Effect of wave-current interaction on waves and circulation over Georges Bank during storm events

The coupled spectral wave and circulation model SWAN+ADCIRC was applied to investigate the wave-current interaction during storm events over Georges Bank, a large shallow submarine bank on the eastern seaboard of North America that separates Gulf of Maine from the North Atlantic Ocean. The current over the Georges Bank displays a rotary feature over a tidal cycle. The wave-induced current is in the same order as the wind-driven current and generally in the same direction as the depth-averaged tidal current, indicating strong nonlinear wave-current interaction. The magnitude of wave-induced current reaches 0.07 m/s at low tide and 0.2 m/s at the other three tidal phases. The effect of wave-current interaction on waves at the four tidal phases is also analyzed. The role of Georges Bank in dissipating wave energy is most significant at rising mid-tide and high tide, which is close to the storm peak. At rising mid-tide, the wave height is decreased by 0.3 m to 0.5 m over the majority of the bank when the wave propagates in the same direction as the current. At falling-mid tide, the wave height is increased by 0.5 m at the southern flank and decreased by 0.5 m at the northern flank of the bank.</jats:p

TACE with Ar-He Cryosurgery Combined Minimal Invasive Technique for the Treatment of Primary NSCLC in 139 Cases

Background and objective TACE, Ar-He target cryosurgery and radioactive seeds implantation are the mainly micro-invasive methods in the treatment of lung cancer. This article summarizes the survival quality after treatment, the clinical efficiency and survival period, and analyzes the advantages and shortcomings of each methods so as to evaluate the clinical effect of non-small cell lung cancer with multiple minimally invasive treatment. Methods All the 139 cases were nonsmall cell lung cancer patients confirmed by pathology and with follow up from July 2006 to July 2009 retrospectively, and all of them lost operative chance by comprehensive evaluation. Different combination of multiple minimally invasive treatments were selected according to the blood supply, size and location of the lesion. Among the 139 cases, 102 cases of primary and 37 cases of metastasis to mediastinum, lung and chest wall, 71 cases of abundant blood supply used the combination of superselective target artery chemotherapy, Ar-He target cryoablation and radiochemotherapy with seeds implantation; 48 cases of poor blood supply use single Ar-He target cryoablation; 20 cases of poor blood supply use the combination of Ar-He target cryoablation and radiochemotheraoy with seeds implantation. And then the pre- and post-treatment KPS score, imaging data and the result of follow up were analyzed. Results The KPS score increased 20.01 meanly after the treatment. Follow up 3 years, 44 cases of CR, 87 cases of PR, 3 cases of NC and 5 cases of PD, and the efficiency was 94.2%. Ninety-nine cases of 1 year survival (71.2%), 43 cases of 2 years survival (30.2%), 4 cases with over 3 years survival and the median survival was 19 months. Average survival was (16±1.5)months. There was no severe complications, such as spinal cord injury, vessel and pericardial aspiration. Conclusion Minimally invasive technique is a highly successful, micro-invasive and effective method with mild complications. To non-small cell lung cancer, we can improve the middle and long term clinical effect by using the different combination of multiple minimally invasive treatments according to the patient's condition

Disruption of CFAP418 interaction with lipids causes widespread abnormal membrane-associated cellular processes in retinal degenerations

Syndromic ciliopathies and retinal degenerations are large heterogeneous groups of genetic diseases. Pathogenic variants in the CFAP418 gene may cause both disorders, and its protein sequence is evolutionarily conserved. However, the disease mechanism underlying CFAP418 mutations has not been explored. Here, we apply quantitative lipidomic, proteomic, and phosphoproteomic profiling and affinity purification coupled with mass spectrometry to address the molecular function of CFAP418 in retinas. We show that CFAP418 protein binds to lipid metabolism precursor phosphatidic acid (PA) and mitochondrion-specific lipid cardiolipin but does not form a tight and static complex with proteins. Loss of Cfap418 in mice disturbs membrane lipid homeostasis and membrane-protein association, which subsequently causes mitochondrial defects and membrane remodeling abnormalities across multiple vesicular trafficking pathways in photoreceptors, especially the endosomal sorting complexes required for transport (ESCRT) pathway. Ablation of Cfap418 also increases the activity of PA-binding protein kinase Cα in the retina. Overall, our results indicate that membrane lipid imbalance is a pathological mechanism underlying syndromic ciliopathies and retinal degenerations, which is associated with other known causative genes of these diseases

A novel non‑selective atypical PKC agonist could protect neuronal cell line from A β ‑oligomer induced toxicity by suppressing A β generation

Atypical protein kinase C (aPKCs) serve key functions in embryonic development by regulating apical-basal polarity. Previous studies have shed light on their roles during adulthood, especially in the development of Alzheimer\u27s disease (AD). Although the crystal structure of PKCι has been resolved, an agonist of aPKCs remains to be discovered. In the present study, by using the Discovery Studio program and LibDock methodology, a small molecule library (K66-X4436 KINA Set) of compounds were screened for potential binding to PKCι. Subsequently, the computational docking results were validated using affinity selection-mass spectrometry, before in vitro kinase activity was used to determine the function of the hit compounds. A cell-based model assay that can mimic the pathology of AD was then established and used to assess the function of these hit compounds. As a result, the aPKC agonist Z640 was identified, which could bind to PKCι in silico, in vitro and in this cell-based model. Z640 was further confirmed as a non-selective aPKC agonist that can activate the kinase activity of both PKCι and PKCζ. In the cell-based assay, Z640 was found to protect neuronal cell lines from amyloid-β (Aβ) oligomer-induced cell death by reducing reactive oxygen species production and restore mitochondrial function. In addition, Z640 could reduce Aβ40 generation in a dose-dependent manner and shift amyloid precursor protein processing towards the non-amyloid pathway. To conclude, the present study is the first, to the best of the authors\u27 knowledge to identify an aPKC agonist by combining computer-assisted drug discovery and cell-based assays. The present study also revealed that aPKC agonists have therapeutic potential for the treatment of AD

Circulating cell-free DNA and IL-10 from cerebrospinal fluids aid primary vitreoretinal lymphoma diagnosis

Primary vitreoretinal lymphoma (PVRL) is a rare variant of primary central nervous system lymphoma (PCNSL) that presents diagnostic challenges. Here, we focused on circulating cell-free DNA (cfDNA) and interleukin-10 (IL-10) isolated from cerebrospinal fluid. Twenty-three VRL patients (17 PVRL, 2 PCNSL/O, and 4 relapsed VRL, from 10/2018 to 12/2021) and 8 uveitis patients were included in this study. CSF samples from 19 vitreoretinal lymphoma patients had sufficient cfDNA for next-generation sequencing. Of these patients, 73.7% (14/19) had at least one meaningful non-Hodgkin lymphoma-related mutation. The characteristic MYD88L265P mutation was detected in the CSF of 12 VRL patients, with a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 63.2%, 100%, 100%, and 46.2%, respectively. No meaningful lymphoma related mutations were found in CSF samples from uveitis controls with typical intraocular lesions. Meanwhile, CSF IL-10 levels were elevated in 95.7% of the VRL patients, with a sensitivity, specificity, PPV, and NPV of 95.7%, 100%, 100% and 88.9%, respectively. Key somatic mutations like MYD88L265P and CD79B detected from CSF cfDNA and elevated CSF IL-10 levels can be promising adjuncts for primary vitreoretinal lymphoma diagnosis

Lenalidomide or bortezomib as maintenance treatment remedy the inferior impact of high-risk cytogenetic abnormalities in non-transplant patients with newly diagnosed multiple myeloma: a real-world multi-centered study in China

Maintenance treatment is a pivotal part in the whole process management of multiple myeloma (MM), which further deepens response and improves survival. However, evidence of maintenance in non-transplant MM patients is inadequate in real-world practice. Here, we retrospectively analyzed the efficacy and survival of 375 non-transplant MM patients from 11 centers between 2010 and 2021 in north China. After a median of seven cycles of front-line regimens, there were 141, 79, and 155 patients receiving lenalidomide maintenance (L-MT), bortezomib maintenance (B-MT), or thalidomide maintenance (T-MT), respectively. Patients on L-MT and B-MT had significantly greater proportions of high-risk cytogenetic abnormalities (HRCAs) detected by fluorescence in situ hybridization (FISH), which was defined as 1q21 gain, 17p deletion, adverse immunoglobulin heavy chain (IgH) translocations. Although the progression-free survival (PFS) and overall survival (OS) were comparable among the three groups, L-MT and B-MT remedied the negative impact of HRCAs on survival (PFS of patients with HRCAs vs. patients without HRCAs: L-MT, 26.9 vs. 39.2 months, p=0.19; B-MT, 20.0 vs. 29.7 months, p=0.36; OS not reached in all groups). Patients with HRCAs in the T-MT group presented inferior clinical outcomes compared to standard-risk patients (PFS, 12.1 vs. 22.8 months, p=0.02, HR=1.8, 95% CI 1.0–3.4; OS, 54.9 months vs. NR, p&lt;0.001, HR=3.2, 95% CI 1.5–7.0). Achieving complete response (CR) after induction therapy led to superior PFS compared to other degrees of response, regardless of maintenance medication. Furthermore, maintenance duration over 24 months correlated with favorable survival. Due to the large gap of transplant eligibility in China, optimizing maintenance therapy is important for non-transplant MM patients. In this real-world multi-centered study, our findings suggest that clinicians prefer to prescribe lenalidomide or bortezomib as maintenance therapy in high-risk settings, which are superior to thalidomide in non-transplant MM patients. Achievement of CR and maintenance duration over 2 years are positive factors that influence survival