THE NOVEL UPSTREAM REGULATOR OF FBXW7

SCFFBXW7 is a tumor suppressor E3 ligase protein that targets numerous oncoproteins such as Cyclin E, c-Myc, c-Jun and MCL1. The deregulation of these proteins often leads to the proliferation of cancer cells. Thus, intracellular stability and functional activity of FBXW7 is critical for regulating cancer. However, there is a gap of knowledge about the intracellular signaling pathway or if there is another ubiquitin ligase that regulates FBXW7 stability. Here, I identify a novel mechanism of FBXW7 stability regulation which involves constitutive photomorphogenic 1 (COP1), AKT and CSN6 (i.e. the COP9 signalosome 6). COP1 is an E3 ubiquitin ligase targeting important substrates such as, p53, 14-3-3-σ, and c-Jun. I found that COP1 binds to FBXW7 at the binding motif at V200 and P201. Interestingly, binding between COP1 and FBXW7 was dissociated by loss function of AKT. In addition, IGF-1 or EGF induced AKT1 directly regulates FBXW7 stability through phosphorylation of FBXW7 at T226 and S227. Moreover, phosphorylation of FBXW7 at T226 and S227 by AKT facilitates its interaction with COP1, and consequently induces ubiquitination of FBXW7 by COP1. Significantly, TSAA FBXW7 mutant reduced cell invasion, migration, proliferation and cell cycle progression. Thus, results define a novel signaling pathway for regulation of FBXW7 through the AKT-COP1 axis which can be applied for therapeutic intervention in cancers overexpressing AKT and COP1. CSN functions as an adaptor between substrate proteins and the 26S proteasome to facilitate proteasomal degradation of ubiquitinated proteins. In this study, I also found that CSN6 associates with, and causes the degradation of, FBXW7. Moreover, CSN6 regulates stabilization of Cyclin E and c-Jun through its negative effect on FBXW7, which in turn reduces ubiquitin-mediated protein degradation of Cyclin E and c-Jun. Therefore, CSN6 knockdown results in reduced cell migration, transformational activity, and tumor growth. Together, my findings indicate the novel signaling pathway for regulation of FBXW7 through COP1, AKT or CSN6 which can be applied for therapeutic intervention in cancers overexpressing AKT and COP1 or Cyclin E and c-Jun

Rational strategies for enhancing mAb binding to SARS-CoV-2 variants through CDR diversification and antibody-escape prediction

Since the emergence of SARS-CoV-2, dozens of variants of interest and half a dozen variants of concern (VOCs) have been documented by the World Health Organization. The emergence of these VOCs due to the continuous evolution of the virus is a major concern for COVID-19 therapeutic antibodies and vaccines because they are designed to target prototype/previous strains and lose effectiveness against new VOCs. Therefore, there is a need for time- and cost-effective strategies to estimate the immune escape and redirect therapeutic antibodies against newly emerging variants. Here, we computationally predicted the neutralization escape of the SARS-CoV-2 Delta and Omicron variants against the mutational space of RBD-mAbs interfaces. Leveraging knowledge of the existing RBD-mAb interfaces and mutational space, we fine-tuned and redirected CT-p59 (Regdanvimab) and Etesevimab against the escaped variants through complementarity-determining regions (CDRs) diversification. We identified antibodies against the Omicron lineage BA.1 and BA.2 and Delta variants with comparable or better binding affinities to that of prototype Spike. This suggests that CDRs diversification by hotspot grafting, given an existing insight into the Ag-Abs interface, is an exquisite strategy to redirect antibodies against preselected epitopes and combat the neutralization escape of emerging SARS-CoV-2 variants

The promoter -1031(T/C) polymorphism in tumor necrosis factor-alpha associated with polycystic ovary syndrome

<p>Abstract</p> <p>Background</p> <p>A <it>tumor necrosis factor-alpha </it>is a multifunctional pro-inflammation cytokine, which has been considered as one of pathogenic factors for various diseases. The promoter -1031(T/C) polymorphism in the <it>tumor necrosis factor-alpha </it>gene was reported that it plays a part in reproduction-related diseases. Among these, polycystic ovary syndrome (PCOS) is known to be a common gynecological disease of women in reproductive age women. Here, we performed a comparative study of -1031(T/C) polymorphism of <it>TNF-alpha </it>gene with PCOS in a Korean population.</p> <p>Methods</p> <p>The -1031(T/C) polymorphism of <it>TNF-alpha </it>gene was analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) in a total of 217 PCOS patients and 144 matched female controls of healthy women. And statistical analysis was performed using HapAnalyzer. <it>X</it>²test and logistic regression were utilized analyze the association between two groups. A <it>p</it>-value under 0.05 was considered statistically significant.</p> <p>Results</p> <p>The genotype and allelic frequencies were in Hardy-Weinberg equilibrium (HWE). There was strong association between the -1031(T/C) polymorphism in the promoter region of <it>TNF-alpha </it>gene and PCOS (<it>p</it>-value = 0.0003, odd ratio (OR) = 2.53). In addition, the frequency of C allele was significantly higher in PCOS patients compared with controls. Sequence analyses also showed the -1031(T/C) polymorphism of <it>TNF-alpha </it>gene.</p> <p>Conclusion</p> <p>This is the first study on the -1031(T/C) polymorphism of <it>TNF-alpha </it>gene in PCOS. We concluded that the -1031(T/C) polymorphism of <it>TNF-alpha </it>gene is associated with PCOS in a Korean population. Therefore, it is possible that it may be considered as a clinical biomarker to diagnose for PCOS, and is helpful in understanding the etiology for the pathogenesis of PCOS.</p

ENSO Teleconnection Pattern Changes over the Southeastern United States under a Climate Change Scenario in CMIP5 Models

A strong teleconnection exists between the sea surface temperature (SST) over the tropical Pacific and the winter precipitation in the southeastern United States (SE US).This feature is adopted to validate the fidelity of Coupled Model Intercomparison Project Phase 5 (CMIP5) in this study. In addition, the authors examine whether the teleconnection pattern persists in the future under a global warming scenario. Generally, most of the eight selected models show a positive correlation between November SST over Ni˜no 3 region and December–February (DJF) mean daily precipitation anomalies over the SE US, consistent with the observation. However, the models with poor realization of skewness of Ni˜no indices fail to simulate the realistic teleconnection pattern in the historical simulation. In the Representative Concentration Pathways 8.5 (RCP8.5) run, all of the models maintain positive and slightly increased correlation patterns. It is noteworthy that the region with strong teleconnection pattern shifts northward in the future. Increased variance of winter precipitation due to the SST teleconnection is shown over Alabama and Georgia rather than over Florida under the RCP8.5 scenario in most of themodels, differing fromthe historical run in which the precipitation in Florida is the most attributable to the eastern Pacific SST

ENSO Teleconnection Pattern Changes over the Southeastern United States under a Climate Change Scenario in CMIP5 Models

A strong teleconnection exists between the sea surface temperature (SST) over the tropical Pacific and the winter precipitation in the southeastern United States (SE US).This feature is adopted to validate the fidelity of Coupled Model Intercomparison Project Phase 5 (CMIP5) in this study. In addition, the authors examine whether the teleconnection pattern persists in the future under a global warming scenario. Generally, most of the eight selected models show a positive correlation between November SST over Ni˜no 3 region and December–February (DJF) mean daily precipitation anomalies over the SE US, consistent with the observation. However, the models with poor realization of skewness of Ni˜no indices fail to simulate the realistic teleconnection pattern in the historical simulation. In the Representative Concentration Pathways 8.5 (RCP8.5) run, all of the models maintain positive and slightly increased correlation patterns. It is noteworthy that the region with strong teleconnection pattern shifts northward in the future. Increased variance of winter precipitation due to the SST teleconnection is shown over Alabama and Georgia rather than over Florida under the RCP8.5 scenario in most of themodels, differing fromthe historical run in which the precipitation in Florida is the most attributable to the eastern Pacific SST

First Confirmed Report of Powdery Mildew Caused by Erysiphe aquilegiae on Casuarina cunninghamiana in Argentina

Casuarina cunninghamiana Miq. (Fam. Casuarinaceae) is native to Australia and was introduced to Argentina and used as a windbreak, shade tree and for ornamental purposes. In autumn 2009, the potted seedlings in the nursery of La Plata University were found to be infected with a powdery mildew. Symptoms first appeared as thin white colonies, which subsequently developed into an abundant growth on the leaves and young stems. The damage caused by the powdery mildew infection has been observed every year after this initial infection and was again confirmed in April, 2011. There have been a few reports on the presence of powdery mildew on Casuarina spp. (Mantz et al., 2008; Farr and Rossman, 2011). In all the reports, the pathogen was cited to be Oidium sp. Thus, the aim of this work was to identify the causal agent of the powdery mildew observed on casuarina in Argentina

Radiofrequency Ablation of Thyroid Nodules: Basic Principles and Clinical Application

Radiofrequency (RF) ablation has been gaining popularity as a minimally invasive treatment for benign thyroid nodules regardless of the extent of the solid component. RF ablation of benign nodules demonstrated volume reductions of 33–58% after one month and 51–85% after six months, while solving nodule-related clinical problems. RF ablation has recently shown positive short-term results for locoregional control as well as symptom improvement in patients with recurrent thyroid cancers. This paper reviews the basic physics, indications, patient preparation, devices, procedures, clinical results, and complications of RF ablation

Dual Therapy with Cidofovir and Mirtazapine for Progressive Multifocal Leukoencephalopathy in a Sarcoidosis Patient

Background: Progressive multifocal leukoencephalopathy (PML) is a demyelinating central nervous system disease caused by JC virus (JCV) reactivation in immunocompromised patients. The disease course of PML is often progressive, fatal and at present, there are few reports on successful treatment outcomes. Case Report: A 45-year-old man with systemic sarcoidosis presented with rapidly progressive dementia and right hemiparesis. The patient was diagnosed with PML as confirmed via brain biopsy and JCV PCR. With a combination treatment of cidofovir and mirtazapine, there was significant improvement of neurological symptoms without measurable functional deficit. Conclusion: This case suggests that dual therapy with cidofovir and mirtazapine might be an effective treatment option in PML patients with sarcoidosis