FOXO Transcription Factors: Their Clinical Significance and Regulation

Members of the class O of forkhead box transcription factors (FOXO) have important roles in metabolism, cellular proliferation, stress resistance, and apoptosis. The activity of FOXOs is tightly regulated by posttranslational modification, including phosphorylation, acetylation, and ubiquitylation. Activation of cell survival pathways such as phosphoinositide-3-kinase/AKT/IKK or RAS/mitogen-activated protein kinase phosphorylates FOXOs at different sites which regulate FOXOs nuclear localization or degradation. FOXO transcription factors are upregulated in a number of cell types including hepatocytes, fibroblasts, osteoblasts, keratinocytes, endothelial cells, pericytes, and cardiac myocytes. They are involved in a number of pathologic and physiologic processes that include proliferation, apoptosis, autophagy, metabolism, inflammation, cytokine expression, immunity, differentiation, and resistance to oxidative stress. These processes impact a number of clinical conditions such as carcinogenesis, diabetes, diabetic complications, cardiovascular disease, host response, and wound healing. In this paper, we focus on the potential role of FOXOs in different disease models and the regulation of FOXOs by various stimuli

Insect adhesion on rough surfaces: analysis of adhesive contact of smooth and hairy pads on transparent microstructured substrates.

Insect climbing footpads are able to adhere to rough surfaces, but the details of this capability are still unclear. To overcome experimental limitations of randomly rough, opaque surfaces, we fabricated transparent test substrates containing square arrays of 1.4 µm diameter pillars, with variable height (0.5 and 1.4 µm) and spacing (from 3 to 22 µm). Smooth pads of cockroaches (Nauphoeta cinerea) made partial contact (limited to the tops of the structures) for the two densest arrays of tall pillars, but full contact (touching the substrate in between pillars) for larger spacings. The transition from partial to full contact was accompanied by a sharp increase in shear forces. Tests on hairy pads of dock beetles (Gastrophysa viridula) showed that setae adhered between pillars for larger spacings, but pads were equally unable to make full contact on the densest arrays. The beetles' shear forces similarly decreased for denser arrays, but also for short pillars and with a more gradual transition. These observations can be explained by simple contact models derived for soft uniform materials (smooth pads) or thin flat plates (hairy-pad spatulae). Our results show that microstructured substrates are powerful tools to reveal adaptations of natural adhesives for rough surfaces

Effect of shear forces and ageing on the compliance of adhesive pads in adult cockroaches.

The flexibility of insect adhesive pads is crucial for their ability to attach on rough surfaces. Here, we used transparent substrates with micropillars to test in adult cockroaches (Nauphoeta cinerea) whether and how the stiffness of smooth adhesive pads changes when shear forces are applied, and whether the insect's age has any influence. We found that during pulls towards the body, the pad's ability to conform to the surface microstructures was improved in comparison to a contact without shear, suggesting that shear forces make the pad more compliant. The mechanism underlying this shear-dependent increase in compliance is still unclear. The effect was not explained by viscoelastic creep, changes in normal pressure, or shear-induced pad rolling, which brings new areas of cuticle into surface contact. Adhesive pads were significantly stiffer in older cockroaches. Stiffness increased most rapidly in cockroaches aged between 2.5 and 4 months. This increase is probably based on wear and repair of the delicate adhesive cuticle. Recent wear (visualised by Methylene Blue staining) was not age dependent, whereas permanent damage (visible as brown scars) accumulated with age, reducing the pads' flexibility.This study was supported by a studentship from the Cambridge Overseas Trust (to Y.Z.) and research grants from the UK Biotechnology and Biological Sciences Research Council [BB/I008667/1], the Human Frontier Science Programme [RGP0034/2012] and AkzoNobel.This is the author accepted manuscript. The final version is available from the Company of Biologists via http://dx.doi.org/10.1242/​jeb.12436

The SJTU System for Short-duration Speaker Verification Challenge 2021

This paper presents the SJTU system for both text-dependent and text-independent tasks in short-duration speaker verification (SdSV) challenge 2021. In this challenge, we explored different strong embedding extractors to extract robust speaker embedding. For text-independent task, language-dependent adaptive snorm is explored to improve the system performance under the cross-lingual verification condition. For text-dependent task, we mainly focus on the in-domain fine-tuning strategies based on the model pre-trained on large-scale out-of-domain data. In order to improve the distinction between different speakers uttering the same phrase, we proposed several novel phrase-aware fine-tuning strategies and phrase-aware neural PLDA. With such strategies, the system performance is further improved. Finally, we fused the scores of different systems, and our fusion systems achieved 0.0473 in Task1 (rank 3) and 0.0581 in Task2 (rank 8) on the primary evaluation metric.Comment: Published by Interspeech 202

Synthesis and Antiproliferative Activity of Some Steroidal Lactams

Using cholesterol as starting material, a series of 6-substituted-3-aza-A-homo-3-oxycholestanes and 6-substituted-4-aza-A-homo-3-oxycholestanes were synthesized by the oxidation, reduction, oximation, Beckman rearrangement and condensation reaction. These synthesized compounds displayed a distinct cytotoxicity against MGC 7901, HeLa and SMMC 7404 cancer cells. Our results revealed that the structures of functional groups at position-6 on the steroidal ring are crucial for the IC50 value of antiproliferative activities of these compounds and the cytotoxic activity against MGC 7901 and SMMC 7404 cells was not significantly different between 4-N-lactams and 3-N-lactams when its 6-substituted group was a carbonyl or a hydroximino, but all 3-N-lactams showed a higher cytotoxicity against HeLa cells than 4-N-lactams. In particular, compounds 6, 8, 9 (IC506: 6.5 μmol/L; 8: 7.7 μmol/L; 9: 5.6 μmol/L) were even more cytotoxic than cisplatin to HeLa cells (positive contrast, 10.1 μmol/L). The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs

Synthesis and Evaluation of Some Steroidal Oximes as Cytotoxic Agents: Structure/Activity Studies (II)

Hydroximinosteroids isolated from marine sponges display a variety of biological functions including cytotoxicity and anti-virus. In this study, we synthesized a series of hydroximinosteroid derivatives with a different functional group on the ring A or B and various side chains at position 17, and analyzed the cytotoxicity of these compounds against sk-Hep-1, H-292, PC-3 and Hey-1B cancer cells. Our results revealed that although a cholesterol-type side chain at position 17 is required for the biological activity of the compounds as we previously confirmed, elimination of the 4,5-double bond augmented the cytotoxic activity for the steroidal oximes. In addition, the presence of a hydroxy on 3- or 6-position of the steroidal nucleus resulted in a remarkable increase of cytotoxic activity. Our findings present more evidence showing the relationship between the chemical structure and biological function

Study on the Imprinting Status of Insulin-Like Growth Factor II (IGF-II) Gene in Villus during 6–10 Gestational Weeks

Objective. To compare the difference of imprinting status of insulin-like growth factor II (IGF-II) gene in villus between normal embryo development group and abnormal embryo development group and to investigate the relationship between karyotype and the imprinting status of IGF-II gene. Methods. A total of 85 pregnant women with singleton pregnancy were divided into two groups: one with abnormal embryo development (n = 38) and the other with normal embryo development (n = 47). Apa I polymorphism of IGF-II gene in chorionic villus was assayed with reverse transcriptase polymerase chain reaction (RT-PCR) and restriction fragment length polymorphism (RFLP). The relationship between chromosomal abnormal karyotype and IGF-II gene imprinting status was analyzed by primary cell culture and G-banding chromosomal karyotype analysis. Results. IGF-II imprinting loss rate was higher in the abnormal embryo development group than the normal embryo development group (44.7% versus 31.6%), but without significant difference (P > .05). The percentage of abnormal chromosomes of chorionic villus in the abnormal embryo development group was 42.5%, in which IGF-II imprinting loss rate reached 64.7%. No abnormal karyotypes were found in the normal embryo development group. However, there was significant difference in IGF-II imprinting loss rate between two groups (P > .05). Conclusion. During weeks 6–10 of gestation, abnormal embryonic development is correlated with chromosomal abnormalities. The imprinting status of IGF-II gene played important roles in embryonic development, and imprinting loss might be related to chromosomal abnormalities

Construction of retrovirus vector taking MDR1/ACBC1 and its transfection into human placenta derived mesenchymal stem cells

In the study, we used both the methods of perfusion and density gradient centrifugation to isolate and purify mesenchymal stem cells (MSCS) from placenta tissue, and constructed a retroviral vector with multiple drug resistant genes, and the green fluorescent protein (GFP) has been used as an indicative mark. The 293T cell was transfected by the retroviral vector PMX-flag-MDR1-GFP together with its peripheral membrane protein gene. After the infective and replication–defective retrovirus were acquired, we transfected them into human placenta-derived mesenchymal stem cells (HPMSCs). We successfully observed the expression of the reporter gene-GFP by using the green light fluorescence microscope and the p-glycoprotein (P-gp) expressed by exogenous gene MDR1 by Western Blotting. All these facts indicated that the retroviral vector PMX-flag-MDR1-GFP had successfully been transfected into HPMSCs and the exogenous gene multidrug resistance (MDR)1 was detected as normally expressed. The daunorubicin (DNR) pump experiment proved that P-gp of HPMSCs transfected with PMX-flag-MDR1-GFP was of biological activity. The result indicates that MDR1 retroviral vector can transfect the HPMSCs. Not only can the exogenous gene be expressed, but also the expression protein had the biological activity. The conclusion lays a solid foundation of the clinical application of MDR1 genetic therapy.Keywords: Transfect, human placenta-derived mesenchymal stem cells, multidrug resistance (MDR)1 gene