bluuebunny/crossref_metadata_2025 huggingface dataset:
PENATAAN INFRASTRUKTUR KAWASAN PARIWISATA UBUD DALAM MENGHADAPI ADAPTASI KEBIASAAN BARU PASCA PANDEMI COVID-19
Authors: Nyoman Trisna Kurniawan
Published: June 2022

Peningkatan perkembangan kegiatan pariwisata dan peningkatan jumlah wisatawan di kawasan Pariwisata Ubud mengakibatkan berbagai persoalan yang berdampak pada buruknya kualitas lingkungan di Kawasan Pariwisata Ubud. Masalah yang paling krusial adalah kemacetan yang disebabkan oleh berbagai hal, masalah lainnya yaitu kondisi infrastruktur dan jaringan utilitas, kebersihan kawasan, dan terbatasnya RTH publik. Tujuan dari penelitian ini adalah untuk merumuskan rekomendasi konsep penataan Kawasan Pariwisata Ubud yang secara komprehensif dapat menjadi panduan dalam mengatasi masalah buruknya kualitas lingkungan, khususnya dalam menghadapi adaptasi kebiasaan baru (new normal) pasca pandemi Covid-19. Kajian ini menggunakan mixed method dengan metode analisis deskriptif-kualitatif berdasarkan kebijakan dan dokumen terkait. Hasil yang didapat dari kajian ini adalah perencanaan penataan infrastruktur di Kawasan Pariwisata Ubud yaitu : penataan arus lalu lintas dan pembangunan jalan baru (ring road dan shortcut), pembangunan fasilitas gedung parkir dan konsep shuttle bus, penataan Jalan Raya Ubud yang terintegrasi, penataan taman telajakan sebagai RTH publik, dan penerapan konsep protokol CHSE pada penataan Kawasan Pariwisata Ubud dalam menghadapi adaptasi kebiasaan baru pasca pandemi Covid-19.
Use of Circular RNAs in Diagnosis, Prognosis and Therapeutics of Renal Cell Carcinoma
Authors: Osca-Verdegal Rebeca , Beltrán-García Jesús , Górriz José Luis , Martínez Jabaloyas José María , Pallardó Federico V. , García-Giménez José Luis
Published: June 2022

Renal cell carcinoma is the most common type of kidney cancer, representing 90% of kidney cancer diagnoses, and the deadliest urological cancer. While the incidence and mortality rates by renal cell carcinoma are higher in men compared to women, in both sexes the clinical characteristics are the same, and usually unspecific, thereby hindering and delaying the diagnostic process and increasing the metastatic potential. Regarding treatment, surgical resection remains the main therapeutic strategy. However, even after radical nephrectomy, metastasis may still occur in some patients, with most metastatic renal cell carcinomas being resistant to chemotherapy and radiotherapy. Therefore, the identification of new biomarkers to help clinicians in the early detection, and treatment of renal cell carcinoma is essential. In this review, we describe circRNAs related to renal cell carcinoma processes reported to date and propose the use of some in therapeutic strategies for renal cell carcinoma treatment.
Satureja khuzistanica Essential Oil-Loaded Solid Lipid Nanoparticles Modified With Chitosan-Folate: Evaluation of Encapsulation Efficiency, Cytotoxic and Pro-apoptotic Properties
Authors: Tabatabaeain Seyedeh Farnoosh , Karimi Ehsan , Hashemi Mehrdad
Published: June 2022

The study aimed to synthesize Satureja khuzistanica essential oil-loaded SLN nanoparticles and to modify the surface of nanoparticles with folate-bound chitosan (SEO-SCF-NPs), and finally to investigate the effects of its toxicity and pro-apoptosis. For this purpose, the SEO-SLN nanoparticles were prepared using stearic acid, lecithin, tween 80, and water by high-pressure homogenization method. After characterization by FTIR, SEM, DLS, and ZETA potential methods, its toxicity effect against normal (HFF) and cancer (MCF-7) cells were evaluated by MTT assay. The occurrence of apoptosis in MCF-7 cells was assessed by flow cytometry and molecular analysis. The obtained results revealed the formation of round nanoparticles with a size of 279.40 nm, single dispersed (PDI: 0.3) and stable (ζ–potential: +31.69 mV). SEO-SCF-NPs indicated the effect of selective toxicity against MCF-7 cells (IC50: 88 μg/ml). Molecular analysis showed that SEO-SCF-NPs could inhibit cancer cells by activating the internal pathway of apoptosis as well as cell cycle disruption. Our finding suggests that SEO-SCF-NPs is a suitable candidate for preclinical cancer studies.
Gut Microbiota-Derived Diaminopimelic Acid Promotes the NOD1/RIP2 Signaling Pathway and Plays a Key Role in the Progression of Severe Acute Pancreatitis
Authors: Jiao Juying , Liu Jianjun , Li Qi , Zhang Guixin , Pan Chen , Luo Fei , Zhang Qingkai , Qi Bing , Zhao Liang , Yin Peiyuan , Shang Dong
Published: June 2022

Impaired intestinal barrier function and gut microbiota dysbiosis are believed to be related to exacerbation of acute pancreatitis (AP). As a bacterial cell wall peptidoglycan component, diaminopimelic acid (DAP) is a specific ligand of NOD1 that regulates the NOD1/RIP2/NF-kB signaling pathway. Here, we investigated the role of DAP in the crosstalk between the gut microbiota and pancreas during the occurrence of AP. Upregulation of NOD1/RIP2/NF-kB and elevated serum DAP levels were found in severe AP (SAP) model rats. The accumulation of DAP in SAP patients corroborated its ability to serve as an indicator of disease severity. Subsequently, SAP rats were treated with oral administration of the traditional Chinese medicine Qingyi Keli (QYKL) as well as neomycin, which can widely eliminate DAP-containing bacteria. Both QYKL and neomycin intervention ameliorated intestinal and pancreatic damage and systemic inflammation in SAP rats. Through 16S rDNA sequencing, we found that QYKL could rehabilitate the gut microbiota structure and selectively inhibit the overgrowth of enteric bacteria, such as Helicobacter and Lactobacillus, in SAP rats without affecting some protective strains, including Romboutsia and Allobaculum. Interestingly, we demonstrated that the decrease in serum DAP was accompanied by suppression of the NOD1/RIP2/NF-kB signaling pathway in both the intestine and pancreas of the two intervention groups. Taken together, these results suggested that the gut microbiota-DAP-NOD1/RIP2 signaling pathway might play a critical role in the progression of AP and that SAP could be alleviated via intervention in the signaling pathway. Our work provides new potential early warning indicators of SAP and targets for intervention.
How Climate Extremes Influence Conceptual Rainfall-Runoff Model Performance and Uncertainty
Authors: Watson Andrew , Midgley Guy , Ray Patrick , Kralisch Sven , Helmschrot Jörg
Published: June 2022

Rainfall-runoff models are frequently used for assessing climate risks by predicting changes in streamflow and other hydrological processes due to anticipated anthropogenic climate change, climate variability, and land management. Historical observations are commonly used to calibrate empirically the performance of conceptual hydrological mechanisms. As a result, calibration procedures are limited when extrapolated to novel climate conditions under future scenarios. In this paper, rainfall-runoff model performance and the simulated catchment hydrological processes were explored using the JAMS/J2000 model for the Berg River catchment in South Africa to evaluate the model in the tails of the current distribution of climatic conditions. An evolutionary multi-objective search algorithm was used to develop sets of parameters which best simulate “wet” and “dry” periods, providing the upper and lower bounds for a temporal uncertainty analysis approach to identify variables which are affected by these climate extremes. Variables most affected included soil-water storage and timing of interflow and groundwater flow, emerging as the overall dampening of the simulated hydrograph. Previous modeling showed that the JAMS/J2000 model provided a “good” simulation for periods where the yearly long-term mean precipitation shortfall was <28%. Above this threshold, and where autumn precipitation was reduced by 50%, this paper shows that the use of a set of “dry” parameters is recommended to improve model performance. These “dry” parameters better account for the change in streamflow timing of concentration and reduced peak flows, which occur in drier winter years, improving the Nash-Sutcliffe Efficiency (NSE) from 0.26 to 0.60 for the validation period 2015–2018, although the availability of climate data was still a potential factor. As the model performance was “good” (NSE > 0.7) during “wet” periods using parameters from a long-term calibration, “wet” parameters were not recommended for the Berg River catchment, but could play a large role in tropical climates. The results of this study are likely transferrable to other conceptual rainfall/runoff models, but may differ for various climates. As greater climate variability drives hydrological changes around the world, future empirically-based hydrological projections need to evaluate assumptions regarding storage and the simulated hydrological processes, to enhanced climate risk management.
Effects of Meal Similarity on Interpersonal Synchronization in Three-Party Remote Dining
Authors: Wang Jui-Ying , Kubota Sho , Inoue Tomoo
Published: June 2022

In recent years, online commensality, such as remote dining, has become a way to connect people in different places. In remote dining, people have drinks, snacks, or meals while chatting with each other via video calls and seek connectedness and belonging. However, many people feel that there is a gap between real-life and digital co-eating and that interaction in current remote dining fails to satisfy the need for companionship. Unlike real-life co-eating, in remote dining, one's meal may not be similar to that of a partner's because people usually prepare their own food separately. In this study, we focused on the effects of meal similarity on interpersonal synchronization and subjective feelings. We conducted a laboratory-based remote dining experiment and video analysis to investigate whether eating similar meals in remote conditions has any effect on eating behavior and to explore the relationship between meal similarity, interpersonal synchronization, and subjective feelings. The results showed that participants ate at a faster pace and conducted eating actions more frequently. They were more synchronized with their partners, and the feeling of togetherness was stronger. Thus, we suggest that preparing similar meals or ordering the same dishes can enhance the remote dining experience.
Identification and Validation of Candidate Gene Module Along With Immune Cells Infiltration Patterns in Atherosclerosis Progression to Plaque Rupture via Transcriptome Analysis
Authors: Xu Jing , Chen Cheng , Yang Yuejin
Published: June 2022

Objective

To explore the differentially expressed genes (DEGs) along with infiltrating immune cells landscape and their potential mechanisms in the progression of atherosclerosis from onset to plaque rupture.

Methods

In this study, three atherosclerosis-related microarray datasets were downloaded from the NCBI-GEO database. The gene set enrichment analysis (GSEA) was performed for interpreting the biological insights of gene expression data. The CIBERSORTx algorithm was applied to infer the relative proportions of infiltrating immune cells of the atherosclerotic samples. DEGs of the datasets were screened using R. The protein interaction network was constructed via STRING. The cluster genes were analyzed by the Cytoscape software. Gene ontology (GO) enrichment was performed via geneontology.org. The least absolute shrinkage and selection operator (LASSO) logistic regression algorithm and receiver operating characteristics (ROC) analyses were performed to build machine learning models for differentiating atherosclerosis status. The Pearson correlation analysis was carried out to illustrate the relationship between cluster genes and immune cells. The expression levels of the cluster genes were validated in two external cohorts. Transcriptional factors and drug-gene interaction analysis were performed to investigate the promising targets for atherosclerosis intervention.

Results

Pathways related to immunoinflammatory responses were identified according to GSEA analysis, and the detailed fractions infiltrating immune cells were compared between the early and advanced atherosclerosis. Additionally, we identified 170 DEGs in atherosclerosis progression (|log2FC|≥1 and adjusted p < 0.05). They were mainly enriched in GO terms relating to inflammatory response and innate immune response. A cluster of nine genes, such as ITGB2, C1QC, LY86, CTSS, C1QA, CSF1R, LAPTM5, VSIG4, and CD163, were found to be significant, and their correlations with infiltrating immune cells were calculated. The cluster genes were also validated to be upregulated in two external cohorts. Moreover, C1QA and ITGB2 may exert pathogenic functions in the entire process of atherogenesis.

Conclusions

We reanalyzed the transcriptomic signature of atherosclerosis development from onset to plaque rupture along with the landscape of the immune cell, as well as revealed new insights and specific prospective DEGs for the investigation of disease-associated dynamic molecular processes and their regulations with immune cells.
Whole Exome Sequencing of Patients With Heritable and Idiopathic Pulmonary Arterial Hypertension in Central Taiwan
Authors: Liang Kae-Woei , Chang Sheng-Kai , Chen Yu-Wei , Lin Wei-Wen , Tsai Wan-Jane , Wang Kuo-Yang
Published: June 2022

Background

Genetic variants could be identified in subjects with idiopathic and heritable pulmonary arterial hypertension (PAH). The 6th World Symposium on Pulmonary Hypertension (WSPH) provided a list of genes with evidence of association with PAH. However, reports using whole exome sequencing (WES) from southeastern Asian PAH cohorts were scarce.

Methods

Subjects with idiopathic and heritable PAH (N = 45) from two medical centers in central Taiwan were screened for PAH related gene variants. The genomic DNA was prepared from peripheral blood lymphocytes. We performed WES for all patients enrolled in this study. All identified gene variants were validated by polymerase-chain reaction and Sanger sequencing. The clinical and hemodynamic data were compared between bone morphogenetic protein receptor type-2 (BMPR2) gene variants carriers vs. non-carriers.

Results

Eight patients (8/45 = 17.8%) was identified carrying BMPR2 gene variants and 8 patients (8/45 = 17.8%) had other WSPH-listed PAH-related gene variants (1 with ACVRL1, 1 with ENG, 1 with SMAD9, 1 with SMAD1, 1 with ATP13A3 and 3 with AQP1). In addition, a total of 14 non-WSPH-listed PAH-related genetic variant sites (ABCC8, NOTCH1, NOTCH2, NOTCH3, JAG1, BMP10, GGCX, FBLN2, ABCA3 and PTGIS) were found in this PAH cohort. Subjects carrying BMPR2 gene variant (N = 8) were younger at diagnosis of PAH (30 ± 11 vs 49 ± 13 years, p = 0.001) than the non-carrier group (N = 37). BMPR2 variant carriers had a trend toward having higher mean pulmonary arterial pressure (PAP) (61 ± 19 vs. 51 ± 13 mmHg, p = 0.076) than the non-carriers upon initial diagnosis. Pulmonary vascular resistance, right atrial pressure, cardiac output, as well as functional class were similar between BMPR2 variant carriers and non-carriers at initial diagnosis.

Conclusions

We identified 17.8% of patients with BMPR2 gene variants and 17.8% subjects with other 6th WSPH-listed PAH-related gene variants in a Taiwanese idiopathic and heritable PAH cohort. PAH patients carrying BMPR2 variants presented at a younger age with a trend toward having higher mean PAP at initial diagnosis.
Successful Immunomodulatory Treatment of COVID-19 in a Patient With Severe ACTH-Dependent Cushing’s Syndrome: A Case Report and Review of Literature
Authors: Popovic Bojana , Radovanovic Spurnic Aleksandra , Velickovic Jelena , Plavsic Aleksandra , Jecmenica-Lukic Milica , Glisic Tijana , Ilic Dusan , Jeremic Danka , Vratonjic Jelena , Samardzic Vladimir , Gluvic Zoran , Adzic-Vukicevic Tatjana
Published: June 2022

Introduction

Patients with Cushing’s syndrome (CS) represent a highly sensitive group during corona virus disease 2019 (COVID-19) pandemic. The effect of multiple comorbidities and immune system supression make the clinical picture complicated and treatment challenging.

Case report

A 70-year-old female was admitted to a covid hospital with a severe form of COVID-19 pneumonia that required oxygen supplementation. Prior to her admission to the hospital she was diagnosed with adrenocorticotropic hormone (ACTH)-dependent CS, and the treatment of hypercortisolism had not been started yet. Since the patient’s condition was quickly deteriorating, and with presumend immmune system supression due to CS, we decided on treatement with intraveonus immunoglobulins (IVIg) that enabled quick onset of immunomodulatory effect. All comorbidities were treated with standard of care. The patient’s condition quickly stabilized with no direct side effects of a given treatment.

Conclusion

Treatment of COVID-19 in patients with CS faces many challenges due to the complexity of comorbidity effects, immunosupression and potential interactions of available medications both for treatment of COVID-19 and CS. So far, there are no guidelines for treatment of COVID-19 in patients with active CS. It is our opinion that immunomodulating therapies like IVIg might be an effective and safe treatment modality in this particularly fragile group of patients.
The Art of Packaging the Sperm Genome: Molecular and Structural Basis of the Histone-To-Protamine Exchange
Authors: Moritz Lindsay , Hammoud Saher Sue
Published: June 2022

Male fertility throughout life hinges on the successful production of motile sperm, a developmental process that involves three coordinated transitions: mitosis, meiosis, and spermiogenesis. Germ cells undergo both mitosis and meiosis to generate haploid round spermatids, in which histones bound to the male genome are replaced with small nuclear proteins known as protamines. During this transformation, the chromatin undergoes extensive remodeling to become highly compacted in the sperm head. Despite its central role in spermiogenesis and fertility, we lack a comprehensive understanding of the molecular mechanisms underlying the remodeling process, including which remodelers/chaperones are involved, and whether intermediate chromatin proteins function as discrete steps, or unite simultaneously to drive successful exchange. Furthermore, it remains largely unknown whether more nuanced interactions instructed by protamine post-translational modifications affect chromatin dynamics or gene expression in the early embryo. Here, we bring together past and more recent work to explore these topics and suggest future studies that will elevate our understanding of the molecular basis of the histone-to-protamine exchange and the underlying etiology of idiopathic male infertility.
Recurrent Hypokalemia and Adrenal Steroids in Patients With APECED
Authors: Borchers Joonatan , Mäkitie Outi , Jääskeläinen Jarmo , Laakso Saila
Published: June 2022

Context

Hypokalemia is a common finding in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) but its exact cause often remains unknown.

Objective

To explore the prevalence and etiology of hypokalemia and the role of adrenal steroids therein in a cohort of patients with APECED.

Methods

We performed a cross-sectional assessment and retrospective data collection on 44 Finnish patients with APECED to identify subjects with episodes of hypokalemia. Also 68 healthy matched controls attended the cross-sectional evaluation. Factors associating with a tendency for hypokalemia were analyzed by reviewing medical records during 1960-2021 and performing a cross-sectional analysis of serum adrenal steroids.

Results

In total 14 of the 44 APECED patients (32%) had episodes of hypokalemia; 2 presented with hypokalemia at cross-sectional evaluation and 12 had a history of hypokalemia before the cross-sectional evaluation. Hypokalemic episodes started at the median age of 14.1 years; 12/14 (86%) had primary adrenal insufficiency (PAI). The median number of hypokalemic periods per year was 0.3 (range 0.04-2.2); the frequency correlated positively with the number of clinical APECED manifestations at the time of cross-sectional evaluation (r=0.811, p<0.001). Etiologies of hypokalemia varied but episodes often occurred when new clinical manifestations developed and during hospitalizations. Three patients had kidney defects, also associated with electrolyte imbalances. Severity of hypokalemia varied (range 2.2-3.2 mmol/L), but no severe complications were observed. At cross-sectional evaluation, patients with PAI (n = 30) had significantly lower median plasma potassium and higher sodium concentration than controls, suggesting that fludrocortisone treatment contributed to hypokalemia. Detailed analysis of adrenal steroids provided no conclusive differences between patients with and without episodes of hypokalemia.

Conclusions

In APECED, hypokalemia is common and varies in terms of frequency, etiology, and severity. PAI and kidney disease predispose to hypokalemia. In addition, hypokalemic periods seem to be more common in patients with more severe phenotype of APECED.
Molecular Mechanisms of AMH Signaling
Authors: Howard James A. , Hart Kaitlin N. , Thompson Thomas B.
Published: June 2022

Anti-Müllerian Hormone (AMH) is a secreted glycoprotein hormone with critical roles in reproductive development and regulation. Its chemical and mechanistic similarities to members of the Transforming Growth Factor β (TGF-β) family have led to its placement within this signaling family. As a member of the TGF-β family, AMH exists as a noncovalent complex of a large N-terminal prodomain and smaller C-terminal mature signaling domain. To produce a signal, the mature domain will bind to the extracellular domains of two type I and two type II receptors which results in an intracellular SMAD signal. Interestingly, as will be discussed in this review, AMH possesses several unique characteristics which set it apart from other ligands within the TGF-β family. In particular, AMH has a dedicated type II receptor, Anti-Müllerian Hormone Receptor Type II (AMHR2), making this interaction intriguing mechanistically as well as therapeutically. Further, the prodomain of AMH has remained largely uncharacterized, despite being the largest prodomain within the family. Recent advancements in the field have provided valuable insight into the molecular mechanisms of AMH signaling, however there are still many areas of AMH signaling not understood. Herein, we will discuss what is known about the biochemistry of AMH and AMHR2, focusing on recent advances in understanding the unique characteristics of AMH signaling and the molecular mechanisms of receptor engagement.
Population Characteristics of Feral Horses Impacted by Anthropogenic Factors and Their Management Implications
Authors: Mendonça Renata S. , Pinto Pandora , Maeda Tamao , Inoue Sota , Ringhofer Monamie , Yamamoto Shinya , Hirata Satoshi
Published: June 2022

Feral horses form relatively stable harems over time that are characterized by long-lasting bonds among their members, a characteristic that makes them an exceptional case of a social system among terrestrial ungulates. Their social system has been described as uniform despite the wide differences in their environment and demography. Horse populations subjected to human interference often show higher levels of population instability that can ultimately compromise their reproductive success. In this article, we describe demographic and dynamic changes of a Portuguese population of Garranos in Serra d’Arga (SA), which is impacted by human and predation pressures, over six breeding seasons. Furthermore, we tested several hypotheses related to the impact of anthropogenic disturbance on the structure and dynamics of this population. Our results revealed that the SA population had relatively little human interference at the start of the project in 2016. This was supported by the natural composition of the herd (total number of individuals, 206), which consisted of several single- and multi-male harems (n= 17 and 7, respectively) and bachelor males (n= 9). However, from 2017 to 2021, SA’s Garrano population suffered a drastic decline. Approximately two-thirds of the individuals and all bachelor males disappeared, and 76% of adult female transfers occurred after the death or disappearance of the harem male. Predatory pressures and poor management of the population, which allowed illegal human interference, contributed to this population crisis. A low population growth rate, reduced birth and foal survival rates, in addition to a delayed primiparous age were observed in this population and exacerbated after its drastic decline; suggesting the viability and survival of this Garrano population were compromised. Investigating the population demographic changes and their causes and consequences can provide guidelines for managing populations and help fight the extinction of horse breeds.
KIFC3 Promotes Proliferation, Migration, and Invasion in Colorectal Cancer via PI3K/AKT/mTOR Signaling Pathway
Authors: Liao Huiling , Zhang Lan , Lu Shimin , Li Wei , Dong Weiguo
Published: June 2022

Background: KIFC3, belongs to kinesin superfamily proteins (KIFs), is well known for its role in intracellular cargo movement. KIFC3 has been identified as a docetaxel resistance gene in breast cancer cells, however, the role of KIFC3 and its potential mechanism in colorectal cancer (CRC) remains elusive.

Objectives: We aims to investigate the effects of KIFC3 in proliferation, migration, and invasion in CRC as well as the potential mechanism inside.

Methods: We investigated the expression of KIFC3 in the Oncomine, Gene Expression Profiling Interactive Analysis databases. The KIFC3 protein expression and mRNA level in CRC cells were evaluated by western blot and qRT-PCR. Cell proliferation ability was detected by CCK-8, EdU, colony formation assay and xenograft tumor in nude mice. Flow cytometry was used to detect the cell cycle. The effect of KIFC3 on the epithelial-to-mesenchymal transition (EMT) was investigated by transwell and wound healing assay. The association of KIFC3 with EMT and PI3K/AKT/mTOR signaling pathway were measured by western blot and immunofluorescence staining.

Results: The expression of KIFC3 was higher in CRC tissues than normal colorectal tissue, and was negatively correlated with the overall survival of patients with CRC. KIFC3 silencing inhibited the proliferation, migration and invasion of CRC cells. Meanwhile, it could decrease the number of cells in S phase. KIFC3 silencing inhibited the expression of proliferating cell nuclear antigen, Cyclin A2, Cyclin E1, and CDK2 and increased the expression of p21 and p53. KIFC3 overexpression promoted the G1/S phase transition. KIFC3 silencing inhibited the EMT process, which decreased the level of N-cadherin, Vimentin, SNAIL 1, TWIST, MMP-2, MMP-9 and increased E-cadherin, while KIFC3 overexpression show the opposite results. Furthermore, the knockdown of KIFC3 suppressed the EMT process by modulating the PI3K/AKT/mTOR signaling pathway. KIFC3 silencing decreased the expression of phosphorylated PI3K, AKT, mTOR, but total PI3K, AKT, mTOR have no change. Inversely, the upregulation of KIFC3 increased the expression of phosphorylated PI3K, AKT and mTOR, total PI3K, AKT, mTOR have no change. In a xenograft mouse model, the depletion of KIFC3 suppressed tumor growth. the increased expression levels of KIFC3 could enhance the proliferation, migration and invasion of CRC cells, and enhance the EMT process through the PI3K/AKT/mTOR pathway.

Conclusion: Our study substantiates that KIFC3 can participate in the regulation of CRC progression by which regulates EMT via the PI3K/AKT/mTOR axis.
Case Report: Successful Immunotherapy Improved the Prognosis of the Unfavorable Subset of Cancer of Unknown Primary
Authors: Mei Jie , Wang Hao , Fan Honghong , Ding Junli , Xu Junying
Published: June 2022

Background

Cancer of unknown primary (CUP) is heterogeneous and has a wide variety of clinical presentations and a poor prognosis in most patients, with a median overall survival of only 6 months. The development of molecular profiling contributes to precision therapy, and targeted drugs and immune checkpoint inhibitors (ICIs) greatly promote individualized treatment.

Case presentation

Here, we reported a case of an unfavorable subset of CUP who had a long time of survival after the immunotherapy-prominent comprehensive treatment. A 48-year-old man presented with back pain and a cough. A diagnostic work-up showed bone marrow, multiple bones, and lymph node metastasis. Lymph node pathology implies metastatic poorly differentiated cancer. Next-generation sequencing (NGS) showed no special targets, but the tumor proportion score (TPS) of programmed death-ligand 1 (PD-L1) was 80% and the tumor mutation burden (TMB) was 16.7 per million bases. After two cycles of pembrolizumab 200 mg D1 plus nanoparticle albumin-bound (nab)-paclitaxel 200 mg D1&8 (q3w), PET-CT and bone marrow aspiration cytology showed a complete response (CR). Subsequently, pembrolizumab alone was used for three months. The left inguinal lymph nodes showed new metastasis. After two cycles of the combination treatment of pembrolizumab and (nab)-paclitaxel, a partial response (PR) was achieved. After seven months, retroperitoneal lymph nodes showed new metastasis, and the sequential treatment with radiotherapy and pembrolizumab exhibited encouraging efficacy. To date, the patient has survived nearly 40 months with the combination therapy.

Conclusions

The ICI-prominent comprehensive treatment provided clinical benefit for the reported case of CUP. Thus, CUP patients with markers of benefiting from immunotherapy should be actively treated with immunotherapy to improve their prognosis.
Promising Immunomodulatory Effects of Bacterial Lysates in Allergic Diseases
Authors: Kaczynska Agnieszka , Klosinska Martyna , Janeczek Kamil , Zarobkiewicz Michał , Emeryk Andrzej
Published: June 2022

In light of an escalating prevalence of allergic disorders, it is crucial to fully comprehend their pathophysiology and etiology. Such knowledge would play a pivotal role in the search for new therapeutic approaches concerning not only diseases’ symptoms, but also their underlying causes. The hygiene hypothesis indicates a high correlation between limited exposure to pathogens in early childhood and the risk of developing allergic disorders. Bearing in mind the significance of respiratory and digestive systems’ mucous membrane’s first-line exposure to pathogens as well as its implications on the host’s immune response, a therapy targeted at aforesaid membranes could guarantee promising and extensive treatment outcomes. Recent years yielded valuable information about bacterial lysates (BLs) known for having immunomodulatory properties. They consist of antigen mixtures obtained through lysis of bacteria which are the most common etiologic agents of respiratory tract infections. They interact with dendritic cells located in the mucous membranes of the upper respiratory tract and the gastrointestinal tract by toll-like receptors. The dendritic cells present acquired antigens resulting in innate immune response development on the release of chemokines, both stimulating monocytes and NK cells maturation and promoting polymorphonuclear neutrophil migration. Moreover, they influence the adaptive immune system by stimulating an increase of specific antibodies against administered bacterial antigens. The significance of BLs includes not only an anti-inflammatory effect on local infections but also restoration of Th1/Th2 balance, as demonstrated mainly in animal models. They decrease Th2-related cytokine levels (IL-4, IL-13) and increase Th1-related cytokine levels (IFN-γ). The reestablishment of the balance of the immune response leads to lowering atopic reactions incidence which, in addition to reduced risk of inflammation, provides the alleviation and improvement of clinical manifestations of allergic disorders. In this review, we hereby describe mechanisms of BLs action, considering their significant immunomodulatory role in innate immunity. The correlation between local, innate, and adaptive immune responses and their impact on the clinical course of allergic disorders are discussed as well. To conclude our review, we present up-to-date literature regarding the outcomes of BLs implemented in atopic dermatitis, allergic rhinitis, and asthma prevention and treatment, especially in children.
Fra-2 Is a Dominant Negative Regulator of Natural Killer Cell Development
Authors: Schnoegl Diana , Hochgerner Mathias , Gotthardt Dagmar , Marsh Leigh M.
Published: June 2022

Natural killer (NK) cells play an important role in recognizing and killing pathogen-infected or malignant cells. Changes in their numbers or activation can contribute to several diseases and pathologies including systemic sclerosis (SSc), an autoimmune disease characterized by inflammation and tissue remodeling. In these patients, increased expression of the AP-1 transcription factor, Fra-2 was reported. In mice ectopic overexpression of Fra-2 (TG) leads to SSc with strong pulmonary fibrosis, pulmonary hypertension, and inflammation. Analysis of the underlying immune cell profile in the lungs of young TG mice, which do not yet show any signs of lung disease, revealed increased numbers of eosinophils and T cells but strongly reduced NK numbers. Therefore, we aimed to identify the cause of the absence of NK cells in the lungs of these mice and to determine the potential role of Fra-2 in NK development. Examination of inflammatory cell distribution in TG mice revealed similar NK deficiencies in the spleen, blood, and bone marrow. Deeper analysis of the WT and TG bone marrow revealed a potential NK cell developmental defect beginning at the preNKP stage. To determine whether this defect was cell-intrinsic or extrinsic, mixed bone marrow chimera and in vitro differentiation experiments were performed. Both experiments showed that the defect caused by Fra-2 was primarily cell-intrinsic and minimally dependent on the environment. Closer examination of surface markers and transcription factors required for NK development, revealed the expected receptor distribution but changes in transcription factor expression. We found a significant reduction in Nfil3, which is essential for the transition of common lymphoid cells to NK committed precursor cells and an AP-1 binding site in the promotor of this gene. In Summary, our data demonstrates that regulation of Fra-2 is essential for NK development and maturation, and suggests that the early NK dysfunction plays an important role in the pathogenesis of systemic sclerosis.
Pathogenic Leptospires Limit Dendritic Cell Activation Through Avoidance of TLR4 and TRIF Signaling
Authors: Cagliero Julie , Vernel-Pauillac Frédérique , Murray Gerald , Adler Ben , Matsui Mariko , Werts Catherine
Published: June 2022

Leptospira interrogans is a bacterial species responsible for leptospirosis, a neglected worldwide zoonosis. Mice and rats are resistant and can become asymptomatic carriers, whereas humans and some other mammals may develop severe forms of leptospirosis. Uncommon among spirochetes, leptospires contain lipopolysaccharide (LPS) in their outer membrane. LPS is highly immunogenic and forms the basis for a large number of serovars. Vaccination with inactivated leptospires elicits a protective immunity, restricted to serovars with related LPS. This protection that lasts in mice, is not long lasting in humans and requires annual boosts. Leptospires are stealth pathogens that evade the complement system and some pattern recognition receptors from the Toll-like (TLR) and Nod-Like families, therefore limiting antibacterial defense. In macrophages, leptospires totally escape recognition by human TLR4, and escape the TRIF arm of the mouse TLR4 pathway. However, very little is known about the recognition and processing of leptospires by dendritic cells (DCs), although they are crucial cells linking innate and adaptive immunity. Here we tested the activation of primary DCs derived from human monocytes (MO-DCs) and mouse bone marrow (BM-DCs) 24h after stimulation with saprophytic or different pathogenic virulent or avirulent L. interrogans. We measured by flow cytometry the expression of DC-SIGN, a lectin involved in T-cell activation, co-stimulation molecules and MHC-II markers, and pro- and anti-inflammatory cytokines by ELISA. We found that exposure to leptospires, live or heat-killed, activated dendritic cells. However, pathogenic L. interrogans, especially from the Icterohaemorraghiae Verdun strain, triggered less marker upregulation and less cytokine production than the saprophytic Leptospira biflexa. In addition, we showed a better activation with avirulent leptospires, when compared to the virulent parental strains in murine BM-DCs. We did not observe this difference in human MO-DCs, suggesting a role for TLR4 in DC stimulation. Accordingly, using BM-DCs from transgenic deficient mice, we showed that virulent Icterohaemorraghiae and Manilae serovars dampened DC activation, at least partly, through the TLR4 and TRIF pathways. This work shows a novel bacterial immune evasion mechanism to limit DC activation and further illustrates the role of the leptospiral LPS as a virulence factor.
The Effect of Hypoxia-Induced Exosomes on Anti-Tumor Immunity and Its Implication for Immunotherapy
Authors: Guo Wenwen , Qiao Tianyun , Dong Bingwei , Li Tian , Liu Qiang , Xu Xiaofeng
Published: June 2022

Hypoxia is a critical feature of solid tumors and is considered to be a key factor in promoting tumorigenesis and progression. Beyond inducing metabolic reprogramming of tumor cells to adapt to the hypoxia tumor microenvironment (TME), hypoxia can also promote tumor growth by affecting the secretion of exosomes. Exosomes are nano-sized (30-150 nm in diameter) extracellular vesicles that can carry numerous substances including lipids, proteins, nucleic acids, and metabolites. Notably, hypoxia-induced exosomes alterations not only exist in tumor cells, but also in various TME cells including stromal cells and immune cells. Besides promoting tumor invasion, angiogenesis, and drug resistance, the secretion of these altered exosomes has recently been found to negatively regulate anti-tumor immune responses. In this review, we focus on the hypoxia-induced changes in exosome secretion and found it can contributes to immune evasion and cancer progression by recruiting protumor immune cells into TME, as well as inhibiting antitumor immune cells. Next, we also describe the recent advances of exosomes in immunotherapy and future direction. In conclusion, ongoing discoveries in this field have brought new insights into hypoxia exosome-led immunosuppression, enabling the development of exosome-based therapeutics and elucidating their potential in immunotherapy.
“Ocean Optimism” and Resilience: Learning From Women’s Responses to Disruptions Caused by COVID-19 to Small-Scale Fisheries in the Gulf of Guinea
Authors: Okafor-Yarwood Ifesinachi Marybenedette , van den Berg Sayra , Collins Yolanda Ariadne , Sefa-Nyarko Clement
Published: June 2022

This study examines the response of women to disruptions caused by COVID-19 in small-scale fisheries (SSF) in the Gulf of Guinea (GOG). It interrogates the concept of resilience and its potential for mitigating women’s vulnerability in times of adversity. We define resilience as the ability to thrive amidst shocks, stresses, and unforeseen disruptions. Drawing on a focus group discussion, in-depth interviews with key informants from Cote d’Ivoire, Ghana and Nigeria, and a literature review, we highlight how COVID-19 disruptions on seafood demand, distribution, labour and production acutely affected women and heightened their pre-existing vulnerabilities. Women responded by deploying both negative and positive coping strategies. We argue that the concept of resilience often romanticises women navigating adversity as having ‘supernatural’ abilities to endure disruptions and takes attention away from the sources of their adversity and from the governments’ concomitant failures to address them. Our analysis shows reasons for “ocean optimism” while also cautioning against simplistic resilience assessments when discussing the hidden dangers of select coping strategies, including the adoption of digital solutions and livelihood diversification, which are often constructed along highly gendered lines with unevenly distributed benefits.
Eco-Plastics in the Sea: Succession of Micro- and Macro-Fouling on a Biodegradable Polymer Augmented With Oyster Shell
Authors: Audrézet François , Pochon Xavier , Floerl Oliver , Le Guen Marie-Joo , Trochel Branwen , Gambarini Victor , Lear Gavin , Zaiko Anastasija
Published: June 2022

Impacts of Marine Plastic Debris (MPD) on marine ecosystems are among the most critical environmental concerns of the past three decades. Virgin plastic is often cheaper to manufacture than recycled plastics, increasing rates of plastic released into the environment and thereby impacting ecosystem health and functioning. Along with other environmental effects, MPD can serve as a vector for marine hitchhikers, facilitating unwanted organisms’ transport and subsequent spread. Consequently, there is a growing demand for more eco-friendly replacements of conventional plastic polymers, ideally with fit-for-purpose properties and a well-understood life cycle. We enriched polybutylene succinate (PBS) with three different concentrations of oyster shell to investigate the dynamics of biofouling formation over 18 weeks at the Nelson Marina, Aotearoa/New Zealand. Our study focused on oyster shell concentration as a determinant of fouling assemblages over time. While generally considered as a waste in the aquaculture sector, we used oyster shells as a variable of interest to investigate their potential for both, environmental and economic benefits. Using bacterial 16S and eukaryotic 18S rRNA gene metabarcoding, our results revealed that following immersion in seawater, time played a more critical role than substrate type in driving biofouling community structures over the study period. In total, 33 putative non-indigenous species (NIS) and 41 bacterial families with putative plastic-degrading capability were detected on the different substrates. Our analysis of NIS recruitment revealed a lower contribution of NIS on shell-enriched substrates than unadulterated polymers samples. In contrast, the different concentrations of oyster shells did not affect the specific recruitment of bacterial degraders. Taken together, our results suggest that bio-based polymers and composites with increased potential for biodegradability, recyclability, and aptitude for the selective recruitment of marine invertebrates might offer a sustainable alternative to conventional polymers, assisting to mitigate the numerous impacts associated with MPD.
Alleviating Pregastroscopy Anxiety Using Mobile Social Media Application
Authors: Lu Dan , Wang Jing-Hua , Lu Chao , Liu Zheng-Lv , Jain Ajay , Ji Feng , Gu Qing
Published: June 2022

Aim

The research aimed to study the effect of using WeChat (a mobile social media application) on pregastroscopy anxiety and the cooperation of patients with different coping styles.

Methods

In order to decrease patients' pregastroscopy anxiety and improve the tolerance of unsedated gastroscopy, WeChat, a widely used mobile social media application, was applied to provide information prior to their endoscopic procedure. Two hundred and thirty patients who underwent initial unsedated gastroscopy in a large teaching hospital in China were classified into two groups based on their coping style: information seekers or information avoiders, using the Information Subscale of the Krantz Health Opinion Survey (KHOS-I). Each of the two groups was prospectively randomly assigned to either receiving the brochure information or conjunctive interactive WeChat-delivered information of gastroscopy. To measure the level of state anxiety, the State Anxiety Scale of Spielberg's State-Trait Anxiety Inventory questionnaire was used. State anxiety, blood pressure and heart rate were measured at enrollment, upon arrival, and before gastroscopy.

Results

Information seekers and avoiders who received information from the brochure and the WeChat platform experienced significantly less state anxiety upon arrival and before gastroscopy. Furthermore, information seekers who received information from the conjunctive WeChat platform had lower frequency of retching, lower scores of nausea and bloating, and better tolerance. Information avoiders who received information from the conjunctive WeChat platform had lower frequency of retching, lower scores of discomfort while swallowing the scope and nausea, and better tolerance. However, we found the percentage of information seekers who preferred no WeChat-delivered pregastroscopy information is greater than WeChat-delivered information at the initial questionnaire. No significant difference was found in blood pressure or heart rate upon arrival and before gastroscopy.

Conclusions

Although people preferred no WeChat-delivered pregastroscopy information, the provision of gastroscopy information through a mobile social media application, such as WeChat, could significantly reduce patients' pregastroscopy anxiety, lower the frequency of retching, reduce the scores of nausea and bloating, and improve tolerance for information seekers. In addition, it could lower the frequency of retching, reduce the scores of discomfort while swallowing the scope and its concurrent nausea, and improve tolerance for information avoiders.
Effect of Preoperative Thoracic Paravertebral Blocks on Emergence Agitation During Tracheal Extubation: A Randomized Controlled Trial
Authors: Liu Wei , Luo Taijun , Wang Fei , Zhang Ding , Liu Tao , Huang Jiapeng , Xu Shaofa
Published: June 2022

Objective

This study aims to compare the effects of preoperative thoracic paravertebral blocks (TPVB) with intercoastal nerve blocks (ICNB) on emergence agitation (EA) during tracheal extubation in patients who underwent thoracoscopic lobectomy.

Design, Setting, and Participants

A randomized clinical trial was conducted in patients undergoing thoracoscopic lobectomy at Beijing Chest Hospital between June 2019 and December 2020.

Interventions

Patients were randomly assigned 1:1 to receive either ultrasound-guided preoperative TPVB or ICNB.

Main Outcomes and Measures

The primary outcome was the occurrence of emergency agitation, which was evaluated by Aono’s four-point scale (AFPS). Secondary outcomes included hemodynamics [mean arterial pressure (MAP) and heart rate (HR)]; and post-operative pain intensity [visual analog scale (VAS), Ramsay sedation score (RSS), and patient-controlled analgesia (PCA) demand times].

Results

Among the 100 patients aged 55–75 years old, 50 were randomized to each group; 97 patients completed the trial. Compared to the ICNB group, the occurrence of EA in the TPVB group was significantly lower [31.3% (15/48) vs. 12.2% (6/49), relative risk = 1.276, 95% CI: 1.02–1.60, P = 0.028]. For patients in the TPVB group, the MAP and HR at 5, 10, and 30 min after extubation were significantly lower; the intraoperative details including emergence time, extubation time, and consumption of sufentanil were significantly shorter than that in the ICNB group. Additionally, patients in the TPVB group showed significantly lower VAS at rest or coughing and significantly lower RSS at 60 and 240 min after extubation than patients in the ICNB group (all P < 0.05).

Conclusion

Preoperative TPVB was associated with less EA during tracheal extubation when compared with ICNB in patients undergoing thoracoscopic lobectomy.

Clinical Trial Registration

[http://www.chictr.org.cn/index.aspx], identifier [ChiCTR1900023852].