HMGCS2 is a key ketogenic enzyme potentially involved in type 1 diabetes with high cardiovascular risk.

Diabetes increases the risk of Cardio-vascular disease (CVD). CVD is more prevalent in type 2 diabetes (T2D) than type 1 diabetes (T1D), but the mortality risk is higher in T1D than in T2D. The pathophysiology of CVD in T1D is poorly defined. To learn more about biological pathways that are potentially involved in T1D with cardiac dysfunction, we sought to identify differentially expressed genes in the T1D heart. Our study used T1D mice with severe hyperglycemia along with significant deficits in echocardiographic measurements. Microarray analysis of heart tissue RNA revealed that the T1D mice differentially expressed 10 genes compared to control. Using Ingenuity Pathway Analysis (IPA), we showed that these genes were significantly involved in ketogenesis, cardiovascular disease, apoptosis and other toxicology functions. Of these 10 genes, the 3-Hydroxy-3-Methylglutaryl-CoA Synthase 2 (HMGCS2) was the highest upregulated gene in T1D heart. IPA analysis showed that HMGCS2 was center to many biological networks and pathways. Our data also suggested that apart from heart, the expression of HMGCS2 was also different in kidney and spleen between control and STZ treated mice. In conclusion, The HMGCS2 molecule may potentially be involved in T1D induced cardiac dysfunction

Pore-scale Modelling of Gravity-driven Drainage in Disordered Porous Media

Multiphase flow through a porous medium involves complex interactions between gravity, wettability and capillarity during drainage process. In contrast to these factors, the effect of pore distribution on liquid retention is less understood. In particular, the quantitative correlation between the fluid displacement and level of disorder has not yet been established. In this work, we employ direct numerical simulation by solving the Navier-Stokes equations and using volume of fluid method to track the liquid-liquid interface during drainage in disordered porous media. The disorder of pore configuration is characterized by an improved index to capture small microstructural perturbation, which is pivotal for fluid displacement in porous media. Then, we focus on the residual volume and morphological characteristics of saturated zones after drainage and compare the effect of disorder under different wettability (i.e., the contact angle) and gravity (characterized by a modified Bond number) conditions. Pore-scale simulations reveal that the highly-disordered porous medium is favourable to improve liquid retention and provide various morphologies of entrapped saturated zones. Furthermore, the disorder index has a positive correlation to the characteristic curve index (n) in van Genuchten equation, controlling the shape of the retention characteristic curves. It is expected that the findings will benefit to a broad range of industrial applications involving drainage processes in porous media, e.g., drying, carbon sequestration, and underground water remediation.Comment: 22 pages, 8 figure

What if keys are leaked? Towards practical and secure re-encryption in deduplication-based cloud storage

By only storing a unique copy of duplicate data possessed by different data owners, deduplication can significantly reduce storage cost, and hence is used broadly in public clouds. When combining with confidentiality, deduplication will become problematic as encryption performed by different data owners may differentiate identical data which may then become not deduplicable. The Message-Locked Encryption (MLE) is thus utilized to derive the same encryption key for the identical data, by which the encrypted data are still deduplicable after being encrypted by different data owners. As keys may be leaked over time, re-encrypting outsourced data is of paramount importance to ensure continuous confidentiality, which, however, has not been well addressed in the literature. In this paper, we design SEDER, a SEcure client-side Deduplication system enabling Efficient Re-encryption for cloud storage by (1) leveraging all-or-nothing transform (AONT), (2) designing a new delegated re-encryption (DRE), and (3) proposing a new proof of ownership scheme for encrypted cloud data (PoWC). Security analysis and experimental evaluation validate security and efficiency of SEDER, respectively

Pogostemon cablin essential oil affects anxiety- and depressive-like behaviors and the gut microbiota in chronic unpredictable mild stress model rats

The gut microbiota is thought to be an important factor that influences brain processes and behaviors through the gut–brain axis. Pogostemon cablin is used in traditional Chinese medicine (TCM) to treat gastrointestinal symptoms. Patchouli essential oil (PCO), the main active agent in P. cablin, is used in aromatherapy for stress relief. The aim of our study was to investigate the effects of orally administered PCO on anxiety- and depressive-like behaviors and the gut microbiota. We constructed a rat model of chronic unpredictable mild stress (CUMS) and explored the anxiolytic- and antidepressant-like effects of PCO using the open field test (OFT) and forced swim test (FST). Changes in the abundance of the gut microbiota, short-chain fatty acids (SCFAs), and other related molecules were assessed to determine the role of the gut microbiota. Our results showed that CUMS induced an anxiety-like phenotype in the OFT, which was reversed by PCO, and that PCO also significantly mitigated the depression-like behaviors caused by CUMS in the FST. Furthermore, we found that PCO increased the relative abundances of several probiotics, including Bacteroides and Blautia, and decreased the relative abundances of Ruminococcus_1 and Ruminococcus_2, which were increased by CUMS. Regarding SCFAs, the metabolites of the gut microbiota, PCO increased the concentration of propionic acid and decreased that of caproic acid. Finally, PCO restored the serotonin (5-hydroxytryptamine, 5-HT) level in the hippocampus, which had been decreased by CUMS. The results of this study suggested that PCO can improve stress-related anxiety- and depression-like behaviors and might exert its effects on the central nervous system through interactions with the gut microbiota

A novel trifunctional IgG-like bispecific antibody to inhibit HIV-1 infection and enhance lysis of HIV by targeting activation of complement

BACKGROUND: The complement system is not only a key component of innate immunity but also provides a first line of defense against invading pathogens, especially for viral pathogens. Human immunodeficiency virus (HIV), however, possesses several mechanisms to evade complement-mediated lysis (CoML) and exploit the complement system to enhance viral infectivity. Responsible for this intrinsic resistance against complement-mediated virolysis are complement regulatory membrane proteins derived from the host cell that inherently downregulates complement activation at several stages of the cascade. In addition, HIV is protected from complement-mediated lysis by binding soluble factor H (fH) through the viral envelope proteins, gp120 and gp41. Whereas inhibition of complement activity is the desired outcome in the vast majority of therapeutic approaches, there is a broader potential for complement-mediated inhibition of HIV by complement local stimulation. PRESENTATION OF THE HYPOTHESIS: Our previous studies have proven that the complement-mediated antibody-dependent enhancement of HIV infection is mediated by the association of complement receptor type 2 bound to the C3 fragment and deposited on the surface of HIV virions. Thus, we hypothesize that another new activator of complement, consisting of two dsFv (against gp120 and against C3d respectively) linked to a complement-activating human IgG1 Fc domain ((anti-gp120 × anti-C3d)-Fc), can not only target and amplify complement activation on HIV virions for enhancing the efficiency of HIV lysis, but also reduce the infectivity of HIV through blocking the gp120 and C3d on the surface of HIV. TESTING THE HYPOTHESIS: Our hypothesis was tested using cell-free HIV-1 virions cultivated in vitro and assessment of virus opsonization was performed by incubating appropriate dilutions of virus with medium containing normal human serum and purified (anti-gp120 × anti-C3d)-Fc proteins. As a control group, viruses were incubated with normal human serum under the same conditions. Virus neutralization assays were used to estimate the degree of (anti-gp120 × anti-C3d)-Fc lysis of HIV compared to untreated virus. IMPLICATIONS OF THE HYPOTHESIS: The targeted complement activator, (anti-gp120 × anti-C3d)-Fc, can be used as a novel approach to HIV therapy by abrogating the complement-enhanced HIV infection of cells

Fertility loss: negative effects of environmental toxicants on oogenesis

There has been a global decline in fertility rates, with ovulatory disorders emerging as the leading cause, contributing to a global lifetime infertility prevalence of 17.5%. Formation of the primordial follicle pool during early and further development of oocytes after puberty is crucial in determining female fertility and reproductive quality. However, the increasing exposure to environmental toxins (through occupational exposure and ubiquitous chemicals) in daily life is a growing concern; these toxins have been identified as significant risk factors for oogenesis in women. In light of this concern, this review aims to enhance our understanding of female reproductive system diseases and their implications. Specifically, we summarized and categorized the environmental toxins that can affect oogenesis. Here, we provide an overview of oogenesis, highlighting specific stages that may be susceptible to the influence of environmental toxins. Furthermore, we discuss the genetic and molecular mechanisms by which various environmental toxins, including metals, cigarette smoke, and agricultural and industrial toxins, affect female oogenesis. Raising awareness about the potential risks associated with toxin exposure is crucial. However, further research is needed to fully comprehend the mechanisms underlying these effects, including the identification of biomarkers to assess exposure levels and predict reproductive outcomes. By providing a comprehensive overview, this review aims to contribute to a better understanding of the impact of environmental toxins on female oogenesis and guide future research in this field

Uncovering the pharmacological mechanisms of Zizhu ointment against diabetic ulcer by integrating network analysis and experimental evaluation in vivo and in vitro

Diabetic ulcer (DU) has been recognized as one of the most prevalent and serious complications of diabetes. However, the clinical efficacy of standard treatments for DU remains poor. Traditional Chinese medicine (TCM) shows a positive therapeutic effect on DU. Specifically, Zizhu ointment (ZZO) has been widely used to treat DU in long-term clinical practice, but the exact mechanism by which it promotes DU wound healing remains unknown. In this study, network analysis and high-performance liquid chromatography–high resolution mass spectrometry (UPLC-HRMS) were conducted to identify the active compounds of ZZO. We detected isovalerylshikonin (ISO), mandenol, daidzein, kaempferol, and formononetin in both network analysis and UPLC-HRMS. Moreover, ZZO could ameliorate DU by regulating the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) and inflammation signaling pathways, according to the results of KEGG analysis. We established a DU mouse model with a high-fat diet and streptozotocin injection in vivo to evaluate the network analysis result. The experimental results showed that ZZO could inhibit inflammation, remodel fibrous tissue, and promote angiogenesis in the DU area, facilitating wound healing in DU mice. Moreover, the PI3K/AKT signaling pathway was indeed activated by ZZO treatment, promoting macrophage M2 polarization. In addition, we used molecular docking technology to evaluate the binding sites between ZZO and the PI3K/AKT pathway. The results showed that ISO has a good binding interaction with AKT. Moreover, ISO promoted M2 polarization in macrophages in a dose-dependent manner in vitro. Our study found that ZZO could promote DU wound healing by inhibiting inflammation, which was achieved by macrophage M2 polarization through activating the PI3K/AKT pathway. Further studies have demonstrated that ISO plays major role in the above process. These findings provide a theoretical basis for further preclinical evaluation and lay a foundation for nano-gel compound treatment with ZZO

Strand antagonism in RNAi: an explanation of differences in potency between intracellularly expressed siRNA and shRNA

Strategies to regulate gene function frequently use small interfering RNAs (siRNAs) that can be made from their shRNA precursors via Dicer. However, when the duplex components of these siRNA effectors are expressed from their respective coding genes, the RNA interference (RNAi) activity is much reduced. Here, we explored the mechanisms of action of shRNA and siRNA and found the expressed siRNA, in contrast to short hairpin RNA (shRNA), exhibits strong strand antagonism, with the sense RNA negatively and unexpectedly regulating RNAi. Therefore, we altered the relative levels of strands of siRNA duplexes during their expression, increasing the level of the antisense component, reducing the level of the sense component, or both and, in this way we were able to enhance the potency of the siRNA. Such vector-delivered siRNA attacked its target effectively. These findings provide new insight into RNAi and, in particular, they demonstrate that strand antagonism is responsible for making siRNA far less potent than shRNA