VSG-GAN: A high-fidelity image synthesis method with semantic manipulation in retinal fundus image.

In recent years, advancements in retinal image analysis, driven by machine learning and deep learning techniques, have enhanced disease detection and diagnosis through automated feature extraction. However, challenges persist, including limited data set diversity due to privacy concerns and imbalanced sample pairs, hindering effective model training. To address these issues, we introduce the vessel and style guided generative adversarial network (VSG-GAN), an innovative algorithm building upon the foundational concept of GAN. In VSG-GAN, a generator and discriminator engage in an adversarial process to produce realistic retinal images. Our approach decouples retinal image generation into distinct modules: the vascular skeleton and background style. Leveraging style transformation and GAN inversion, our proposed hierarchical variational autoencoder module generates retinal images with diverse morphological traits. In addition, the spatially adaptive denormalization module ensures consistency between input and generated images. We evaluate our model on MESSIDOR and RITE data sets using various metrics, including structural similarity index measure, inception score, Fréchet inception distance, and kernel inception distance. Our results demonstrate the superiority of VSG-GAN, outperforming existing methods across all evaluation assessments. This underscores its effectiveness in addressing data set limitations and imbalances. Our algorithm provides a novel solution to challenges in retinal image analysis by offering diverse and realistic retinal image generation. Implementing the VSG-GAN augmentation approach on downstream diabetic retinopathy classification tasks has shown enhanced disease diagnosis accuracy, further advancing the utility of machine learning in this domain.

AIM2 inflammasome: A potential therapeutic target in ischemic stroke.

Ischemic stroke (IS) is a significant global public health issue with a high incidence, disability, and mortality rate. A robust inflammatory cascade with complex and wide-ranging mechanisms occurs following ischemic brain injury. Inflammasomes are multiprotein complexes in the cytoplasm that modulate the inflammatory response by releasing pro-inflammatory cytokines and inducing cellular pyroptosis. Among these inflammasomes, the Absent in Melanoma 2 (AIM2) inflammasome shows the ability to detect a wide range of pathogen DNAs, thereby triggering an inflammatory response. Recent studies have indicated that the aberrant expression of AIM2 inflammasome in various cells is closely associated with the pathological processes of ischemic brain injury. This paper summarizes the expression and regulatory role of AIM2 in CNS and peripheral immune cells and discusses current therapeutic approaches targeting AIM2 inflammasome. These findings aim to serve as a reference for future research in this field.

Cellular communication among smooth muscle cells: The role of membrane potential via connexins.

Communication via action potentials among neurons has been extensively studied. However, effective communication without action potentials is ubiquitous in biological systems, yet it has received much less attention in comparison. Multi-cellular communication among smooth muscles is crucial for regulating blood flow, for example. Understanding the mechanism of this non-action potential communication is critical in many cases, like synchronization of cellular activity, under normal and pathological conditions. In this paper, we employ a multi-scale asymptotic method to derive a macroscopic homogenized bidomain model from the microscopic electro-neutral (EN) model. This is achieved by considering different diffusion coefficients and incorporating nonlinear interface conditions. Subsequently, the homogenized macroscopic model is used to investigate communication in multi-cellular tissues. Our computational simulations reveal that the membrane potential of syncytia, formed by interconnected cells via connexins, plays a crucial role in propagating oscillations from one region to another, providing an effective means for fast cellular communication. Statement of Significance: In this study, we investigated cellular communication and ion transport in vascular smooth muscle cells, shedding light on their mechanisms under normal and abnormal conditions. Our research highlights the potential of mathematical models in understanding complex biological systems. We developed effective macroscale electro-neutral bi-domain ion transport models and examined their behavior in response to different stimuli. Our findings revealed the crucial role of connexinmediated membrane potential changes and demonstrated the effectiveness of cellular communication through syncytium membranes. Despite some limitations, our study provides valuable insights into these processes and emphasizes the importance of mathematical modeling in unraveling the complexities of cellular communication and ion transport.

Astrocytes in ischemic stroke: Crosstalk in central nervous system and therapeutic potential.

In the central nervous system (CNS), a large group of glial cells called astrocytes play important roles in both physiological and disease conditions. Astrocytes participate in the formation of neurovascular units and interact closely with other cells of the CNS, such as microglia and neurons. Stroke is a global disease with high mortality and disability rate, most of which are ischemic stroke. Significant strides in understanding astrocytes have been made over the past few decades. Astrocytes respond strongly to ischemic stroke through a process known as activation or reactivity. Given the important role played by reactive astrocytes (RAs) in different spatial and temporal aspects of ischemic stroke, there is a growing interest in the potential therapeutic role of astrocytes. Currently, interventions targeting astrocytes, such as mediating astrocyte polarization, reducing edema, regulating glial scar formation, and reprogramming astrocytes, have been proven in modulating the progression of ischemic stroke. The aforementioned potential interventions on astrocytes and the crosstalk between astrocytes and other cells of the CNS will be summarized in this review.

The gut microbiome: an important role in neurodegenerative diseases and their therapeutic advances.

There are complex interactions between the gut and the brain. With increasing research on the relationship between gut microbiota and brain function, accumulated clinical and preclinical evidence suggests that gut microbiota is intimately involved in the pathogenesis of neurodegenerative diseases (NDs). Increasingly studies are beginning to focus on the association between gut microbiota and central nervous system (CNS) degenerative pathologies to find potential therapies for these refractory diseases. In this review, we summarize the changes in the gut microbiota in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis and contribute to our understanding of the function of the gut microbiota in NDs and its possible involvement in the pathogenesis. We subsequently discuss therapeutic approaches targeting gut microbial abnormalities in these diseases, including antibiotics, diet, probiotics, and fecal microbiota transplantation (FMT). Furthermore, we summarize some completed and ongoing clinical trials of interventions with gut microbes for NDs, which may provide new ideas for studying NDs.

Mimicking effects of cholesterol in lipid bilayer membranes by self-assembled amphiphilic block copolymers.

The effect of cholesterol on biological membranes is important in biochemistry. In this study, a polymer system is used to simulate the consequences of varying cholesterol content in membranes. The system consists of an AB-diblock copolymer, a hydrophilic homopolymer hA, and a hydrophobic rigid homopolymer C, corresponding to phospholipid, water, and cholesterol, respectively. The effect of the C-polymer content on the membrane is studied within the framework of a self-consistent field model. The results show that the liquid-crystal behavior of B and C has a great influence on the chemical potential of cholesterol in bilayer membranes. The effects of the interaction strength between components, characterized by the Flory-Huggins parameters and the Maier-Saupe parameter, were studied. Some consequences of adding a coil headgroup to the C-rod are presented. Results of our model are compared to experimental findings for cholesterol-containing lipid bilayer membranes.

New Insights into Stroke Prevention and Treatment: Gut Microbiome.

Stroke, a lethal neurological disease, accounts for a grave economic burden on society. Despite extensive basic and clinical studies on stroke prevention, a precise effective treatment approach for stroke at this stage remains unavailable. The majority of our body's gut microbiota plays a vital role in food digestion, immune regulation, and nervous system development, which is highly associated with the development of some diseases. Multiple clinical studies have documented variation in the composition of gut microbiota between stroke patients and healthy counterparts. Moreover, the intervention of intestinal symbiotic microorganisms via several mechanisms plays an active role in stroke prognosis. In the prevention and treatment of stroke, the gut microbiota gives off a seductive glow, this is a promising therapeutic target. This paper summarizes the current knowledge of stroke and gut microbiota, and systematically describes the possible mechanisms of interaction between stroke and gut microbiota, the relationship between stroke-related risk factors and gut microbiota, and the treatment of gut flora using microorganisms. Thus, it could valuably elucidate the correlation of gut microbiota with stroke incidence, providing stroke researchers with a new strategy for stroke prevention and treatment by regulating gut microbiota.

A tridomain model for potassium clearance in optic nerve of Necturus.

Complex fluids flow in complex ways in complex structures. Transport of water and various organic and inorganic molecules in the central nervous system are important in a wide range of biological and medical processes. However, the exact driving mechanisms are often not known. In this work, we investigate flows induced by action potentials in an optic nerve as a prototype of the central nervous system. Different from traditional fluid dynamics problems, flows in biological tissues such as the central nervous system are coupled with ion transport. They are driven by osmosis created by concentration gradient of ionic solutions, which in turn influence the transport of ions. Our mathematical model is based on the known structural and biophysical properties of the experimental system used by the Harvard group Orkand et al. Asymptotic analysis and numerical computation show the significant role of water in convective ion transport. The full model (including water) and the electrodiffusion model (excluding water) are compared in detail to reveal an interesting interplay between water and ion transport. In the full model, convection due to water flow dominates inside the glial domain. This water flow in the glia contributes significantly to the spatial buffering of potassium in the extracellular space. Convection in the extracellular domain does not contribute significantly to spatial buffering. Electrodiffusion is the dominant mechanism for flows confined to the extracellular domain.

A mathematical model for persistent post-CSD vasoconstriction.

Cortical spreading depression (CSD) is the propagation of a relatively slow wave in cortical brain tissue that is linked to a number of pathological conditions such as stroke and migraine. Most of the existing literature investigates the dynamics of short term phenomena such as the depolarization and repolarization of membrane potentials or large ion shifts. Here, we focus on the clinically-relevant hour-long state of neurovascular malfunction in the wake of CSDs. This dysfunctional state involves widespread vasoconstriction and a general disruption of neurovascular coupling. We demonstrate, using a mathematical model, that dissolution of calcium that has aggregated within the mitochondria of vascular smooth muscle cells can drive an hour-long disruption. We model the rate of calcium clearance as well as the dynamical implications on overall blood flow. Based on reaction stoichiometry, we quantify a possible impact of calcium phosphate dissolution on the maintenance of F0F1-ATP synthase activity.

Emergence of livestock-associated MRSA ST398 from bulk tank milk, China.

OBJECTIVES: To detect livestock-associated MRSA (LA-MRSA) ST398 from bulk tank milk in China and to determine the phenotypic and genomic characteristics of the strains. METHODS: LA-MRSA ST398 strains were isolated from bulk tank milk samples in Shanghai and their susceptibilities to antimicrobials were determined using the broth dilution method. Genomic characterization of MRSA ST398 strains was performed by WGS and their evolutionary relationships were assessed by phylogenetic analysis. RESULTS: Two LA-MRSA ST398 isolates were recovered from bulk tank milk samples in two geographically distant farms in China. Whole-genome analysis strongly suggested that the LA-MRSA ST398 strains were closely related to the highly virulent hospital-associated MRSA (HA-MRSA) ST398 strains in China. CONCLUSIONS: The presence of LA-MRSA ST398 in bulk tank milk might be a serious threat to public health, highlighting the need for active surveillance of LA-MRSA in healthy cattle in China.

A Bidomain Model for Lens Microcirculation.

There exists a large body of research on the lens of the mammalian eye over the past several decades. The objective of this work is to provide a link between the most recent computational models and some of the pioneering work in the 1970s and 80s. We introduce a general nonelectroneutral model to study the microcirculation in the lens of the eye. It describes the steady-state relationships among ion fluxes, between water flow and electric field inside cells, and in the narrow extracellular spaces between cells in the lens. Using asymptotic analysis, we derive a simplified model based on physiological data and compare our results with those in the literature. We show that our simplified model can be reduced further to the first-generation models, whereas our full model is consistent with the most recent computational models. In addition, our simplified model captures in its equations the main features of the full computational models. Our results serve as a useful link intermediate between the computational models and the first-generation analytical models. Simplified models of this sort may be particularly helpful as the roles of similar osmotic pumps of microcirculation are examined in other tissues with narrow extracellular spaces, such as cardiac and skeletal muscle, liver, kidney, epithelia in general, and the narrow extracellular spaces of the central nervous system, the "brain." Simplified models may reveal the general functional plan of these systems before full computational models become feasible and specific.

Formononetin ameliorates cholestasis by regulating hepatic SIRT1 and PPARα.

Cholestasis, which is characterized by bile acid (BA) overload within the hepatocytes, is a major contributor to liver injury. The dysregulation of bile acid homeostasis, such as excessive bile acid synthesis and defected secretion, leads to intracellular retention of hydrophobic bile acid which undermines the physiological function of hepatocytes. Cholestasis can further develop into hepatic fibrosis and cirrhosis, and eventually life-threating liver failure. In the liver, BA-activated FXR can reduce hepatic BA concentration by negative feedback regulation. Clinically, FXR and PPARα are the pharmacological targets of obeticholic acid and fenofibrate for the treatment of primary biliary cirrhosis, respectively. Formononetin, a natural isoflavone compound, exerts beneficial effects in various biological processes, such as anti-inflammation, anti-tumor. However, the role of formononetin in bile acid metabolism remains unclear. Herein, we show that formononetin improves hepatic/systemic bile acid metabolism and protects against ANIT-induced liver injury. Mechanistically, formononetin improves the genes profile orchestrating bile acid homeostasis through modulating SIRT1-FXR signaling pathway. Moreover, formononetin attenuated ANIT-induced inflammatory response by inactivating JNK inflammation pathway in PPARα dependent manner. Taken together, our study demonstrates that formononetin ameliorates hepatic cholestasis by upregulating expression of SIRT1 and activating PPARα, which is an important anti-cholestatic mechanism of formononetin.

MMP Gene Polymorphisms, MMP-1 -1607 1G/2G, -519 A/G, and MMP-12 -82 A/G, and Ischemic Stroke: A Meta-Analysis.

BACKGROUND: Several polymorphisms in the human gene encoding MMP have been investigated for the association with ischemic stroke (IS) in the population, of which the MMP-1 -1607 1G/2G, -519 A/G, and MMP-12 -82 A/G polymorphisms gain more and more attention; however, the results are controversial and ambiguous. We therefore carried out the meta-analysis to yield a valid conclusion. METHODS: The literature database was comprehensively searched to identify potentially eligible reports. RESULTS: A total of 15 studies with 3237 cases and 3075 controls were included in this meta-analysis. CONCLUSIONS: There was a significant association in MMP-1 -1607 1G/2G and MMP-12 -82 A/G gene polymorphisms, but none was observed in MMP-1 -519 A/G. When a subgroup analysis by ethnicity and HWE, MMP-12 -82 A/G gene polymorphisms may be a risk factor for IS in Europe. In Africa, MMP-1 -1607 1G/2G and MMP-12 -82 A/G also showed a significant effect on IS. Further investigation on a larger sample size of different ethnic populations is needed to confirm the findings.

Cannabinoid 2 Receptor Agonist Improves Systemic Sensitivity to Insulin in High-Fat Diet/Streptozotocin-Induced Diabetic Mice.

BACKGROUND/AIMS: The endocannabinoid signalling (ECS) system has been known to regulate glucose homeostasis. Previous studies have suggested that the cannabinoid 2 (CB2) receptor may play a regulatory role on insulin secretion, immune modulation and insulin resistance. Given that diabetes and insulin resistance are attributable to elevated inflammatory tone, we investigated the role of CB2 receptor on glucose tolerance and insulin sensitivity in high-fat diet (HFD)/streptozotocin (STZ)-induced mice. METHODS: Diabetes was induced in male ICR mice by HFD/STZ and exposed to a CB2 receptor agonist, SER601, for 2- or 4-weeks via subcutaneous implantation of osmotic minipumps. Glucose and insulin tolerance tests were performed at the end of treatment. Islets were isolated for assessment of ß-cell function. Pancreases and skeletal muscles were also obtained for histological analyses. RESULTS: Despite a lack of impact on glucose tolerance, substantial improvement on insulin sensitivity was observed in SER601-treated mice, which could partly be attributed to improved islet ß-cell function, shown as increased glucose-induced insulin secretion and insulin content. No changes on islet macrophage infiltration or skeletal muscle fat deposition were detectable from SER601-treated mice. However, a major decrease in body weight was recorded at the end of 4-week SER601 exposure, accompanied by a lack of epididymal adipose mass in SER601-treated mice. CONCLUSION: Our data suggest a lipolytic role of SER601 in HFD/STZ-induced diabetic mice, which results in significant improvement of systemic insulin sensitivity. Thus, the CB2 receptor may be considered a promising target for therapeutic development against insulin resistance and obesity-related diabetes.

Dual actions of Netrin-1 on islet insulin secretion and immune modulation.

Netrin-1 is typically known as a neural guidance cue, which has been implicated in pancreas development. Since regenerative, angiogenic and anti-inflammatory properties of Netrin-1 have been reported in multiple tissues, we have investigated the potential role of Netrin-1 in the endocrine islet and its implication in mice with high-fat diet (HFD)/streptozotocin (STZ)-induced diabetes. Effects of exogenous Netrin-1 on ß-cell [Ca(2+)]i, cyclic AMP (cAMP) and insulin production were assessed in vitro The long-term impact of Netrin-1 treatment was then evaluated in HFD/STZ-induced diabetic mice by subcutaneous implantation of osmotic minipumps which release Netrin-1 in a sustained manner for 4 weeks. Immunostaining of pancreases of Netrin-1-treated and control animals were employed to examine islet morphology, vascularization and macrophage infiltration. Plasma insulin, glucagon and pro-inflammatory cytokine concentrations were quantified by ELISA. Expression of endogenous Netrin-1 was also assessed by PCR and immunohistochemistry. We observed a stimulatory effect of Netrin-1 on in vitro insulin secretion by promoting ß-cell Ca(2+) influx and cAMP production. After 4-week continuous exposure, a hypoglycaemic property of Netrin-1 was demonstrated, which is probably attributable to improved ß-cell function, shown as increased insulin content and preproinsulin mRNA expression. Enhanced islet vascularization, reduced islet macrophage infiltration and ameliorated systemic inflammation were detected from HFD/STZ-induced diabetic mice after Netrin-1 administration. We propose a dual action of Netrin-1 in islets during pathophysiological hyperglycaemia: by maintaining insulin secretion while attenuating inflammation.

Preparation of valnemulin hydrogen fumarate and its enhanced stability compared with valnemulin hydrochloride.

CONTEXT: It is necessary to develop a new salt of valnemulin to replace the veterinary antibiotic, e.g. valnemulin hydrochloride, in order to overcome its instability during storage and preparation. OBJECTIVE: The objective of this study was to prepare a novel organic acid salt, valnemulin hydrogen fumarate, and to investigate its stability compared with valnemulin hydrochloride. MATERIALS AND METHODS: The crystal of valnemulin hydrogen fumarate was prepared by modified crystallization method; the enhanced stabilities of valnemulin hydrogen fumarate were conducted under irradiation and humid conditions, and the experimental results were simulated at AM1 level of calculations. RESULTS: Valnemulin hydrogen fumarate was more stable than valnemulin hydrochloride. After irradiation for 180 days, the content of valnemulin hydrogen fumarate decreased slightly 2.7%, whereas the content of valnemulin hydrochloride had an obvious decrease of 32.8%. Meanwhile, valnemulin hydrogen fumarate showed better anti-RH (relative humidity) ability than valnemulin hydrochloride. Under conditions of 65% and 85% RH, the absorption values of valnemulin hydrogen fumarate towards water were 0.75% and 1.20% at 48 h, whereas those of valnemulin hydrochloride were 4.50% and 9.71%, respectively. CONCLUSION: The enhanced stability of valnemulin hydrogen fumarate could be attributed to its good crystallinity in comparison with the amorphous valnemulin hydrochloride.

MicroRNAs Regulate Mitochondrial Function in Cerebral Ischemia-Reperfusion Injury.

Cerebral ischemia-reperfusion injury involves multiple independently fatal terminal pathways in the mitochondria. These pathways include the reactive oxygen species (ROS) generation caused by changes in mitochondrial membrane potential and calcium overload, resulting in apoptosis via cytochrome c (Cyt c) release. In addition, numerous microRNAs are associated with the overall process. In this review, we first briefly summarize the mitochondrial changes in cerebral ischemia-reperfusion and then describe the possible molecular mechanism of miRNA-regulated mitochondrial function, which likely includes oxidative stress and energy metabolism, as well as apoptosis. On the basis of the preceding analysis, we conclude that studies of microRNAs that regulate mitochondrial function will expedite the development of treatments for cerebral ischemia-reperfusion injury.

Bone marrow mesenchymal stem cells therapy regulates sphingolipid and glycerophospholipid metabolism to promote neurological recovery in stroke rats: A metabolomics analysis.

Bone marrow mesenchymal stem cells (BMSCs) have therapeutic potential in the subacute/chronic phase of acute ischemic stroke (AIS), but the underlying mechanisms are not yet fully elucidated. There is a knowledge gap in understanding the metabolic mechanisms of BMSCs in stroke therapy. In this study, we administered BMSCs intravenously 24 h after reperfusion in rats with transient cerebral artery occlusion (MCAO). The treatment with BMSCs for 21 days significantly reduced the modified neurological severity score of MCAO rats (P < 0.01) and increased the number of surviving neurons in both the striatum and hippocampal dentate gyrus region (P < 0.01, respectively). Moreover, BMSCs treatment resulted in significant enhancements in various structural parameters of dendrites in layer V pyramidal neurons in the injured hemispheric motor cortex, including total length (P < 0.05), number of branches (P < 0.05), number of intersections (P < 0.01), and spine density (P < 0.05). Then, we performed plasma untargeted metabolomics analysis to study the metabolic changes of BMSCs on AIS. There were 65 differential metabolites identified in the BMSCs treatment group. Metabolic profiling analysis revealed that BMSCs modulate abnormal sphingolipid metabolism and glycerophospholipid metabolism, particularly affecting core members such as sphingomyelin (SM), ceramide (Cer) and sphingosine-1-phosphate (S1P). The metabolic network analysis and pathway-based compound-reaction-enzyme-gene network analysis showed that BMSCs inhibited the Cer-induced apoptotic pathway and promoted the S1P signaling pathway. These findings suggest that the enhanced effects of BMSCs on neuronal survival and synaptic plasticity after stroke may be mediated through these pathways. In conclusion, our study provides novel insight into the potential mechanisms of BMSCs treatment in stroke and sheds light on the possible clinical translation of BMSCs.

Size-Related Pathway Flux Analysis of Ultrasmall Iron Oxide Nanoparticles in Macrophage Cell RAW264.7 for Safety Evaluation.

The endocytosis, intracellular transport, and exocytosis of different-sized nanoparticles were reported to greatly affect their efficacy and biosafety. The quantitation of endocytosis and exocytosis as well as subcellular distribution of nanoparticles might be an effective approach based on transport pathway flux analysis. Thus, the key parameters that could present the effects of three different-sized ultrasmall iron oxide nanoparticles (USIONPs) were systematically investigated in RAW264.7 cells. The endocytosis and exocytosis of USIONPs were related to their sizes; 15.4 nm of S2 could be quickly and more internalized and excreted in comparison to S1 (7.8 nm) and S3 (30.7 nm). In RAW264.7 cells, USIONPs were observed in endosomes, lysosomes, the Golgi apparatus, and autophagosomes via a transmission electron microscope. Based on flux analysis of intracellular transport pathways of USIONPs, it was found that 43% of S1, 40% of S2, and 44% of S3 were individually transported extracellularly through the Golgi apparatus-involved middle-fast pathway, while 24% of S1, 23% of S2, and 26% of S3 were transported through the fast recycling endosomal pathway, and the residues were transported through the slower speed lysosomal pathway. USIONPs might be transported via size-related endocytosis and exocytosis pathways. The pathway flux could be calculated on the basis of disturbance analysis of special transporters as well as their coding genes. Because there were rate differences among these transport pathways, this pathway flux could anticipate the intracellular remaining time and distribution of different-sized nanoparticles, the function exertion, and side effects of nanomaterials. The size of the nanomaterials could be optimized for improving functions and safety.