bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of Information Technology Governance In Bina Darma Foundation of Salatiga Using COBIT 5 Framework
Authors: Puspitasari Dwi , Chernovita Hanna Prillysca
Published: April 2021

Bina Darma foundation is a non-profit organization established by SWCU and GMKI. The main activities of the Bina Darma foundation are a leadership training program, journal publishing, and guesthouse rental. Problems that occur in the foundation include the management of human resources related to IT is not appropriate. To solve the problem, there needs to be control and evaluation to see how the condition of IT governance in Bina Darma Foundation uses the framework COBIT 5 domain DSS (Delivery, Service, and Support). The result of this research is capability level is currently at level 1 (Performed process), while the capability level is expected to be at level 2 (Managed process). Therefore, recommendations are given so that the IT governance in Bina Darma Foundation can work optimally to support the achievement of the organization's business objectives efficiently.
Perencanaan Strategis SI/TI Menggunakan Metode Ward and Peppard di Institusi Pendidikan (Studi Kasus: SMK Bina Nusantara Ungaran)
Authors: Bhakti Galang Krisnawa , Manuputty Augie David
Published: April 2021

Business competition in this fast-paced information age has become very tight. especially in the field of education. Thus the organization must have a business strategy that is very mature in order to face the competition. The application of information systems and technology has become one of the most influential business strategies for staying in competition. Bina Nusantara Vocational School has implemented an information system and technology, but apparently it has not run optimally because some parts have not yet implemented an information system. In this study discusses how to plan an IS / IT strategy using ward and peppard methods with supporting analyzes such as Value Chain Porter's, SWOT, and McFarlan's Strategic Grid. Which produces a portfolio of IS / IT that is aligned with the vision and mission and roadmaps of its implementation to support the business processes that are run and make the Bina Nusantara Vocational School excel in education.
Sessile serrated adenoma of appendix
Authors: KAYA Tayfun , DEMİRLİ ATICI Semra
Published: April 2021

Purpose: Sessile serrated adenoma of the appendix is rarely seen as a cause of acute appendicitis. These premalignant lesions of the appendix, which cannot be detected by preoperative imaging and tests, can be definitively diagnosed by histopathological examination. This study aims to evaluate the diagnosis and management of sessile serrated adenoma.

Methods: The patients underwent surgey due to the diagnosis of acute appendicitis between December 2014 and December 2018 were evaluated retrospectively. Seven patients' postoperative histopathological reports were compatible with sessile serrated adenoma of the appendix. Each patient's presenting symptoms, laboratory tests, imaging methods, type of surgical procedure, length of hospital stay, postoperative mortality and morbidities, postoperative colonoscopy reports were recorded.

Results: The patient's median age was 48 (29-72) years. Three of the patients were male, and four were female. All the patients were diagnosed as acute appendicitis and operated with an open technique under general anesthesia. Postoperative mortality and morbidity weren't seen in patients. All appendectomy specimens which were compatible with sessile serrated adenoma were evaluated carefully for invasion and carcinoma. Two months after the surgery, colonoscopy was performed to all patients. Although four patient's colonoscopies were unremarkable, three of the patient's colonoscopies were reported as tubular adenoma with low-grade dysplasia in descending and sigmoid colon.

Conclusion: The diagnosis, treatment and postoperative follow-up require more careful evaluation for sessile serrated adenoma of the appendix. Postoperative colonoscopy recommended due to the possibility of a high risk of sessile serrated adenoma or carcinoma in the rest of the colon.
Sık Karşılaşılan Kemik Mineral Yoğunluk Ölçümü (DXA: Dual X-ray Absorbsiyometri) Hataları: Tek Merkezli, Retrospektif Kesitsel Çalışma
Authors: BAĞÇACI Sinan , UĞURLU İbrahim
Published: April 2021

ÖZET

AMAÇ: Tek merkezli retrospektif ve kesitsel olarak yapılan bu çalışmanın amacı; merkezimizde yaygın yapılan DXA çekim hatalarının tanımlanması, bu sayede standardizasyon ve operatör eğitimine katkı sunmaktır.

GEREÇ VE YÖNTEM: DXA ölçümlerinde lomber ve proksimal femur ölçümleri kayıt altına alınmıştır. Ön kol ölçümü, total vücut ölçümü ve çocuklarda yapılan ölçümler çalışmaya alınmamıştır. Lomber ve kalça ölçümlerine ait DXA hataları ayrı ayrı tanımlanarak kaydedildi.

BULGULAR: 762 DXA ölçümü değerlendirildi. Değerlendirme sonucunda, 616 DXA çekiminde hatalı ölçüm tespit edildi. Bu hataların 374’ü proksimal femur ölçümünde, 242 tanesi ise lomber omurga ölçümünde tespit edildi.

SONUÇ: Tek merkezli retrospektif ve kesitsel olarak yapılan bu çalışma ile; merkezimizde yaygın olarak DXA çekim hataları yapıldığı ve bu durumun düzeltilmesi için standardizasyon, operatör eğitimi ve analiz bilgisi verilmesi gerektiği ortaya konulmuştur.
Readiness to introduce digital currency: is the central bank independence important?
Authors:   West Ukrainian National University, KOZIUK Viktor
Published: April 2021

The paper put forward the hypothesis suggesting that central bank’s advances on the way of CBDC projects depend on the level of their independence. At the same time, the theory demonstrates some ambiguity of how to interpret independence in respect of CBDC involvement especially in the case of empirical tests because indexes of central banks independence are tailored to the assessment of relations between monetary authorities’ status and inflation. A high level of the central bank independence index rank may mean a narrow focus on monetary policy, while a low level of independence may mean a lack of resources to be allocated to execute the innovative projects. To avoid such theoretic ambiguity in the empirical test the linearly and quadratic functions are applied in the case of the central bank independence proxy. Such proxy is added by proxies for economic development, innovations and financial development. The role of political regimes is also examined. The empirical results show that the intermediate central banks independence level might play the role in how deeply central banks are plunged in CBDC projects. The Intermediate level is interpreted as a situation when central banks operate with enough financial independence to realize innovative projects but scope of responsibilities goes beyond a narrow focus on monetary policy. But central banks status proxy is valid in the multivariate regression. The most statistically significant driver of advances toward CBDC is financial development. Proxy for innovations is valid only in the univariate regression. In the case of multivariate regression the innovation capacity of the country is less important than financial development and central bank’s status.
Fiscal and regulatory effects of the tobacco excise duty reform in Moldova: lessons for Ukraine
Authors:   NGO IDIS Viitorul, IONITSE Vyacheslav , KOSCHUK Tetiana ,   SESE “The Academy of Financial Management”
Published: April 2021

The article analyses the experience of reforming the excise duty on tobacco products in Moldova in order to build an information base of how innovations in taxation have been integrated abroad and how this experience is taken into account when making administrative decisions in Ukraine. Moldova has implemented a somewhat radical fiscally oriented excise policy, and its excise duty reform for certain types of tobacco products has often been ambiguous in terms of ensuring compliance with EU standards and attaining the claimed objectives. Up to 2020, the country had diverging excise duty rates for filter and non-filter cigarettes and minimum retail prices for these products, a practice that was contrary to the requirements of European harmonized excise duty accrual. In Moldova, the excise duty on heated tobacco products, which are potentially less harmful to human health, is set at the minimum excise duty for cigarettes, but e-cigarette liquids are subject to no excise taxation at all. The Moldovan excise duty on fine-cut tobacco is greater than 160% of the excise duty on cigarettes, but the steep rise in excise taxes has left cigars, cigarillos and other smoking tobacco unaffected. The country still has a room to increase the sales of certain types of tobacco products that will be in demand among smokers for their low cost, while paying rather modest excise duties. In conclusion, Moldova's experience in tobacco excise duty reform is controversial. None of the “taxation know-how” initiatives in Moldova can be called a success and cannot be recommended as an example for Ukraine to follow. Rather, Moldova's excise policy should be considered as an example of introducing ambiguous measures in order to hedge itself from making any glaring mistakes.
Digital transformation of the banking sector of the economy of Ukraine
Authors:   Odesa National Economic University, KOVALENKO Viktoriia
Published: April 2021

The article considers the main digital transformational changes in the banking business. The current state of banks' use of financial digital technologies is analyzed, and the factors of digital transformation that affect their financially stable development are singled out. It is determined that the digitalization of the world economy over the past decade has posed new challenges to the banking system, which are caused by increased competition in the financial services market. The factors of emergence of financial intermediaries of the new generation and the need for digital transformation of contemporary banks are described. It is proved that the digital transformation of the banking sector of the economy is due to the development of financial technologies, digital marketing channels and innovation. Three main holistic proposals for FinTech development have been identified. The digital transformation of the banking business is changing not only the supply to customers. It is changing the contours of the business and staffing requirements. Such tools as ATMs and self-service terminals, telephone banking, SMS banking, Internet banking and mobile banking represent the evolution of customer access channels to banking services based on the use of information and communication technologies. The article considers the basic scheme of transformation of a classical bank into a dynamic system of a digital bank by gradually forming the directions of digital distribution. Further digital transformational changes in the banking business should be aimed at the vectors of financial education of consumers of banking services, regulation of the cryptocurrency market in Ukraine, definition of common standards of regulation and supervision of banks and non-banking institutions in the area of digital financial services.
Effects of Porcine Immature Oocyte Vitrification on Actin Microfilament Distribution and Chromatin Integrity During Early Embryo Development in vitro
Authors: López Alma , Ducolomb Yvonne , Casas Eduardo , Retana-Márquez Socorro , Betancourt Miguel , Casillas Fahiel
Published: April 2021

Vitrification is mainly used to cryopreserve female gametes. This technique allows maintaining cell viability, functionality, and developmental potential at low temperatures into liquid nitrogen at −196°C. For this, the addition of cryoprotectant agents, which are substances that provide cell protection during cooling and warming, is required. However, they have been reported to be toxic, reducing oocyte viability, maturation, fertilization, and embryo development, possibly by altering cell cytoskeleton structure and chromatin. Previous studies have evaluated the effects of vitrification in the germinal vesicle, metaphase II oocytes, zygotes, and blastocysts, but the knowledge of its impact on their further embryo development is limited. Other studies have evaluated the role of actin microfilaments and chromatin, based on the fertilization and embryo development rates obtained, but not the direct evaluation of these structures in embryos produced from vitrified immature oocytes. Therefore, this study was designed to evaluate how the vitrification of porcine immature oocytes affects early embryo development by the evaluation of actin microfilament distribution and chromatin integrity. Results demonstrate that the damage generated by the vitrification of immature oocytes affects viability, maturation, and the distribution of actin microfilaments and chromatin integrity, observed in early embryos. Therefore, it is suggested that vitrification could affect oocyte repair mechanisms in those structures, being one of the mechanisms that explain the low embryo development rates after vitrification.
The Ringleaders: Understanding the Apicomplexan Basal Complex Through Comparison to Established Contractile Ring Systems
Authors: Morano Alexander A. , Dvorin Jeffrey D.
Published: April 2021

The actomyosin contractile ring is a key feature of eukaryotic cytokinesis, conserved across many eukaryotic kingdoms. Recent research into the cell biology of the divergent eukaryotic clade Apicomplexa has revealed a contractile ring structure required for asexual division in the medically relevant genera Toxoplasma and Plasmodium; however, the structure of the contractile ring, known as the basal complex in these parasites, remains poorly characterized and in the absence of a myosin II homolog, it is unclear how the force required of a cytokinetic contractile ring is generated. Here, we review the literature on the basal complex in Apicomplexans, summarizing what is known about its formation and function, and attempt to provide possible answers to this question and suggest new avenues of study by comparing the Apicomplexan basal complex to well-studied, established cytokinetic contractile rings and their mechanisms in organisms such as S. cerevisiae and D. melanogaster. We also compare the basal complex to structures formed during mitochondrial and plastid division and cytokinetic mechanisms of organisms beyond the Opisthokonts, considering Apicomplexan diversity and divergence.
Beneficial Effect of Alkaloids From Sophora alopecuroides L. on CUMS-Induced Depression Model Mice via Modulating Gut Microbiota
Authors: Zhang Ming , Li Aoqiang , Yang Qifang , Li Jingyi , Wang Lihua , Liu Xiuxian , Huang Yanxin , Liu Lei
Published: April 2021

It was recently shown that the gut microbiota of both depression patients and depression model animals is significantly altered, suggesting that gut microbes are closely related to depression. Here, we investigated the effects of Sophora alopecuroides L.-derived alkaloids on the gut microbiota of mice with depression-like behaviors. We first established a mouse model of depression via chronic unpredictable mild stress (CUMS) and detected changes in depression-like behaviors and depression-related indicators. Simultaneously, 16S rRNA sequencing was performed to investigate gut microbiota changes. Sophora alopecuroides L.-derived alkaloids improved depression-like behaviors and depression-related indicators in mice. The alkaloids decreased the gut microbiota diversity of CUMS mice and depleted intestinal differentially abundant “harmful” microbiota genera. Spearman analysis showed that there is a certain correlation between the differential microbiota (Lactobacillus, Helicobacter, Oscillospira, Odoribacter, Mucispirillum, Ruminococcus), depression-like behaviors, and depression-related indicators. Combined with the predictive analysis of gut microbiota function, these results indicate that alkaloids improve depression in mice through modulating gut microbiota.
Targeting SLC1A5 and SLC3A2/SLC7A5 as a Potential Strategy to Strengthen Anti-Tumor Immunity in the Tumor Microenvironment
Authors: Nachef Marianna , Ali Alaa Kassim , Almutairi Saeedah Musaed , Lee Seung-Hwan
Published: April 2021

Cancer cells are metabolically vigorous and are superior in the uptake of nutrients and in the release of the tumor microenvironment (TME)-specific metabolites. They create an acidic, hypoxic, and nutrient-depleted TME that makes it difficult for the cytotoxic immune cells to adapt to the metabolically hostile environment. Since a robust metabolism in immune cells is required for optimal anti-tumor effector functions, the challenges caused by the TME result in severe defects in the invasion and destruction of the established tumors. There have been many recent developments in NK and T cell-mediated immunotherapy, such as engineering them to express chimeric antigen receptors (CARs) to enhance tumor-recognition and infiltration. However, to defeat the tumor and overcome the limitations of the TME, it is essential to fortify these novel therapies by improving the metabolism of the immune cells. One potential strategy to enhance the metabolic fitness of immune cells is to upregulate the expression of nutrient transporters, specifically glucose and amino acid transporters. In particular, the amino acid transporters SLC1A5 and SLC7A5 as well as the ancillary subunit SLC3A2, which are required for efficient uptake of glutamine and leucine respectively, could strengthen the metabolic capabilities and effector functions of tumor-directed CAR-NK and T cells. In addition to enabling the influx and efflux of essential amino acids through the plasma membrane and within subcellular compartments such as the lysosome and the mitochondria, accumulating evidence has demonstrated that the amino acid transporters participate in sensing amino acid levels and thereby activate mTORC1, a master metabolic regulator that promotes cell metabolism, and induce the expression of c-Myc, a transcription factor essential for cell growth and proliferation. In this review, we discuss the regulatory pathways of these amino acid transporters and how we can take advantage of these processes to strengthen immunotherapy against cancer.
A Comparison Between Recombinant Listeria GAPDH Proteins and GAPDH Encoding mRNA Conjugated to Lipids as Cross-Reactive Vaccines for Listeria, Mycobacterium, and Streptococcus
Authors: Teran-Navarro Hector , Salcines-Cuevas David , Calderon-Gonzalez Ricardo , Tobes Raquel , Calvo-Montes Jorge , Pérez-Del Molino Bernal Inmaculada Concepción , Yañez-Diaz Sonsoles , Fresno Manuel , Alvarez-Dominguez Carmen
Published: April 2021

Cross-reactive vaccines recognize common molecular patterns in pathogens and are able to confer broad spectrum protection against different infections. Antigens common to pathogenic bacteria that induce broad immune responses, such as the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of the genera Listeria, Mycobacterium, or Streptococcus, whose sequences present more than 95% homology at the N-terminal GAPDH1−22 peptide, are putative candidates for universal vaccines. Here, we explore vaccine formulations based on dendritic cells (DC) loaded with two molecular forms of Listeria monocytogenes GAPDH (LM-GAPDH), such as mRNA carriers or recombinant proteins, and compare them with the same molecular forms of three other antigens used in experimental vaccines, listeriolysin O of Listeria monocytogeness, Ag85A of Mycobacterium marinum, and pneumolysin of Streptococcus pneumoniae. DC loaded with LM-GAPDH recombinant proteins proved to be the safest and most immunogenic vaccine vectors, followed by mRNA encoding LM-GAPDH conjugated to lipid carriers. In addition, macrophages lacked sufficient safety as vaccines for all LM-GAPDH molecular forms. The ability of DC loaded with LM-GAPDH recombinant proteins to induce non-specific DC activation explains their adjuvant potency and their capacity to trigger strong CD4+ and CD8+ T cell responses explains their high immunogenicity. Moreover, their capacity to confer protection in vaccinated mice against challenges with L. monocytogenes, M. marinum, or S. pneumoniae validated their efficiency as cross-reactive vaccines. Cross-protection appears to involve the induction of high percentages of GAPDH1−22 specific CD4+ and CD8+ T cells stained for intracellular IFN-γ, and significant levels of peptide-specific antibodies in vaccinated mice. We concluded that DC vaccines loaded with L. monocytogenes GAPDH recombinant proteins are cross-reactive vaccines that seem to be valuable tools in adult vaccination against Listeria, Mycobacterium, and Streptococcus taxonomic groups.
Infection Temperature Affects the Phenotype and Function of Chimeric Antigen Receptor T Cells Produced via Lentiviral Technology
Authors: Jin Xin , Lu Wenyi , Zhang Meng , Xiong Xia , Sun Rui , Wei Yunxiong , He Xiaoyuan , Zhao Mingfeng
Published: April 2021

Chimeric antigen receptor (CAR)-T cell therapy has become an important method for the treatment of hematological tumors. Lentiviruses are commonly used gene transfer vectors for preparing CAR-T cells, and the conditions for preparing CAR-T cells vary greatly. This study reported for the first time the influence of differences in infection temperature on the phenotype and function of produced CAR-T cells. Our results show that infection at 4 degrees produces the highest CAR-positive rate of T cells, infection at 37 degrees produces the fastest proliferation in CAR-T cells, and infection at 32 degrees produces CAR-T cells with the greatest proportion of naive cells and the lowest expression of immune checkpoints. Therefore, infection at 32 degrees is recommended to prepare CAR-T cells. CAR-T cells derived from infection at 32 degrees seem to have a balance between function and phenotype. Importantly, they have increased oncolytic ability. This research will help optimize the generation of CAR-T cells and improve the quality of CAR-T cell products.
Lymphocyte Non-Specific Function Detection Facilitating the Stratification of Mycobacterium tuberculosis Infection
Authors: Luo Ying , Xue Ying , Cai Yimin , Lin Qun , Tang Guoxing , Song Huijuan , Liu Wei , Mao Liyan , Yuan Xu , Zhou Yu , Liu Weiyong , Wu Shiji , Sun Ziyong , Wang Feng
Published: April 2021

Background

Inadequate tuberculosis (TB) diagnostics, especially for discrimination between active TB (ATB) and latent TB infection (LTBI), are major hurdle in the reduction of the disease burden. The present study aims to investigate the role of lymphocyte non-specific function detection for TB diagnosis in clinical practice.

Methods

A total of 208 participants including 49 ATB patients, 64 LTBI individuals, and 95 healthy controls were recruited at Tongji hospital from January 2019 to October 2020. All subjects were tested with lymphocyte non-specific function detection and T-SPOT assay.

Results

Significantly positive correlation existed between lymphocyte non-specific function and phytohemagglutinin (PHA) spot number. CD4+ T cell non-specific function showed the potential for differentiating patients with negative T-SPOT results from those with positive T-SPOT results with an area under the curve (AUC) of 0.732 (95% CI, 0.572-0.893). The non-specific function of CD4+ T cells, CD8+ T cells, and NK cells was found significantly lower in ATB patients than in LTBI individuals. The AUCs presented by CD4+ T cell non-specific function, CD8+ T cell non-specific function, and NK cell non-specific function for discriminating ATB patients from LTBI individuals were 0.845 (95% CI, 0.767-0.925), 0.770 (95% CI, 0.683-0.857), and 0.691 (95% CI, 0.593-0.789), respectively. Application of multivariable logistic regression resulted in the combination of CD4+ T cell non-specific function, NK cell non-specific function, and culture filtrate protein-10 (CFP-10) spot number as the optimally diagnostic model for differentiating ATB from LTBI. The AUC of the model in distinguishing between ATB and LTBI was 0.939 (95% CI, 0.898-0.981). The sensitivity and specificity were 83.67% (95% CI, 70.96%-91.49%) and 90.63% (95% CI, 81.02%-95.63%) with the threshold as 0.57. Our established model showed superior performance to TB-specific antigen (TBAg)/PHA ratio in stratifying TB infection status.

Conclusions

Lymphocyte non-specific function detection offers an attractive alternative to facilitate TB diagnosis. The three-index diagnostic model was proved to be a potent tool for the identification of different events involved in TB infection, which is helpful for the treatment and management of patients.
Neuro-Immune Cross-Talk in the Striatum: From Basal Ganglia Physiology to Circuit Dysfunction
Authors: Mancini Andrea , Ghiglieri Veronica , Parnetti Lucilla , Calabresi Paolo , Di Filippo Massimiliano
Published: April 2021

The basal ganglia network is represented by an interconnected group of subcortical nuclei traditionally thought to play a crucial role in motor learning and movement execution. During the last decades, knowledge about basal ganglia physiology significantly evolved and this network is now considered as a key regulator of important cognitive and emotional processes. Accordingly, the disruption of basal ganglia network dynamics represents a crucial pathogenic factor in many neurological and psychiatric disorders. The striatum is the input station of the circuit. Thanks to the synaptic properties of striatal medium spiny neurons (MSNs) and their ability to express synaptic plasticity, the striatum exerts a fundamental integrative and filtering role in the basal ganglia network, influencing the functional output of the whole circuit. Although it is currently established that the immune system is able to regulate neuronal transmission and plasticity in specific cortical areas, the role played by immune molecules and immune/glial cells in the modulation of intra-striatal connections and basal ganglia activity still needs to be clarified. In this manuscript, we review the available evidence of immune-based regulation of synaptic activity in the striatum, also discussing how an abnormal immune activation in this region could be involved in the pathogenesis of inflammatory and degenerative central nervous system (CNS) diseases.
pH-Controlled Release of Antigens Using Mesoporous Silica Nanoparticles Delivery System for Developing a Fish Oral Vaccine
Authors: Zhang Weibin , Zhu Chunhua , Xiao Fangnan , Liu Xiaodong , Xie Anhua , Chen Fangman , Dong Panpan , Lin Pingdong , Zheng Chenyang , Zhang Hong , Gong Hui , Wu Yunkun
Published: April 2021

The development of effective vaccines and delivery systems in aquaculture is a long-term challenge for controlling emerging and reemerging infections. Cost-efficient and advanced nanoparticle vaccines are of tremendous applicability in prevention of infectious diseases of fish. In this study, dihydrolipoamide dehydrogenase (DLDH) antigens of Vibrio alginolyticus were loaded into mesoporous silica nanoparticles (MSN) to compose the vaccine delivery system. Hydroxypropyl methylcellulose phthalate (HP55) was coated to provide protection of immunogen. The morphology, loading capacity, acid-base triggered release were characterized and the toxicity of nanoparticle vaccine was determined in vitro. Further, the vaccine immune effects were evaluated in large yellow croaker via oral administration. In vitro studies confirmed that the antigen could be stable in enzymes-rich artificial gastric fluid and released under artificial intestinal fluid environment. In vitro cytotoxicity assessment demonstrated the vaccines within 120 μg/ml have good biocompatibility for large yellow croaker kidney cells. Our data confirmed that the nanoparticle vaccine in vivo could elicit innate and adaptive immune response, and provide good protection against Vibrio alginolyticus challenge. The MSN delivery system prepared may be a potential candidate carrier for fish vaccine via oral administration feeding. Further, we provide theoretical basis for developing convenient, high-performance, and cost-efficient vaccine against infectious diseases in aquaculture.
Oxidative Stress-Mediated YAP Dysregulation Contributes to the Pathogenesis of Pemphigus Vulgaris
Authors: Huang Yunying , Jedličková Hana , Cai Yang , Rehman Ambreen , Gammon Luke , Ahmad Usama Sharif , Uttagomol Jutamas , Parkinson Eric Kenneth , Fortune Farida , Wan Hong
Published: April 2021

Pemphigus Vulgaris (PV) is a life-threatening autoimmune disease manifested with blisters in the skin and mucosa and caused by autoantibodies against adhesion protein desmoglein-3 (Dsg3) expressed in epithelial membrane linings of these tissues. Despite many studies, the pathogenesis of PV remains incompletely understood. Recently we have shown Dsg3 plays a role in regulating the yes-associated protein (YAP), a co-transcription factor and mechanical sensor, and constraining reactive oxygen species (ROS). This study investigated the effect of PV sera as well as the anti-Dsg3 antibody AK23 on these molecules. We detected elevated YAP steady-state protein levels in PV cells surrounding blisters and perilesional regions and in keratinocytes treated with PV sera and AK23 with concomitant transient ROS overproduction. Cells treated with hydrogen peroxide also exhibited augmented nuclear YAP accompanied by reduction of Dsg3 and α-catenin, a negative regulator of YAP. As expected, transfection of α-catenin-GFP plasmid rendered YAP export from the nucleus evoked by hydrogen peroxide. In addition, suppression of total YAP was observed in hydrogen peroxide treated cells exposed to antioxidants with enhanced cell-cell adhesion being confirmed by decreased fragmentation in the dispase assay compared to hydrogen peroxide treatment alone. On the other hand, the expression of exogenous YAP disrupted intercellular junction assembly. In contrast, YAP depletion resulted in an inverse effect with augmented expression of junction assembly proteins, including Dsg3 and α-catenin capable of abolishing the effect of AK23 on Dsg3 expression. Finally, inhibition of other kinase pathways, including p38MAPK, also demonstrated suppression of YAP induced by hydrogen peroxide. Furthermore, antioxidant treatment of keratinocytes suppressed PV sera-induced total YAP accumulation. In conclusion, this study suggests that oxidative stress coupled with YAP dysregulation attributes to PV blistering, implying antioxidants may be beneficial in the treatment of PV.
Targeting Enclysis in Liver Autoimmunity, Transplantation, Viral Infection and Cancer
Authors: Aghabi Yara O. , Yasin Alia , Kennedy James I. , Davies Scott P. , Butler Amber E. , Stamataki Zania
Published: April 2021

Persistent liver inflammation can lead to cirrhosis, which associates with significant morbidity and mortality worldwide. There are no curative treatments beyond transplantation, followed by long-term immunosuppression. The global burden of end stage liver disease has been increasing and there is a shortage of donor organs, therefore new therapies are desperately needed. Harnessing the power of the immune system has shown promise in certain autoimmunity and cancer settings. In the context of the liver, regulatory T cell (Treg) therapies are in development. The hypothesis is that these specialized lymphocytes that dampen inflammation may reduce liver injury in patients with chronic, progressive diseases, and promote transplant tolerance. Various strategies including intrinsic and extracorporeal expansion of Treg cells, aim to increase their abundance to suppress immune responses. We recently discovered that hepatocytes engulf and delete Treg cells by enclysis. Herein, we propose that inhibition of enclysis may potentiate existing regulatory T cell therapeutic approaches in patients with autoimmune liver diseases and in patients receiving a transplant. Moreover, in settings where the abundance of Treg cells could hinder beneficial immunity, such us in chronic viral infection or liver cancer, enhancement of enclysis could result in transient, localized reduction of Treg cell numbers and tip the balance towards antiviral and anti-tumor immunity. We describe enclysis as is a natural process of liver immune regulation that lends itself to therapeutic targeting, particularly in combination with current Treg cell approaches.
Cytotoxic Lymphocytes Target HIV-1 Gag Through Granzyme M-Mediated Cleavage
Authors: Saccon Elisa , Mikaeloff Flora , Figueras Ivern Pol , Végvári Ákos , Sönnerborg Anders , Neogi Ujjwal , van Domselaar Robert
Published: April 2021

Untreated HIV-1 infection leads to a slow decrease in CD4+ T cell lymphocytes over time resulting in increased susceptibility to opportunistic infections (acquired immunodeficiency syndrome, AIDS) and ultimately death of the infected individual. Initially, the host’s immune response controls the infection, but cannot eliminate the HIV-1 from the host. Cytotoxic lymphocytes are the key effector cells in this response and can mediate crucial antiviral responses through the release of a set of proteases called granzymes towards HIV-1-infected cells. However, little is known about the immunological molecular mechanisms by which granzymes could control HIV-1. Since we noted that HIV-1 subtype C (HIV-1C) Gag with the tetrapeptide insertion PYKE contains a putative granzyme M (GrM) cleavage site (KEPL) that overlaps with the PYKE insertion, we analyzed the proteolytic activity of GrM towards Gag. Immunoblot analysis showed that GrM could cleave Gag proteins from HIV-1B and variants from HIV-1C of which the Gag-PYKE variant was cleaved with extremely high efficiency. The main cleavage site was directly after the insertion after leucine residue 483. GrM-mediated cleavage of Gag was also observed in co-cultures using cytotoxic lymphocytes as effector cells and this cleavage could be inhibited by a GrM inhibitor peptide. Altogether, our data indicate towards a noncytotoxic immunological mechanism by which GrM-positive cytotoxic lymphocytes target the HIV-1 Gag protein within infected cells to potentially control HIV-1 infection. This mechanism could be exploited in new therapeutic strategies to treat HIV-1-infected patients to improve immunological control of the infection.
Role of ILC2 in Viral-Induced Lung Pathogenesis
Authors: Fonseca Wendy , Lukacs Nicholas W. , Elesela Srikanth , Malinczak Carrie-Anne
Published: April 2021

Innate lymphoid type-2 cells (ILC2) are a population of innate cells of lymphoid origin that are known to drive strong Type 2 immunity. ILC2 play a key role in lung homeostasis, repair/remodeling of lung structures following injury, and initiation of inflammation as well as more complex roles during the immune response, including the transition from innate to adaptive immunity. Remarkably, dysregulation of this single population has been linked with chronic lung pathologies, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrotic diseases (IPF). Furthermore, ILC2 have been shown to increase following early-life respiratory viral infections, such as respiratory syncytial virus (RSV) and rhinovirus (RV), that may lead to long-term alterations of the lung environment. The detrimental roles of increased ILC2 following these infections may include pathogenic chronic inflammation and/or alterations of the structural, repair, and even developmental processes of the lung. Respiratory viral infections in older adults and patients with established chronic pulmonary diseases often lead to exacerbated responses, likely due to previous exposures that leave the lung in a dysregulated functional and structural state. This review will focus on the role of ILC2 during respiratory viral exposures and their effects on the induction and regulation of lung pathogenesis. We aim to provide insight into ILC2-driven mechanisms that may enhance lung-associated diseases throughout life. Understanding these mechanisms will help identify better treatment options to limit not only viral infection severity but also protect against the development and/or exacerbation of other lung pathologies linked to severe respiratory viral infections.
Vaccination With the Commensal Streptococcus mitis Expressing Pneumococcal Serotype 5 Capsule Elicits IgG/IgA and Th17 Responses Against Streptococcus pneumoniae
Authors: Shekhar Sudhanshu , Åmdal Heidi A. , Petersen Fernanda Cristina
Published: April 2021

Recent studies have identified a clinical isolate of the commensal Streptococcus mitis that expresses Streptococcus pneumoniae serotype 5 capsule (S. mitis serotype 5) and shows serospecificity toward pneumococcal serotype 5. However, it remains unknown whether S. mitis serotype 5 induces protective immunity against pneumococcal serotype 5. In this study, we evaluated the ability of S. mitis serotype 5 to generate protective immunity in a mouse model of lung infection with pneumococcal serotype 5. Upon challenge infection with S. pneumoniae serotype 5, mice intranasally immunized with S. mitis serotype 5 exhibited reduced pneumococcal loads in the lungs, nasal wash, and bronchoalveolar lavage fluid compared with those receiving PBS (control). The immunized mice displayed significantly higher levels of IgG and IgA antibodies reactive to S. mitis serotype 5, S. pneumoniae serotype 5 or S. pneumoniae serotype 4 than the antibody levels in control mice. In vaccinated mice, the IgG/IgA antibody levels reactive to S. mitis serotype 5 or S. pneumoniae serotype 5 were higher than the levels reactive to S. pneumoniae serotype 4. Furthermore, in-vitro restimulation of the lung-draining mediastinal lymph node cells and splenocytes from immunized mice with killed S. mitis serotype 5, S. pneumoniae serotype 5 or S. pneumoniae serotype 4 showed enhanced Th17, but not Th1 and Th2, responses. Overall, our findings show that mucosal immunization with S. mitis serotype 5 protects against S. pneumoniae serotype 5 infection and induces Th17 and predominant serotype-specific IgG/IgA antibody responses against pneumococcal infection.
Recent Advances on Nanocomposite Resists With Design Functionality for Lithographic Microfabrication
Authors: Martínez E. D. , Prado A. , Gonzalez M. , Anguiano S. , Tosi L. , Salazar Alarcón L. , Pastoriza H.
Published: April 2021

Nanocomposites formed by a phase-dispersed nanomaterial and a polymeric host matrix are highly attractive for nano- and micro-fabrication. The combination of nanoscale and bulk materials aims at achieving an effective interplay between extensive and intensive physical properties. Nanofillers display size-dependent effects, paving the way for the design of tunable functional composites. The matrix, on the other hand, can facilitate or even enhance the applicability of nanomaterials by allowing their easy processing for device manufacturing. In this article, we review the field of polymer-based nanocomposites acting as resist materials, i.e. being patternable through radiation-based lithographic methods. A comprehensive explanation of the synthesis of nanofillers, their functionalization and the physicochemical concepts behind the formulation of nanocomposites resists will be given. We will consider nanocomposites containing different types of fillers, such as metallic, magnetic, ceramic, luminescent and carbon-based nanomaterials. We will outline the role of nanofillers in modifying various properties of the polymer matrix, such as the mechanical strength, the refractive index and their performance during lithography. Also, we will discuss the lithographic techniques employed for transferring 2D patterns and 3D shapes with high spatial resolution. The capabilities of nanocomposites to act as structural and functional materials in novel devices and selected applications in photonics, electronics, magnetism and bioscience will be presented. Finally, we will conclude with a discussion of the current trends in this field and perspectives for its development in the near future.
Knock-Down of Mucolipin 1 Channel Promotes Tumor Progression and Invasion in Human Glioblastoma Cell Lines
Authors: Santoni Giorgio , Amantini Consuelo , Nabissi Massimo , Maggi Federica , Arcella Antonietta , Marinelli Oliviero , Eleuteri Anna Maria , Santoni Matteo , Morelli Maria Beatrice
Published: April 2021

Among cancers that affect the central nervous system, glioblastoma is the most common. Given the negative prognostic significance of transient receptor potential mucolipin 1 (TRPML1) channel reduction in patients with glioblastoma, as discussed in previous publications, the aim of the current study was to investigate the biological advantage of TRPML1 loss for glioma cells. Human glioblastoma primary cancer cells (FSL and FCL) and glioblastoma cell lines (T98 and U251) were used for that purpose. TRPML1 silencing in T98 cells induces defective autophagy, nitric oxide (NO) production, and cathepsin B-dependent apoptosis in the first 48 h and then apoptotic-resistant cells proliferate with a high growth rate with respect to control cells. In U251 cells, knock-down of TRPML1 stimulates NO generation and protein oxidation, arrests cell cycle at G2/M phase, and induces autophagy leading to cathepsin B-dependent senescence. Finally, in both cell lines, the long-term effects of TRPML1 silencing promote survival and invasion capacity with respect to control cells. Silencing of TRPML1 also affects the phenotype of glioblastoma primary cells. FSL cells show increased proliferation ability, while FCL cells enter into senescence associated with an increased invasion ability. In conclusion, although the molecular heterogeneity among different glioblastoma cell lines mirrors the intercellular heterogeneity in cancer cells, our data support TRPML1 downregulation as a negative prognostic factor in glioblastoma.
Tyrosine Kinase Inhibitor Cabozantinib Inhibits Murine Renal Cancer by Activating Innate and Adaptive Immunity
Authors: Liu Hongyan , Sun Shishuo , Wang Gang , Lu Mengmeng , Zhang Xiaokang , Wei Xiaohuan , Gao Xiaoge , Huang Chao , Li Zhen , Zheng Junnian , Zhang Qing
Published: April 2021

Background

Advanced renal cell carcinoma (RCC) has a very dismal prognosis. Cabozantinib, a tyrosine kinase inhibitor, has been approved for the treatment of advanced RCC. However, the impact of cabozantinib on the immune microenvironment of RCC remains poorly understood.

Methods

Kaplan-Meier survival curves were constructed to examine the correlation between intratumor infiltration of neutrophils and patient prognosis in RCC. Infiltration and effector function of neutrophils and T cells in response to cabozantinib treatment were investigated in a murine RCC model.

Results

A retrospective study of 307 RCC patients indicated that neutrophils were recruited into tumor tissues, and increased neutrophil infiltration was associated with improved clinical outcomes. In a murine model of RCC, cabozantinib treatment significantly increased both intratumor infiltration and anti-tumor function of neutrophils and T cells. Mechanistically, we found that cabozantinib treatment induced expression of neutrophil-related chemokines (CCL11 and CXCL12) and T cell-related chemokines (CCL8 and CX3CL1) in the tumor microenvironment. Furthermore, depletion of neutrophils and CD8+ T cells compromised the therapeutic efficacy of cabozantinib. Importantly, cabozantinib treatment induced long-term anti-tumor T cell response.

Conclusions

Our study revealed novel mechanisms of the therapeutic effects of cabozantinib on RCC by activating both neutrophil-mediated innate immunity and T cell-mediated adaptive immunity. These findings are of great significance for guiding the clinical use of cabozantinib and provide a good candidate for future combination therapy with T-cell therapies or other immunotherapies.
Inflammation as a Risk Factor in Cardiotoxicity: An Important Consideration for Screening During Drug Development
Authors: Campana Chiara , Dariolli Rafael , Boutjdir Mohamed , Sobie Eric A.
Published: April 2021

Numerous commonly prescribed drugs, including antiarrhythmics, antihistamines, and antibiotics, carry a proarrhythmic risk and may induce dangerous arrhythmias, including the potentially fatal Torsades de Pointes. For this reason, cardiotoxicity testing has become essential in drug development and a required step in the approval of any medication for use in humans. Blockade of the hERG K+ channel and the consequent prolongation of the QT interval on the ECG have been considered the gold standard to predict the arrhythmogenic risk of drugs. In recent years, however, preclinical safety pharmacology has begun to adopt a more integrative approach that incorporates mathematical modeling and considers the effects of drugs on multiple ion channels. Despite these advances, early stage drug screening research only evaluates QT prolongation in experimental and computational models that represent healthy individuals. We suggest here that integrating disease modeling with cardiotoxicity testing can improve drug risk stratification by predicting how disease processes and additional comorbidities may influence the risks posed by specific drugs. In particular, chronic systemic inflammation, a condition associated with many diseases, affects heart function and can exacerbate medications’ cardiotoxic effects. We discuss emerging research implicating the role of inflammation in cardiac electrophysiology, and we offer a perspective on how in silico modeling of inflammation may lead to improved evaluation of the proarrhythmic risk of drugs at their early stage of development.
Relational Processes in Ayahuasca Groups of Palestinians and Israelis
Authors: Roseman Leor , Ron Yiftach , Saca Antwan , Ginsberg Natalie , Luan Lisa , Karkabi Nadeem , Doblin Rick , Carhart-Harris Robin
Published: April 2021

Psychedelics are used in many group contexts. However, most phenomenological research on psychedelics is focused on personal experiences. This paper presents a phenomenological investigation centered on intersubjective and intercultural relational processes, exploring how an intercultural context affects both the group and individual process. Through 31 in-depth interviews, ceremonies in which Palestinians and Israelis drink ayahuasca together have been investigated. The overarching question guiding this inquiry was how psychedelics might contribute to processes of peacebuilding, and in particular how an intercultural context, embedded in a protracted conflict, would affect the group’s psychedelic process in a relational sense. Analysis of the interviews was based on grounded theory. Three relational themes about multilocal participatory events which occurred during ayahuasca rituals have emerged from the interviews: 1)Unity-Based Connection– collective events in which a feeling of unity and ‘oneness’ is experienced, whereby participants related to each other based upon a sense of shared humanity, and other social identities seemed to dissolve (such as national and religious identities). 2)Recognition and Difference-Based Connection –events where a strong connection was made to the other culture. These events occurred through the expression of the other culture or religion through music or prayers, which resulted in feelings of awe and reverence 3)Conflict-related revelations– events where participants revisited personal or historical traumatic elements related to the conflict, usually through visions. These events weretriggeredby the presence of ‘the Other,’ and there was a political undertone in those personal visions. This inquiry has revealed that psychedelic ceremonies have the potential to contribute to peacebuilding. This can happen not just by ‘dissolution of identities,’ but also by providing a space in which shared spiritual experiences can emerge from intercultural and interfaith exchanges. Furthermore, in many cases, personal revelations were related to the larger political reality and the history of the conflict. Such processes can elucidate the relationship between personal psychological mental states and the larger sociopolitical context.