A sustainable shipping management framework in the marine environment: Institutional pressure, eco-design, and cross-functional perspectives

The shipping industry plays a vital role in the world trading system and in maintaining the stability of global supply chains. However, we cannot ignore the damage it brings to the marine environment. With a focus on protecting the marine environment, the sustainable development of shipping companies has also drawn growing attention. This study examines the sustainable shipping management practice system and develops a comprehensive framework to evaluate the significance of influencing elements and prioritizes those factors. This paper adopts a fuzzy analytic hierarchy process method. It establishes a total of 11 sub-index systems from three aspects: the external policy pressure of shipping companies, the ecological design of shipping services, and the cross-functional green management within shipping companies. We used the fuzzy analytic hierarchy process (FAHP) to analyze data collected from 37 experts in the Chinese shipping industry. The findings show that external policy pressure is the most critical factor influencing sustainable shipping management, followed by eco-design and cross-functional green management. These factors have a big impact and provide management references for shipping company managers and policymakers. They also give the government a company perspective when creating pertinent regulations

Cellular Origins of EGFR-Driven Lung Cancer Cells Determine Sensitivity to Therapy

Targeting the epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKIs) is one of the major precision medicine treatment options for lung adenocarcinoma. Due to common development of drug resistance to first- and second-generation TKIs, third-generation inhibitors, including osimertinib and rociletinib, have been developed. A model of EGFR-driven lung cancer and a method to develop tumors of distinct epigenetic states through 3D organotypic cultures are described here. It is discovered that activation of the EGFR T790M/L858R mutation in lung epithelial cells can drive lung cancers with alveolar or bronchiolar features, which can originate from alveolar type 2 (AT2) cells or bronchioalveolar stem cells, but not basal cells or club cells of the trachea. It is also demonstrated that these clones are able to retain their epigenetic differences through passaging orthotopically in mice and crucially that they have distinct drug vulnerabilities. This work serves as a blueprint for exploring how epigenetics can be used to stratify patients for precision medicine decisions

Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica

<div><p>Gerodermia osteodysplastica (GO) is characterized by skin laxity and early-onset osteoporosis. <i>GORAB</i>, the responsible disease gene, encodes a small Golgi protein of poorly characterized function. To circumvent neonatal lethality of the <i>Gorab</i>^<i>Null</i> full knockout, <i>Gorab</i> was conditionally inactivated in mesenchymal progenitor cells (Prx1-cre), pre-osteoblasts (Runx2-cre), and late osteoblasts/osteocytes (Dmp1-cre), respectively. While in all three lines a reduction in trabecular bone density was evident, only <i>Gorab</i>^Prx1 and <i>Gorab</i>^Runx2 mutants showed dramatically thinned, porous cortical bone and spontaneous fractures. Collagen fibrils in the skin of <i>Gorab</i>^<i>Null</i> mutants and in bone of <i>Gorab</i>^Prx1 mutants were disorganized, which was also seen in a bone biopsy from a GO patient. Measurement of glycosaminoglycan contents revealed a reduction of dermatan sulfate levels in skin and cartilage from <i>Gorab</i>^<i>Null</i> mutants. In bone from <i>Gorab</i>^Prx1 mutants total glycosaminoglycan levels and the relative percentage of dermatan sulfate were both strongly diminished. Accordingly, the proteoglycans biglycan and decorin showed reduced glycanation. Also in cultured <i>GORAB</i>-deficient fibroblasts reduced decorin glycanation was evident. The Golgi compartment of these cells showed an accumulation of decorin, but reduced signals for dermatan sulfate. Moreover, we found elevated activation of TGF-β in <i>Gorab</i>^Prx1 bone tissue leading to enhanced downstream signalling, which was reproduced in <i>GORAB</i>-deficient fibroblasts. Our data suggest that the loss of <i>Gorab</i> primarily perturbs pre-osteoblasts. GO may be regarded as a congenital disorder of glycosylation affecting proteoglycan synthesis due to delayed transport and impaired posttranslational modification in the Golgi compartment.</p></div

Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer

As a master regulator of chromatin function, the lysine methyltransferase EZH2 orchestrates transcriptional silencing of developmental gene networks. Overexpression of EZH2 is commonly observed in human epithelial cancers, such as non-small cell lung carcinoma (NSCLC), yet definitive demonstration of malignant transformation by deregulated EZH2 remains elusive. Here, we demonstrate the causal role of EZH2 overexpression in NSCLC with new genetically-engineered mouse models of lung adenocarcinoma. Deregulated EZH2 silences normal developmental pathways leading to epigenetic transformation independent from canonical growth factor pathway activation. As such, tumors feature a transcriptional program distinct from KRAS- and EGFR-mutant mouse lung cancers, but shared with human lung adenocarcinomas exhibiting high EZH2 expression. To target EZH2-dependent cancers, we developed a novel and potent EZH2 inhibitor JQEZ5 that promoted the regression of EZH2-driven tumors in vivo, confirming oncogenic addiction to EZH2 in established tumors and providing the rationale for epigenetic therapy in a subset of lung cancer

\u3cem\u3eLkb1\u3c/em\u3e Inactivation Drives Lung Cancer Lineage Switching Governed by Polycomb Repressive Complex 2

Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours

Overcoming EGFR T790M and C797S resistance with mutant-selective allosteric inhibitors

EGFR tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib and afatinib are approved treatments for non-small cell lung cancers harboring activating mutations in the EGFR kinase1,2, but resistance arises rapidly, most frequently due to the secondary T790M mutation within the ATP-site of the receptor.3,4 Recently developed mutant-selective irreversible inhibitors are highly active against the T790M mutant5,6, but their efficacy can be compromised by acquired mutation of C797, the cysteine residue with which they form a key covalent bond7. All current EGFR TKIs target the ATP-site of the kinase, highlighting the need for therapeutic agents with alternate mechanisms of action. Here we describe rational discovery of EAI045, an allosteric inhibitor that targets selected drug-resistant EGFR mutants but spares the wild type receptor. A crystal structure shows that the compound binds an allosteric site created by the displacement of the regulatory C-helix in an inactive conformation of the kinase. The compound inhibits L858R/T790M-mutant EGFR with low-nanomolar potency in biochemical assays, but as a single agent is not effective in blocking EGFR-driven proliferation in cells due to differential potency on the two subunits of the dimeric receptor, which interact in an asymmetric manner in the active state8. We observe dramatic synergy of EAI045 with cetuximab, an antibody therapeutic that blocks EGFR dimerization9,10, rendering the kinase uniformly susceptible to the allosteric agent. EAI045 in combination with cetuximab is effective in mouse models of lung cancer driven by L858R/T790M EGFR and by L858R/T790M/C797S EGFR, a mutant that is resistant to all currently available EGFR TKIs. More generally, our findings illustrate the utility of purposefully targeting allosteric sites to obtain mutant-selective inhibitors

Untersuchung der molekularen Mechanismen bei Geroderma Osteodysplastica (GO) Syndrom

Geroderma osteodysplastica (GO; OMIM 231070) is an autosomal recessive segmental progeroid syndrome characterized by cutis laxa and osteoporosis. By genetic mapping mutations in SCYL1BP1 had been identified as the molecular basis of this disease. Co-localization studies using polyclonal and monoclonal antibodies generated by immunization with different SCYL1BP1 fragments revealed a localization of SCYL1BP1 in the medial and/or trans Golgi compartment. By a Y2H screening against a library of small GTPases, we identified the activated form of Rab6 as a specific interaction partner, a central regulator of anterograde and retrograde Golgi trafficking. Deletion mutants showed that the coiled-coil domain of SCYL1BP1 is sufficient to mediate Rab6 binding. Therefore, SCYL1BP1 belongs to the Golgin protein family. The mouse model generated by insertion of a gene trap cassette into the first intron of the murine Scyl1bp1 gene recapitulated the skin and bone phenotype of human GO. However, a thorough analysis of the phenotype was hampered by perinatal lethality of homozygous mutants that was attributed to a defect in lung development. Staining with different lectins demonstrated a dramatic reduction of complex N-glycans in the dermis and in the perichondrium adjacent to the growth plate of Scyl1bp1 deficient mice. MALDI-TOF analysis of skin lysates corroborated a striking rarefaction of complex N-glycans while some high mannose and hybrid N-glycans were more abundant. In contrast, no major glycosylation abnormalities could be identified in liver, lung or other tissues. Therefore, a tissue-specific glycosylation defect is correlated to the connective tissue abnormality in GO. Collectively, our results show that two common ageing phenomena, skin wrinkling and osteoporosis can be associated with mutations in a novel golgin, SCYL1BP1. Deficiency of Scyl1bp1 in mice is associated with a segmental alteration of glycosylation that is confined to skin and bone. Our data indicate that tissue-specific glycosylation changes can be associated with premature ageing.Geroderma osteodysplastica (GO; OMIM 231070) ist ein autosomal rezessives segmentales progeroides Syndrom, das durch erhöhte Hautschlaffheit und Osteoporose charakterisiert ist. Durch genetisches Mapping konnten Mutationen in SCYL1BP1 als Basis dieser Erkrankung identifiziert werden. Mittels polyklonaler und monoklonaler Antikörper, die durch Immunisierung mit unterschiedlichen SCYL1BP1 Fragmenten erzeugt worden waren, wurde in Kolokalisations-Studien eine Lokalisation von SCYL1BP1 im medialen/trans Golgi Kompartiment gezeigt. Durch ein Y2H Screening gegen eine Library von kleinen GTPasen konnte aktiviertes Rab6 als spezifischer Interaktionspartner identifiziert werden, ein zentraler Regulator des retrograden und anterograden Golgi-Trafficking. Deletionsmutanten verdeutlichten, dass die Interaktion mit Rab6 durch die Coiled-Coil Domänen von SCYL1BP1 vermittelt wird. Somit ist SCYL1BP1 das erste Mitglied der Golgin Proteinfamilie, das eine erbliche Erkrankung verursacht. Ein Scyl1bp1-defizientes Mausmodell wurde durch die Insertion einer Gene Trap Kassette in das erste Intron des Scyl1bp1-Gens erzeugt und zeigte Anomalien der Haut und der Knochen, die der humanen Erkrankung ähneln. Eine perinatale Lethalität, vermutlich durch eine respiratorische Insuffizienz auf Grund verzögerter Lungenreifung, verhinderte eine tiefergehende Analyse dieses Phänotyps. Durch histologische Färbungen mittels verschiedener Lektine wurde in Scyl1bp1-defizienten Mutanten eine starke Verminderung komplexer N-Glykane in der Haut und im Perichondrium des Knochens detektiert. Eine entsprechende Verminderung der komplexen N-Glykane wurde durch MALDI-TOF Massenspektrometrie bestätigt. Die Analyse weiterer Gewebelysate zeigte, dass dieser Glykosylieungsdefekt spezifisch für die betroffenen Gewebe war. Diese Resultate zeigen, dass progeroide Veränderungen in Haut und Knochen durch den Verlust eines Golgin Proteins verursacht werden können, der zu einem Gewebe-spezifischen Glykosylierungsdefekt führt

Solder Joint Defect Detection in the Connectors Using Improved Faster-RCNN Algorithm

The miniaturization and high integration of electronic products have higher and higher requirements for welding of internal components of electronic products. A welding quality detection method has always been one of the important research contents in the industry, among which, the research on solder joint defect detection of a connector has gradually attracted people&rsquo;s attention with the development of image detection algorithm. The traditional solder joint detection method of connector adopts manual detection or automatic detection methods, which is inefficient and not safe enough. With the development of deep learning, the application of a deep convolutional neural network to target detection has become a research hotspot. In this paper, a data set of connector solder joint samples was made and the number of image samples was expanded to more than 3 times of the original by using data augmentation. Clustering generates anchor boxes and transfer learning with ResNet-101 were fused, so an improved faster region-based convolutional neural networks (Faster RCNN) algorithm was proposed. The experiment verified that the improved algorithm proposed in this paper had a great improvement in all aspects compared with the original algorithm. The average detection accuracy of this method can reach 94%, and the detection rate of some defects can even reach 100%, which can completely meet the industrial requirements

Construction of the Pilot Free Trade Zone and Chinese Green Total Factor Energy Efficiency

In the context of China’s “double carbon” target, paying attention to regional green total factor energy efficiency (GTFEE) is crucial for ensuring a fundamental guarantee for China’s free trade zones for the promotion of sustainable development in China’s free trade zones. However, the existing literature lacks focus on the environmental effects of these zones. This study takes advantage of the pilot free trade zone (PFTZ) implemented in 2013 as a natural experiment, utilizing panel data from 2009 to 2020 for Chinese prefecture-level cities. It adopted a progressive difference-in-difference model to assess the effect of the PFTZ on GTFEE. The findings demonstrate a remarkable improvement in GTFEE due to the PFTZ, which remains robust even after conducting robustness checks, including the parallel trend test. The PFTZ achieves this improvement by facilitating industrial structure upgrading and promoting green technology innovation. The positive influence of the PFTZ on GTFEE is particularly prominent in coastal cities and non-resource-based cities. This study contributes to the understanding of the environmental effects of free trade zones, providing a direct response to the key question of whether the free trade zone policy can effectively support high-quality economic development in the new era. Moreover, it offers useful policy implications for advancing further openness, winning the battle against pollution, and boosting high-quality economic development