Hemoglobin and Serum Uric Acid: A US NHANES 2011-2020.

Background: Serum uric acid (SUA) and glycosylated hemoglobin (HbA1c) were closely related to the body's metabolism. This study aimed to investigate the relationship between HbA1c and SUA in adults. Methods: This study selected 7293 participants aged ≥20 from 2011 to 2020 in the National Health and Nutrition Examination Survey (NHANES). The multivariate linear regression model was used to test the association between HbA1c and SUA. Subgroup analysis was performed according to age, gender, race, and body mass index (BMI). This study solved the relationship between HbA1c and SUA by fitting a smooth curve. Finally, the inflection point in the nonlinear relationship was calculated by the recursive algorithm, and the relationship between HbA1c and SUA on both sides of the inflection point was analyzed by the two-segment piecewise linear regression model. Results: All 7293 participants found a negative correlation between HbA1c and SUA by completely adjusting the model (ß = -7.93 and 95% CI: -9.49--6.37). In addition, when this study was stratified by gender, age, race, and BMI status, this negative correlation was still statistically significant. In the subgroup analysis, we found that the relationship between the two had different results due to gender differences. In men, HbA1c had a significant negative correlation with SUA. However, in women, the HbA1c value was positively correlated with SUA before 6.8%, and the HbA1c value was negatively correlated with SUA after 6.8%, which indicates that the relationship between HbA1c and SUA in women has changed in prediabetes and diabetes. Conclusion: This study shows that HbA1c is positively correlated with SUA in American adults before 7%. There is a negative correlation after the HbA1c value of 7%.

Rat hepatocytes secrete free oligosaccharides.

We recently established a method for the isolation of serum-free oligosaccharides, and characterized various features of their structures. However, the precise mechanism for how these glycans are formed still remains unclarified. To further investigate the mechanism responsible for these serum glycans, here, we utilized rat primary hepatocytes to examine whether they are able to secrete free glycans. Our findings indicated that a diverse array of free oligosaccharides such as sialyl/neutral free N-glycans (FNGs), as well as sialyl lactose/LacNAc-type glycans, were secreted into the culture medium by primary hepatocytes. The structural features of these free glycans in the medium were similar to those isolated from the sera of the same rat. Further evidence suggested that an oligosaccharyltransferase is involved in the release of the serum-free N-glycans. Our results indicate that the liver is indeed secreting various types of free glycans directly into the serum.

Identifying potential ferroptosis key genes for diagnosis and treatment of postmenopausal osteoporosis through competitive endogenous RNA network analysis.

Objective: Postmenopausal osteoporosis (PMOP) is a common systemic metabolic bone disorder that is owing to the reduced estrogen secretion and imbalance of bone absorption and bone formation in postmenopausal women. Ferroptosis has been identified as a novel modulatory mechanism of osteoporosis. Nevertheless, the particular modulatory mechanism between ferroptosis and PMOP is still unclear. The objective of the current investigation was to detect potential biomarkers connected to ferroptosis in PMOP and discover its probable mechanism through bioinformatics. Methods: We downloaded PMOP-related microarray datasets from the database of Gene Expression Omnibus (GEO) and obtained the differentially expressed genes (DEGs). Utilizing bioinformatics analysis, the DEGs were intersected with the ferroptosis dataset to obtain ferroptosis-connected mRNAs. Enrichment analysis employing KOBAS 3.0 was conducted to comprehend the biological functions and enrichment pathways of the DEGs. The generation of the protein-protein interaction (PPI) network was conducted with the aim of identifying central genes. Lastly, the coexpression and competitive endogenous RNA (ceRNA) networks were built using Cytoscape. With the help of external datasets GSE56815 to verify the reliability of the hub genes by plotting ROC curves. Results: We identified 178 DE microRNAs (miRNAs), 138 DE circular RNAs (circRNAs), and 86 ferroptosis-related mRNAs. Enrichment analysis exhibited that mRNAs were primarily connected with the signaling pathways of PI3K/Akt, metabolism, mTOR, FoxO, HIF-1, AMPK, MAPK, ferroptosis, VEGF, and NOD-like receptors. Generation of the PPI network detected eight hub genes. The circRNA/miR-23b-3p/PTEN axis may relieve PMOP by inhibiting ferroptosis through targeting the pathway of PI3K/Akt signaling, which is a vital modulatory pathway for PMOP progression. Moreover, the ROC curves ultimately indicates that the four hub genes have greater diagnostic importance in PMOP samples in contrast to the normal group samples, which may be possible markers for PMOP diagnosis. Conclusions: Bioinformatics analysis identified four hub genes, namely, PTEN, SIRT1, VEGFA, and KRAS, as potential biomarkers for PMOP diagnosis and management. Moreover, the circRNA/miR-23b-3p/PTEN axis may relieve PMOP by suppressing ferroptosis through targeting the pathway of PI3K/Akt signaling, providing a new avenue to explore the pathogenesis of PMOP.

RGD-p21Ras-scFv expressed prokaryotically on a pilot scale inhibits ras-driven colorectal cancer growth by blocking p21Ras-GTP.

BACKGROUND: Ras gene mutation and/or overexpression are drivers in the progression of cancers, including colorectal cancer. Blocking the Ras signaling has become a significant strategy for cancer therapy. Previously, we constructed a recombinant scFv, RGD-p21Ras-scFv by linking RGD membrane-penetrating peptide gene with the anti-p21Ras scFv gene. Here, we expressed prokaryotically RGD-p21Ras-scFv on a pilot scale, then investigated the anti-tumor effect and the mechanism of blocking Ras signaling. METHODS: The E. coli bacteria which could highly express RGD-p21Ras-scFv was screened and grown in 100 L fermentation tank to produce RGD-p21Ras-scFv on optimized induced expression conditions. The scFv was purified from E. coli bacteria using His Ni-NTA column. ELISA was adopted to test the immunoreactivity of RGD-p21Ras-scFv against p21Ras proteins, and the IC50 of RGD-p21Ras-scFv was analyzed by CCK-8. Immunofluorescence colocalization and pull-down assays were used to determine the localization and binding between RGD-p21Ras-scFv and p21Ras. The interaction forces between RGD-p21Ras-scFv and p21Ras after binding were analyzed by molecular docking, and the stability after binding was determined by molecular dynamics simulations. p21Ras-GTP interaction was detected by Ras pull-down. Changes in the MEK-ERK /PI3K-AKT signaling paths downstream of Ras were detected by WB assays. The anti-tumor activity of RGD-p21Ras-scFv was investigated by nude mouse xenograft models. RESULTS: The technique of RGD-p21Ras-scFv expression on a pilot scale was established. The wet weight of the harvested bacteria was 31.064 g/L, and 31.6 mg RGD-p21Ras-scFv was obtained from 1 L of bacterial medium. The purity of the recombinant antibody was above 85%, we found that the prepared on a pilot scale RGD-p21Ras-scFv could penetrate the cell membrane of colon cancer cells and bind to p21Ras, then led to reduce of p21Ras-GTP (active p21Ras). The phosphorylation of downstream effectors MEK-ERK /PI3K-AKT was downregulated. In vivo antitumor activity assays showed that the RGD-p21Ras-scFv inhibited the proliferation of colorectal cancer cell lines. CONCLUSION: RGD-p21Ras-scFv prokaryotic expressed on pilot-scale could inhibited Ras-driven colorectal cancer growth by partially blocking p21Ras-GTP and might be able to be a hidden therapeutic antibody for treating RAS-driven tumors.

Hydrolytic activity of yeast oligosaccharyltransferase is enhanced when misfolded proteins accumulate in the endoplasmic reticulum.

It is known that oligosaccharyltransferase (OST) has hydrolytic activity toward dolichol-linked oligosaccharides (DLO), which results in the formation of free N-glycans (FNGs), i.e. unconjugated oligosaccharides with structural features similar to N-glycans. The functional importance of this hydrolytic reaction, however, remains unknown. In this study, the hydrolytic activity of OST was characterized in yeast. It was shown that the hydrolytic activity of OST is enhanced in ubiquitin ligase mutants that are involved in endoplasmic reticulum-associated degradation. Interestingly, this enhanced hydrolysis activity is completely suppressed in asparagine-linked glycosylation (alg) mutants, bearing mutations related to the biosynthesis of DLO, indicating that the effect of ubiquitin ligase on OST-mediated hydrolysis is context-dependent. The enhanced hydrolysis activity in ubiquitin ligase mutants was also found to be canceled upon treatment of the cells with dithiothreitol, a reagent that potently induces protein unfolding in the endoplasmic reticulum (ER). Our results clearly suggest that the hydrolytic activity of OST is enhanced under conditions in which the formation of unfolded proteins is promoted in the ER in yeast. The possible role of FNGs on protein folding is discussed.

GreenPhos, a universal method for in-depth measurement of plant phosphoproteomes with high quantitative reproducibility.

Protein phosphorylation regulates a variety of important cellular and physiological processes in plants. In-depth profiling of plant phosphoproteomes has been more technically challenging than that of animal phosphoproteomes. This is largely due to the need to improve protein extraction efficiency from plant cells, which have a dense cell wall, and to minimize sample loss resulting from the stringent sample clean-up steps required for the removal of a large amount of biomolecules interfering with phosphopeptide purification and mass spectrometry analysis. To this end, we developed a method with a streamlined workflow for highly efficient purification of phosphopeptides from tissues of various green organisms including Arabidopsis, rice, tomato, and Chlamydomonas reinhardtii, enabling in-depth identification with high quantitative reproducibility of about 11 000 phosphosites, the greatest depth achieved so far with single liquid chromatography-mass spectrometry (LC-MS) runs operated in a data-dependent acquisition (DDA) mode. The mainstay features of the method are the minimal sample loss achieved through elimination of sample clean-up before protease digestion and of desalting before phosphopeptide enrichment and hence the dramatic increases of time- and cost-effectiveness. The method, named GreenPhos, combined with single-shot LC-MS, enabled in-depth quantitative identification of Arabidopsis phosphoproteins, including differentially phosphorylated spliceosomal proteins, at multiple time points during salt stress and a number of kinase substrate motifs. GreenPhos is expected to serve as a universal method for purification of plant phosphopeptides, which, if samples are further fractionated and analyzed by multiple LC-MS runs, could enable measurement of plant phosphoproteomes with an unprecedented depth using a given mass spectrometry technology.

Terahertz Liquid Biosensor Based on A Graphene Metasurface for Ultrasensitive Detection with A Quasi-Bound State in the Continuum.

The concept of a quasi-bound state in a continuum (QBIC) has garnered significant attention in various fields such as sensing, communication, and optical switching. Within metasurfaces, QBICs offer a reliable platform that enables sensing capabilities through potent interactions between local electric fields and matter. Herein, a novel terahertz (THz) biosensor based on the integration of QBIC with graphene is reported, which enables multidimensional detection. The proposed biosensor is distinctive because of its ability to discern concentrations of ethanol and N-methylpyrrolidone in a wide range from 100% to 0%, by monitoring the changes in the resonance intensity and maximum wavelet coefficient. This approach demonstrates an excellent linear fit, which ensures robust quantitative analysis. The remarkable sensitivity of our biosensor enables it to detect minute changes in low-concentration solutions, with the lowest detection concentration value (LDCV) of 0.21 pg mL-1 . 2D wavelet coefficient intensity cards are effectively constructed through continuous wavelet transforms, which presents a more accurate approach for determining the concentration of the solution. Ultimately, the novel sensing platform offers a host of advantages, including heightened sensitivity and reusability. This pioneering approach establishes a new avenue for liquid-based terahertz biosensing.

Automated customization of large-scale spiking network models to neuronal population activity.

Understanding brain function is facilitated by constructing computational models that accurately reproduce aspects of brain activity. Networks of spiking neurons capture the underlying biophysics of neuronal circuits, yet the dependence of their activity on model parameters is notoriously complex. As a result, heuristic methods have been used to configure spiking network models, which can lead to an inability to discover activity regimes complex enough to match large-scale neuronal recordings. Here we propose an automatic procedure, Spiking Network Optimization using Population Statistics (SNOPS), to customize spiking network models that reproduce the population-wide covariability of large-scale neuronal recordings. We first confirmed that SNOPS accurately recovers simulated neural activity statistics. Then, we applied SNOPS to recordings in macaque visual and prefrontal cortices and discovered previously unknown limitations of spiking network models. Taken together, SNOPS can guide the development of network models and thereby enable deeper insight into how networks of neurons give rise to brain function.

Effects of Blocking NLRP3 Inflammasome on Type II Innate Lymphoid Cell Response in Allergic Rhinitis.

Background: Type 2 innate lymphoid cells (ILC2s) and NLRP3 inflammasome are related to allergic and inflammatory responses. NLRP3 inflammasome inhibitor MCC950 was demonstrated to ameliorate allergic rhinitis (AR) in animal models. Objective: To elucidate the effect of MCC950 on ILC2 responses in AR. Methods: NLRP3 inflammasome, ILC2s, IL-5+ILC2s, IL-13+ILC2s, and Th2-related factors were examined in 30 AR patients. ILC2s were identified as Lin-CRTH2+CD127+lymphocytes. ILC2s isolated from PBMCs were stimulated with LPS plus ATP. The effect of MCC950, IL-1ß, and IL-18 on ILC2 responses was detected by flow cytometry. AR models were established in 60 BALB/c mice. Nasal symptoms and ILC2 responses in the AR models after MCC950 treatment were detected. Human nasal epithelial cells were stimulated with IL-13 (10 ng/mL) and treated with MCC950 (10 µM). Results: AR patients showed activated NLRP3 inflammasome and increased ILC2 responses compared to controls. NLRP3 inflammasome levels in the AR patients were positively related to the proportion of ILC2s, IL-5+ILC2s, and IL-13+ILC2s in total PBMCs. MCC950 treatment or IL-1ß/IL-18 suppression inhibited ILC2 proliferation and Th2-related factors (GATA3, RORα, IL-5, and IL-13). MCC950 administration alleviated frequencies of nasal rubbing and sneezes in the AR models. ILC2s, IL-5+ILC2s, and IL-13+ILC2s in mice were reduced by MCC950. MCC950 inhibited NLRP3 inflammasome in the in vitro models of AR. Conclusion: MCC950 inhibited ILC2 responses in AR and mice models, suggesting that blocking NLRP3 inflammasome may be a promising target for AR clinical treatment.

Association between the Weight-Adjusted Waist Index and Serum Uric Acid: A Cross-Sectional Study.

Background: Serum uric acid (SUA) was closely related to body metabolism. This study aimed to investigate the relationship between the adult weight-adjusted waist index (WWI) and SUA. Methods: In the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2020, 6494 eligible participants aged ≥20 were included. The multivariate logistic regression model was used to test the correlation between WWI and SUA. At the same time, subgroup analysis was carried out by using multivariate logistic regression according to age, sex, and race. Then, the fitting smooth curve was applied to solve the association between WWI and SUA. Finally, the recursive algorithm was used to calculate the inflection point in the nonlinear relationship, and the two-stage piecewise linear regression model was used to analyze the relationship between WWI and SUA on both sides of the inflection point. Results: In all the 6494 participants, through the fully adjusted model, this study found that there was a positive correlation between WWI and SUA (ß = 5.64; 95% CI: 2.62 and 8.66). In addition, this positive correlation still had certain statistical significance in the subgroup analysis stratified by sex, age, and race. Our research team found a significant positive correlation between the WWI and SUA in females, but the correlation was not significant in males. We also found a small inverted U-shaped curve between the WWI and SUA in men when we stratified the sex subgroups. The small inflection point was determined to be 11.5 cm/√ kg. In racial subgroup analysis, we also found a U-shaped relationship between the WWI and SUA in non-Hispanic White and other race/ethnicity (the inflection point was 11.08 cm/√ kg and 12.14 cm/√ kg, respectively). Conclusion: This study showed that the WWI was a newly developed and new predictor of centripetal obesity independent of body weight and there was a positive correlation between the WWI and SUA.

Topological insights into the neural basis of flexible behavior.

It is widely accepted that there is an inextricable link between neural computations, biological mechanisms, and behavior, but it is challenging to simultaneously relate all three. Here, we show that topological data analysis (TDA) provides an important bridge between these approaches to studying how brains mediate behavior. We demonstrate that cognitive processes change the topological description of the shared activity of populations of visual neurons. These topological changes constrain and distinguish between competing mechanistic models, are connected to subjects' performance on a visual change detection task, and, via a link with network control theory, reveal a tradeoff between improving sensitivity to subtle visual stimulus changes and increasing the chance that the subject will stray off task. These connections provide a blueprint for using TDA to uncover the biological and computational mechanisms by which cognition affects behavior in health and disease.

Parallel Proteomic Comparison of Mutants With Altered Carbon Metabolism Reveals Hik8 Regulation of PII Phosphorylation and Glycogen Accumulation in a Cyanobacterium.

Carbon metabolism is central to photosynthetic organisms and involves the coordinated operation and regulation of numerous proteins. In cyanobacteria, proteins involved in carbon metabolism are regulated by multiple regulators including the RNA polymerase sigma factor SigE, the histidine kinases Hik8, Hik31 and its plasmid-borne paralog Slr6041, and the response regulator Rre37. To understand the specificity and the cross-talk of such regulations, we simultaneously and quantitatively compared the proteomes of the gene knockout mutants for the regulators. A number of proteins showing differential expression in one or more mutants were identified, including four proteins that are unanimously upregulated or downregulated in all five mutants. These represent the important nodes of the intricate and elegant regulatory network for carbon metabolism. Moreover, serine phosphorylation of PII, a key signaling protein sensing and regulating in vivo carbon/nitrogen (C/N) homeostasis through reversible phosphorylation, is massively increased with a concomitant significant decrease in glycogen content only in the hik8-knockout mutant, which also displays impaired dark viability. An unphosphorylatable PII S49A substitution restored the glycogen content and rescued the dark viability of the mutant. Together, our study not only establishes the quantitative relationship between the targets and the corresponding regulators and elucidated their specificity and cross-talk but also unveils that Hik8 regulates glycogen accumulation through negative regulation of PII phosphorylation, providing the first line of evidence that links the two-component system with PII-mediated signal transduction and implicates them in the regulation of carbon metabolism.

Effect of Sintering Temperature and Solution Treatment on Phase Changes and Mechanical Properties of High-Nitrogen Stainless Steel Prepared by MIM.

High-nitrogen stainless steel (HNSS) has been widely concerned and studied owing to its excellent mechanical, corrosion resistance, and biocompatibility properties. A series of HNSS was prepared by metal injection molding (MIM) using gas atomized Fe-Cr-Mn-Mo-0.3 N duplex stainless steel powders. Both sintering and solution treatments were carried out in an N2 atmosphere. The effects of nitrogen distribution and phase transformation on the mechanical properties of MIM HNSS during sintering and solution were studied. The results show that as the sintering temperature increased, the sample density increased, but the total nitrogen content decreased. Nitrogen and Cr2N concentration gradients along the cross-section of as-sintered samples were formed after cooling. The high nitrogen content promotes the decomposition of γ: γsaturated translated to γ and Cr2N. Meanwhile, the low Mn content in austenite also decomposes γ: γ translated to α and Cr2N. After solution treatment, a single γ phase was obtained for samples sintered at 1200 to 1320 °C. For solution treatment samples sintered at 1320 and 1350 °C, their tensile strength was 988.76 and 1036.12 MPa; yield strength was 615.61 and 636.14 MPa, and elongation was 42.58 and 40.08%, respectively. These values vastly exceeded the published MIM HNSS values.

Spatial Proteome Reorganization of a Photosynthetic Model Cyanobacterium in Response to Abiotic Stresses.

Spatial proteome reorganization in response to a changing environment represents a different layer of adaptation mechanism in addition to differential expression of a subset of stress responsive genes in photosynthetic organisms. Profiling such reorganization events is critically important to extend our understanding how photosynthetic organisms adapt to adverse environments. Thus, we treated a unicellular photosynthetic model cyanobacterium, Synechocystis sp. PCC 6803 (hereafter referred to as Synechocystis), with five different types of abiotic stresses including nitrogen starvation, iron deficiency, cold, heat, and darkness, and systematically identified proteins showing stress-induced differential expression and/or redistribution between the membrane and the soluble fractions using a quantitative proteomics approach. A number of proteins showing such a redistribution in response to a single or multiple types of abiotic stresses were identified. These include 12 ribosomal proteins displaying unanimous cold-induced redistribution to the membrane and the protein FurA, a master regulator of iron acquisition, displaying iron deficiency- and nitrogen starvation-induced redistribution to the membrane. Such findings shed light on a novel regulatory mechanism underlying the corresponding stress responses, and establish the results in the present study as an important resource for future studies intended to understand how photosynthetic organisms cope with adverse environments.