The upregulation of peripheral CD3-CD56+CD16+ natural killer cells correlates with Th1/Th2 imbalance in asthma patients during acute upper respiratory viral infections.

PURPOSE: The aim of this study is to clarify the changes of peripheral CD3-CD56+CD16+ NK cells and their correlation with Th1/Th2 immunity profiles in asthma during the phase of acute upper respiratory viral infections (AURVIs). METHODS: Peripheral venous blood and induced sputum samples were collected from 56 mild asthma patients, 49 asthma patients with AURVIs and 50 healthy subjects. Peripheral CD3-CD56+CD16+ NK cells were monitored by flow cytometry during the course of acute viral infections. Meanwhile, the induced sputum Th2 cytokines IL-4 and IL-5, and Th1 cytokine IFN-γ were also detected by ELISA assay. RESULTS: The asthmatics had lower levels of peripheral CD3-CD56+CD16+ NK cells populations as well as higher induced sputum cytokines (IL-4, IL-5 and IFN-γ) compared to healthy controls at baseline. Upon upper respiratory viral infections, peripheral CD3-CD56+CD16+ NK cells numbers in asthma patients sharply elevated on day 3 and slowly decreased by day 14, in accordance with induced sputum IFN-γ changes. IL-4 and IL-5 levels spiked much later (day 8) and lasted until day 14. Compared with asthma alone group, the IFN-γ/IL-4 and IFN-γ/IL-5 ratios of the asthma patients with AURVIs on day 1 were higher and peaked on day 3. The changes of peripheral CD3-CD56+CD16+ NK cells proportions positively correlated with the IFN-γ/IL-4 and IFN-γ/IL-5 ratios on day 1 to day 3 in asthma subsequent to upper respiratory viral infections. CONCLUSIONS: Our findings showed an imbalanced Th1/Th2 immunity in airways of asthma with acute upper respiratory viral infections. Upregulated peripheral CD3-CD56+CD16+ NK cells play a crucial role in biased Th1 immunity of airways in asthma during the acute phase of viral infections. The anti-viral Th1 immunity by targeting NK cells may be a possible therapeutic option for virus-induced asthma exacerbation.

Inhibition of AHNAK nucleoprotein 2 alleviates pulmonary fibrosis by downregulating the TGF-ß1/Smad3 signaling pathway.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and advanced interstitial lung disease with poor prognosis. AHNAK nucleoprotein 2 (AHNAK2) is a macromolecular protein that is important for cell migration and muscle membrane repair. The protein acts via epithelial-mesenchymal transition (EMT), which is a key mechanism in the pathogenesis of IPF. However, very few studies have elucidated the effect of AHNAK2 in the development of IPF. Therefore, we aimed to determine the role of AHNAK2 in IPF development. METHODS: C57BL/6 mice were induced with bleomycin, while A549 and Beas-2b pulmonary epithelial cell lines were treated with TGF-ß1 to induce IPF model. The expression of AHNAK2 was detected using immunohistochemistry staining in vivo, and real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB) in vitro. C57BL/6 mice were injected with adeno-associated virus (AAV)-sh NC or AAV-sh AHNAK2 and the pulmonary function and EMT marker expression were measured. The migratory abilities of the two transforming growth factor beta 1 (TGF-ß1)-induced cell lines were examined using wound-healing and Transwell assays after transfection with si-NC, si-AHNAK2-1 and -2. EMT marker expression was detected using RT-qPCR and WB. Smad3 and phosphorylated-Smad3 of the two cells were examined using WB. Following Smad3 inhibition by Smad3 phosphorylation inhibitor (SIS3), TGF-ß1-induced cell migration and EMT marker expression were evaluated again after different transfections. RESULTS: AHNAK2 expression was higher in the IPF model than in the normal model in vivo and in vitro. Partial inhibition of AHNAK2 suppressed the EMT process and improved pulmonary ventilation and compliance in the mouse model of IPF. Similarly, knockdown of AHNAK2 suppressed the migration of pulmonary epithelial cells and reversed EMT. Furthermore, Smad3 of the two TGF-ß1-induced cell lines was not activated when AHNAK2 was inhibited. When SIS3 inhibited the activation of Smad3, the suppression of AHNAK2 had no effect on A549 and Beas-2b, regardless of TGF-ß1 induction. CONCLUSIONS: Inhibition of AHNAK2 alleviates pulmonary fibrosis and partially reverses EMT by inhibiting the TGF-ß1/Smad3 signaling pathway. Therefore, AHNAK2 is a potential therapeutic target for IPF.

Clara cell 16 KDa protein mitigates house dust mite-induced airway inflammation and damage via regulating airway epithelial cell apoptosis in a manner dependent on HMGB1-mediated signaling inhibition.

BACKGROUND: House dust mite (HDM) inhalation can cause airway epithelial damage which is implicated in the process of airway inflammation in asthma. High mobility group box 1 (HMGB1) is critically required for cellular damage and apoptosis as an important endogenous danger signal. Recently, Clara cell 16KDa protein (CC16) has been identified to exert anti-inflammatory and immunomodulatory influence in various injury-related diseases model. However, little is known about its ability to protect against airway epithelial injury in allergic asthma. This study was aimed to clarify the protective roles of CC16 on airway epithelia in HDM-induced asthma and the regulation of HMGB1 by CC16. METHODS: Mice were sensitized and challenged by HDM extract and administrated intranasally with CC16 (5 µg/g or 10 µg/g) or saline in the challenged period. The BEAS-2B human airway epithelial cell line were cultured with CC16 or the control vehicle and then exposed to HDM. Knockdown or overexpression of HMGB1 was induced by cell transfection or intratracheal injection of recombinant adenovirus. RESULTS: CC16 treatment decreased airway inflammation and histological damage of airway epithelium dose-dependently in HDM-induced asthma model. Airway epithelia apoptosis upon HDM stimulation was noticeably abrogated by CC16 in vivo and in vitro. In addition, upregulation of HMGB1 expression and its related signaling were also detected under HDM conditions, while silencing HMGB1 significantly inhibited the apoptosis of BEAS-2B cells. Furthermore, the activity of HMGB1-mediated signaling was restrained after CC16 treatment whereas HMGB1 overexpression abolished the protective effect of CC16 on HDM-induced airway epithelia apoptosis. CONCLUSIONS: Our data confirm that CC16 attenuates HDM-mediated airway inflammation and damage via suppressing airway epithelial cell apoptosis in a HMGB1-dependent manner, suggesting the role of CC16 as a potential protective option for HDM-induced asthma.

Hydrogen/oxygen therapy for the treatment of an acute exacerbation of chronic obstructive pulmonary disease: results of a multicenter, randomized, double-blind, parallel-group controlled trial.

BACKGROUND: To investigate whether the administration of hydrogen/oxygen mixture was superior to oxygen in improving symptoms in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: This prospective, randomized, double-blind, controlled clinical trial in 10 centres enrolled patient with AECOPD and a Breathlessness, Cough, and Sputum Scale (BCSS) score of at least 6 points. Eligible patients were randomly assigned (in a 1:1 ratio) to receive either hydrogen/oxygen mixture or oxygen therapy. Primary endpoint was the change from baseline in BCSS score at day 7. Adverse events (AEs) were recorded to evaluate safety. RESULTS: Change of BCSS score in Hydrogen/oxygen group was larger than that in Oxygen group (- 5.3 vs. - 2.4 point; difference: - 2.75 [95% CI - 3.27 to - 2.22], meeting criteria for superiority). Similar results were observed in other time points from day 2 through day 6. There was a significant reduction of Cough Assessment Test score in Hydrogen/oxygen group compared to control (- 11.00 vs. - 6.00, p < 0.001). Changes in pulmonary function, arterial blood gas and noninvasive oxygen saturation did not differ significantly between groups as well as other endpoints. AEs were reported in 34 (63.0%) patients in Hydrogen/oxygen group and 42 (77.8%) in Oxygen group. No death and equipment defects were reported during study period. CONCLUSIONS: The trial demonstrated that hydrogen/oxygen therapy is superior to oxygen therapy in patient with AECOPD with acceptable safety and tolerability profile. TRIAL REGISTRATION: Name of the registry: U.S National Library of Medicine Clinical Trials; Trial registration number: NCT04000451; Date of registration: June 27, 2019-Retrospectively registered; URL of trial registry record: https://www.clinicaltrials.gov/ct2/show/study/NCT04000451?term=04000451&draw=2&rank=1 .

Bayesian Algorithm for Retrosynthesis.

The identification of synthetic routes that end with the desired product is considered an inherently time-consuming process that is largely dependent on expert knowledge regarding a limited proportion of the entire reaction space. At present, emerging machine learning technologies are reformulating the process of retrosynthetic planning. This study aimed to discover synthetic routes backwardly from a given desired molecule to commercially available compounds. The problem is reduced to a combinatorial optimization task with the solution space subject to the combinatorial complexity of all possible pairs of purchasable reactants. We address this issue within the framework of Bayesian inference and computation. The workflow consists of the training of a deep neural network, which is used to forwardly predict a product of the given reactants with a high level of accuracy, followed by inversion of the forward model into the backward one via Bayes' law of conditional probability. Using the backward model, a diverse set of highly probable reaction sequences ending with a given synthetic target is exhaustively explored using a Monte Carlo search algorithm. With a forward model prediction accuracy of approximately 87%, the Bayesian retrosynthesis algorithm successfully rediscovered 81.8 and 33.3% of known synthetic routes of one-step and two-step reactions, respectively, with top-10 accuracy. Remarkably, the Monte Carlo algorithm, which was specifically designed for the presence of multiple diverse routes, often revealed a ranked list of hundreds of reaction routes to the same synthetic target. We also investigated the potential applicability of such diverse candidates based on expert knowledge of synthetic organic chemistry.

Clinical characteristics and factors affecting the duration of positive nucleic acid test for patients of COVID-19 in XinYu, China.

BACKGROUND: The outbreak of a new coronavirus, COVID-19, which was earliest reported in Wuhan, China, is now transmitting throughout the world. The aim of this study was to articulate the clinical characteristics of COVID-19 and to reveal possible factors that may affect the persistent time of positive SARS-CoV-2 nucleic acid test, so as to identify which patients may deteriorate or have poor prognoses as early as possible. METHODS: Retrospective cohort study was carried out on 47 patients with confirmed COVID-19 infection admitted to XinYu People's Hospital of JiangXi Province. Epidemiological, demographic, clinical, laboratorial, management, treatment, and outcome data were also collected and analyzed. RESULTS: In this study, patients were divided into two groups based on whether their SARS-CoV-2 nucleic acid tests in respiratory specimens turn negative within (Group Rapid or Group R) or over (Group Slow or Group S) a week. There was no significant difference in age, sex, travel or exposure history, and smoking history between the two groups. Forty-two patients had been observed with comorbidities. Similar clinical manifestations, for instance fever, cough, sputum, and fatigue, have been observed among patients in both groups, except that patients in Group S were obviously more likely to get fatigue than patients in Group R. Both groups had shown decrease in white blood cell or lymphocyte counts. Chest X-ray or computed tomography scan showed unilateral or bilateral infiltrates. High proportion in both groups has used nasal cannula (89.47% vs. 85.71%) to inhale oxygen. 10.53% of Group S have applied high-flow nasal cannula, while Group R used none. The current treatment is mainly antibiotics, antiviral, and traditional Chinese medicine, while a couple of patients has used methylprednisolone. Only 1 patient out of both groups got even worse despite this active treatment. CONCLUSION: Clinical characteristics of COVID-19 include the exposure history and typical systemic symptoms such as fever, cough, fatigue, decreased WBC and lymphocyte counts, and infiltration in both lower lobes on CT imaging. Among them, fatigue appears to be an important factor that affects the duration of positive SARS-CoV-2 nucleic acid test in respiratory specimens.

Nuclear TAZ activity distinctly associates with subtypes of non-small cell lung cancer.

The transcription co-factor TAZ plays critical roles in the regulation of human carcinogenesis. However, the pathological role for TAZ in lung cancer has remained incompletely understood. TAZ expression was examined by immunohistochemistry for 163 NSCLC tissues. TAZ expression was also examined by western blotting for 20 frozen paired NSCLC and adjacent normal lung tissues. We report that TAZ is overexpressed in non-small cell lung cancer (NSCLC) tissues and correlates with shorter patient survival. Intriguingly, we find that TAZ is overexpressed primarily in lung squamous cell carcinomas (LUSC) but not lung adenocarcinomas (LUAD) compared to normal lung tissues, and that the expression levels of TAZ are significantly higher in LUSC than LUAD. The nuclear localization of TAZ correlates worse clinical outcomes in LUSC, but not LUAD, further suggesting a prognostic value for activated TAZ in LUSC. A meta-analysis of the public datasets from TCGA, Broad institute, and Oncomine shows that the TAZ gene (WWTR1) copy numbers are significantly increased in LUSC and correlate with the increase of TAZ mRNA expression, suggesting that TAZ is overexpressed in LUSC at least partly through gene amplifications. Collectively, our results suggest that TAZ expression distinctly associates with subtypes of NSCLC and may be useful for developing novel therapeutics treating LUSC.

Acute fibrinous and organizing pneumonia: two case reports and literature review.

BACKGROUND: Acute fibrinous and organizing pneumonia (AFOP) is a very rare form of acute or subacute lung injury, which is characterized by patches of "fibrin balls" distributed within the alveoli. Given the lack of typical clinical manifestations, AFOP is often misdiagnosed as pneumonia, tuberculosis, etc. Definitive diagnosis is obtained from a lung biopsy. Corticosteroids are usually effective. CASE PRESENTATION: We report two cases of patients with histopathological manifestations of AFOP, which were significantly improved after corticosteroid therapy. Previous reports of the clinical and pathological characteristics of AFOP were reviewed to improve clinicians' understanding of this disease. CONCLUSIONS: Early identification and diagnosis are very important for AFOP treatment. The prognosis is acceptable after timely and effective treatment.

LncRNA-DANCR contributes to lung adenocarcinoma progression by sponging miR-496 to modulate mTOR expression.

Long non-coding RNAs (lncRNAs) have emerged as new and important regulators of pathological processes including tumour development. In this study, we demonstrated that differentiation antagonizing non-protein coding RNA (DANCR) was up-regulated in lung adenocarcinoma (ADC) and that the knockdown of DANCR inhibited tumour cell proliferation, migration and invasion and restored cell apoptosis rescued; cotransfection with a miR-496 inhibitor reversed these effects. Luciferase reporter assays showed that miR-496 directly modulated DANCR; additionally, we used RNA-binding protein immunoprecipitation (RIP) and RNA pull-down assays to further confirm that the suppression of DANCR by miR-496 was RISC-dependent. Our study also indicated that mTOR was a target of miR-496 and that DANCR could modulate the expression levels of mTOR by working as a competing endogenous RNA (ceRNA). Furthermore, the knockdown of DANCR reduced tumour volumes in vivo compared with those of the control group. In conclusion, this study showed that DANCR might be an oncogenic lncRNA that regulates mTOR expression through directly binding to miR-496. DANCR may be regarded as a biomarker or therapeutic target for ADC.

miR-34b-5p inhibition attenuates lung inflammation and apoptosis in an LPS-induced acute lung injury mouse model by targeting progranulin.

Inflammation and apoptosis play important roles in the initiation and progression of acute lung injury (ALI). Our previous study has shown that progranulin (PGRN) exerts lung protective effects during LPS-induced ALI. Here, we have investigated the potential roles of PGRN-targeting microRNAs (miRNAs) in regulating inflammation and apoptosis in ALI and have highlighted the important role of PGRN. LPS-induced lung injury and the protective roles of PGRN in ALI were first confirmed. The function of miR-34b-5p in ALI was determined by transfection of a miR-34b-5p mimic or inhibitor in intro and in vivo. The PGRN level gradually increased and subsequently significantly decreased, reaching its lowest value by 24 hr; PGRN was still elevated compared to the control. The change was accompanied by a release of inflammatory mediators and accumulation of inflammatory cells in the lungs. Using bioinformatics analysis and RT-PCR, we demonstrated that, among 12 putative miRNAs, the kinetics of the miR-34b-5p levels were closely associated with PGRN expression in the lung homogenates. The gain- and loss-of-function analysis, dual-luciferase reporter assays, and rescue experiments confirmed that PGRN was the functional target of miR-34b-5p. Intravenous injection of miR-34b-5p antagomir in vivo significantly inhibited miR-34b-5p up-regulation, reduced inflammatory cytokine release, decreased alveolar epithelial cell apoptosis, attenuated lung inflammation, and improved survival by targeting PGRN during ALI. miR-34b-5p knockdown attenuates lung inflammation and apoptosis in an LPS-induced ALI mouse model by targeting PGRN. This study shows that miR-34b-5p and PGRN may be potential targets for ALI treatments.

Antisense oligonucleotide treatment enhances the recovery of acute lung injury through IL-10-secreting M2-like macrophage-induced expansion of CD4+ regulatory T cells.

MicroRNAs (miRNAs) have been shown as an important regulator in the pathologies of acute lung injury (ALI). However, the potential effect of miRNA-based therapeutic studies in ALI remains poorly understood. We assessed the effect of antisense oligonucleotides (ASOs) against miR-155 on the development of ALI using a murine ALI model. We found that miR-155 ASO treatment could enhance the recovery of ALI as evidenced by accelerated body weight back, reduced level of bronchoalveolar lavage (BAL) protein and proinflammatory cytokines, and reduced number of BAL cells. Adoptive cell transfer assay in RAG1(-/-) mice showed that CD4(+)CD25(+) regulatory T cells (Tregs) mediated the enhanced recovery of ALI. Mechanistic evidence showed that enhanced expansion of Tregs in vivo, dominantly induced by IL-10-secreting M2-like macrophages, was critical for their elevated proportion in miR-155 ASO-treated ALI mice. Finally, we report that C/EBPß, a target molecule of miR-155, was upregulated and associated with IL-10 secretion and M2-like phenotype of macrophages. These data provided a previously unknown mechanism for miRNA-based therapy against ALI, which could ultimately aid the understanding of recovery of ALI and the development of new therapeutic strategies against clinical inflammatory lung disease.

Correction: Guo et al. A Siamese Transformer Network for Zero-Shot Ancient Coin Classification. J. Imaging 2023, 9, 107.

Jochen Büttner was not included as an author in the original publication [...].

Deciphering the potential role of PGRN in regulating CD8+ T cell antitumor immunity.

A key factor contributing to resistance in immune checkpoint blockade (ICB) therapies is CD8+ T-cell tolerance in the tumor microenvironment (TME), partly resulting from upregulating coinhibitory receptors. Here, we describe the role of PGRN as a coinhibitory molecule that modulates the antitumor response of CD8+ T cells, thus presenting a novel immunosuppressive target for lung cancer. The in vivo subcutaneous transplanted lung cancer model showed that PGRN expression was elevated on CD8+ T cells that infiltrated transplanted lung cancers. Furthermore, PGRN deficiency was found to specifically encourage the infiltration of CD8+ T cells, enhance their proliferation, migration, and activation, and resist apoptosis, ultimately inhibiting tumor growth. This was achieved by PGRN knockout, increasing the production of T cell chemokine CCL3, which boosts the antitumor immune response induced by CD8+ T cells. Critically, the PD-L1 inhibitor exhibited a synergistic effect in enhancing the antitumor response in PGRN-/- mice. In summary, our findings highlight the significance of PGRN as a novel target for boosting CD8+ T cells antitumor immunity and its potential to overcome the resistance in ICB therapy.

Dynasore Alleviates LPS-Induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome-Mediated Pyroptosis.

Background: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders without available pharmacological therapies. Dynasore is a cell-permeable molecule that inhibits GTPase activity and exerts protective effects in several disease models. However, whether dynasore can alleviate lipopolysaccharide (LPS)-induced ALI is unknown. This study investigated the effect of dynasore on macrophage activation and explored its potential mechanisms in LPS-induced ALI in vitro and in vivo. Methods: Bone marrow-derived macrophages (BMDMs) were activated classically with LPS or subjected to NLRP3 inflammasome activation with LPS+ATP. A mouse ALI model was established by the intratracheal instillation (i.t.) of LPS. The expression of PYD domains-containing protein 3 (NLRP3), caspase-1, and gasdermin D (GSDMD) protein was detected by Western blots. Inflammatory mediators were analyzed in the cell supernatant, in serum and bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assays. Morphological changes in lung tissues were evaluated by hematoxylin and eosin staining. F4/80, Caspase-1 and GSDMD distribution in lung tissue was detected by immunofluorescence. Results: Dynasore downregulated nuclear factor (NF)-κB signaling and reduced proinflammatory cytokine production in vitro and inhibited the production and release of interleukin (IL)-1ß, NLRP3 inflammasome activation, and macrophage pyroptosis through the Drp1/ROS/NLRP3 axis. Dynasore significantly reduced lung injury scores and proinflammatory cytokine levels in both BALF and serum in vivo, including IL-1ß and IL-6. Dynasore also downregulated the co-expression of F4/80, caspase-1 and GSDMD in lung tissue. Conclusion: Collectively, these findings demonstrated that dynasore could alleviate LPS-induced ALI by regulating macrophage pyroptosis, which might provide a new therapeutic strategy for ALI/ARDS.

Anticancer potential of grifolin in lung cancer treatment through PI3K/AKT pathway inhibition.

Objective: Grifolin is a natural secondary metabolite isolated from edible fruiting bodies of the mushroom Albatrellus confluens. Grifolin has antitumor activities in several types of cancer. We aimed to determine the effects of grifolin on lung cancer. Methods: We determined the proliferation, migration, invasion, and apoptosis of lung cancer cells using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Ethynyl deoxyuridine, colony formation, wound scratch, transwell, flow cytometry, and xenograft mouse assays. Molecular docking evaluated the binding relation between grifolin and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA). The levels of PIK3CA, AKT, and p-AKT were measured by western blot. Results: Grifolin (10, 20, or 40 µM) inhibited the proliferation, migration, and invasion of lung cancer cells, and induced cell cycle arrest and apoptosis. Grifolin also decreased CDK4, CDK6, and CyclinD1 expression and significantly decreased PIK3CA and p-AKT expression in lung cancer cells. These anticancer effects were abolished by 740Y-P. Conclusions: Grifolin regulates the PI3K/AKT pathway, thus inhibiting lung cancer progression.

Apelin-13 facilitates mitochondria homeostasis via mitophagy to prevent against airway oxidative injury in asthma.

Oxidative stress is a major mediator in the pathogenesis of allergens-induced asthma. Mitochondria damage and dysfunction is considered to be closely related with oxidative stress. Apelin-13 is a novel multifunctional protein with anti-inflammatory and anti-oxidative properties in neuroinflammation and ischemia-reperfusion injury. However, its role in mitochondria homeostasis under asthma-associated airway oxidative injury and the potential mechanisms have not been elucidated. A murine model of asthma was established by house dust mite (HDM) allergen sensitization and challenge. The mice were received Apelin-13 protein through intraperitoneal administration before HDM challenge. Airway inflammation, histopathological changes and oxidative stress were examined. The regulatory effects of Apelin-13 on mitochondria function were evaluated using airway epithelial BEAS-2B cells, including mitochondria membrane potential (MMP), mitophagy and the possible signaling pathway. The HDM-challenged mice group exhibited robust inflammation and apoptosis in airway epithelium compared to the control group. The airway impairment in asthmatic mice was partly lessened after Apelin-13 administration. Meanwhile, protein expressions of mitophagy-related markers PINK1, Parkin, Tomm20 and LC3 were significantly increased in the lungs of Apelin-13-treated asthmatic mice. In vitro, Apelin-13 treatment significantly improved MMP levels and reduced ROS production in BEAS-2B cells exposed to HDM, accompanied with the increase of cell viability. Furthermore, Apelin-13 was found to promote the activation of PINK1/Parkin signaling in BEAS-2B cells, thereby increasing mitophagy activity and facilitating mitochondria homeostasis. These results demonstrate that Apelin-13 acts as a regulator of mitochondria homeostasis by driving mitophagy to protect against HDM allergen-induced airway oxidative injury. Apelin-13 may serve as a promising protective agent for treating asthma.

A Siamese Transformer Network for Zero-Shot Ancient Coin Classification.

Ancient numismatics, the study of ancient coins, has in recent years become an attractive domain for the application of computer vision and machine learning. Though rich in research problems, the predominant focus in this area to date has been on the task of attributing a coin from an image, that is of identifying its issue. This may be considered the cardinal problem in the field and it continues to challenge automatic methods. In the present paper, we address a number of limitations of previous work. Firstly, the existing methods approach the problem as a classification task. As such, they are unable to deal with classes with no or few exemplars (which would be most, given over 50,000 issues of Roman Imperial coins alone), and require retraining when exemplars of a new class become available. Hence, rather than seeking to learn a representation that distinguishes a particular class from all the others, herein we seek a representation that is overall best at distinguishing classes from one another, thus relinquishing the demand for exemplars of any specific class. This leads to our adoption of the paradigm of pairwise coin matching by issue, rather than the usual classification paradigm, and the specific solution we propose in the form of a Siamese neural network. Furthermore, while adopting deep learning, motivated by its successes in the field and its unchallenged superiority over classical computer vision approaches, we also seek to leverage the advantages that transformers have over the previously employed convolutional neural networks, and in particular their non-local attention mechanisms, which ought to be particularly useful in ancient coin analysis by associating semantically but not visually related distal elements of a coin's design. Evaluated on a large data corpus of 14,820 images and 7605 issues, using transfer learning and only a small training set of 542 images of 24 issues, our Double Siamese ViT model is shown to surpass the state of the art by a large margin, achieving an overall accuracy of 81%. Moreover, our further investigation of the results shows that the majority of the method's errors are unrelated to the intrinsic aspects of the algorithm itself, but are rather a consequence of unclean data, which is a problem that can be easily addressed in practice by simple pre-processing and quality checking.

Prevention of LPS-induced acute lung injury in mice by progranulin.

The acute respiratory distress syndrome (ARDS), a clinical complication of severe acute lung injury (ALI) in humans, is a leading cause of morbidity and mortality in critically ill patients. Despite decades of research, few therapeutic strategies for clinical ARDS have emerged. Here we carefully evaluated the effect of progranulin (PGRN) in treatment of ARDS using the murine model of lipopolysaccharide (LPS)-induced ALI. We reported that administration of PGRN maintained the body weight and survival of ALI mice. We revealed that administration of PGRN significantly reduced LPS-induced pulmonary inflammation, as reflected by reductions in total cell and neutrophil counts, proinflammatory cytokines, as well as chemokines in bronchoalveolar lavage (BAL) fluid. Furthermore, administration of PGRN resulted in remarkable reversal of LPS-induced increases in lung permeability as assessed by reductions in total protein, albumin, and IgM in BAL fluid. Consistently, we revealed a significant reduction of histopathology changes of lung in mice received PGRN treatment. Finally, we showed that PGRN/TNFR2 interaction was crucial for the protective effect of PGRN on the LPS-induced ALI. Our findings strongly demonstrated that PGRN could effectively ameliorate the LPS-induced ALI in mice, suggesting a potential application for PGRN-based therapy to treat clinical ARDS.

SEC61G participates in endoplasmic reticulum stress by interacting with CREB3 to promote the malignant progression of lung adenocarcinoma.

As the most common type of lung cancer, lung adenocarcinoma (LUAD) poses a great threat to human health worldwide and severely compromises the quality of life of the patients. The present study aimed to explore the potential pathogenesis of LUAD. Reverse transcription-quantitative PCR and western blotting were applied to measure the expression levels of SEC61 translocon subunit γ (SEC61G) and cyclic AMP-responsive element-binding protein 3 (CREB3). Western blotting was also used to determine the expression of endoplasmic reticulum (ER) stress-, apoptosis- and migration-related proteins. Cell Counting Kit-8, colony formation, TUNEL, wound healing and Transwell assays were used, respectively, to determine the viability, proliferation, apoptosis, migration and invasion of LUAD A549 cells. The association between SEC61G and CREB3 was verified by co-immunoprecipitation assay. The results revealed that SEC61G was upregulated in A549 cells and its downregulation could activate ER stress. It was also found that silencing SEC61G inhibited the malignant development of LUAD through ER stress. In addition, SEC61G was verified to participate in ER stress in LUAD via CREB3 and silencing SEC61G exerted inhibitory effects on the malignant progression of LUAD by regulating CREB3. In summary, SEC61G participated in ER stress and its knockdown exerted inhibitory effects on A549 cells via regulating CREB3, which suggests that SEC61G may be a potential therapy for patients with LUAD.

Machine learning methods for protein-protein binding affinity prediction in protein design.

Protein-protein interactions govern a wide range of biological activity. A proper estimation of the protein-protein binding affinity is vital to design proteins with high specificity and binding affinity toward a target protein, which has a variety of applications including antibody design in immunotherapy, enzyme engineering for reaction optimization, and construction of biosensors. However, experimental and theoretical modelling methods are time-consuming, hinder the exploration of the entire protein space, and deter the identification of optimal proteins that meet the requirements of practical applications. In recent years, the rapid development in machine learning methods for protein-protein binding affinity prediction has revealed the potential of a paradigm shift in protein design. Here, we review the prediction methods and associated datasets and discuss the requirements and construction methods of binding affinity prediction models for protein design.