bluuebunny/crossref_metadata_2025 huggingface dataset:
An electrostatic switch displaces phosphatidylinositol phosphate kinases from the membrane during phagocytosis
Authors: Fairn Gregory D , Ogata Koji , Botelho Roberto , D. Stahl Philip , A. Anderson Richard , Camilli Pietro De , Meyer Tobias , Wodak Shoshana , Grinstein Sergio
Published: January 2023

Plasmalemmal phosphatidylinositol (PI) 4,5-bisphosphate (PI4,5P(2)) synthesized by PI 4-phosphate (PI4P) 5-kinase (PIP5K) is key to the polymerization of actin that drives chemotaxis and phagocytosis. We investigated the means whereby PIP5K is targeted to the membrane and its fate during phagosome formation. Homology modeling revealed that all PIP5K isoforms feature a positively charged face. Together with the substrate-binding loop, this polycationic surface is proposed to constitute a coincidence detector that targets PIP5Ks to the plasmalemma. Accordingly, manipulation of the surface charge displaced PIP5Ks from the plasma membrane. During particle engulfment, PIP5Ks detached from forming phagosomes as the surface charge at these sites decreased. Precluding the change in surface charge caused the PIP5Ks to remain associated with the phagosomal cup. Chemically induced retention of PIP5K-gamma prevented the disappearance of PI4,5P(2) and aborted phagosome formation. We conclude that a bistable electrostatic switch mechanism regulates the association/dissociation of PIP5Ks from the membrane during phagocytosis and likely other processes.

 
Lysosome enlargement during inhibition of the lipid kinase PIKfyve proceeds through lysosome coalescence
Authors: Choy Christopher H , Saffi Golam , Gray Matthew A , Wallace Callen , Dayam Roya Monica , Ou Zhen-Yi A , M. Lenk Guy , Puertollano Rosa , Watkins Simon C. , Botelho Roberto
Published: January 2023

Lysosomes receive and degrade cargo from endocytosis, phagocytosis and autophagy. They also play an important role in sensing and instructing cells on their metabolic state. The lipid kinase PIKfyve generates phosphatidylinositol-3,5-bisphosphate to modulate lysosome function. PIKfyve inhibition leads to impaired degradative capacity, ion dysregulation, abated autophagic flux and a massive enlargement of lysosomes. Collectively, this leads to various physiological defects, including embryonic lethality, neurodegeneration and overt inflammation. The reasons for such drastic lysosome enlargement remain unclear. Here, we examined whether biosynthesis and/or fusion-fission dynamics contribute to swelling. First, we show that PIKfyve inhibition activates TFEB, TFE3 and MITF, enhancing lysosome gene expression. However, this did not augment lysosomal protein levels during acute PIKfyve inhibition, and deletion of TFEB and/or related proteins did not impair lysosome swelling. Instead, PIKfyve inhibition led to fewer but enlarged lysosomes, suggesting that an imbalance favouring lysosome fusion over fission causes lysosome enlargement. Indeed, conditions that abated fusion curtailed lysosome swelling in PIKfyve-inhibited cells.
Phagosome resolution regenerates lysosomes and maintains the degradative capacity in phagocytes
Authors: Lancaster Charlene E. , Fountain Aaron , Dayam Roaya M. , Somerville Elliott , Sheth Javal , Jacobelli Vanessa , Somerville Alex , R. Terebiznik Mauricio , Botelho Roberto
Published: January 2023

Phagocytes engulf unwanted particles into phagosomes that then fuse with lysosomes to degrade the enclosed particles. Ultimately, phagosomes must be recycled to help recover membrane resources that were consumed during phagocytosis and phagosome maturation, a process referred to as “phagosome resolution.” Little is known about phagosome resolution, which may proceed through exocytosis or membrane fission. Here, we show that bacteria-containing phagolysosomes in macrophages undergo fragmentation through vesicle budding, tubulation, and constriction. Phagosome fragmentation requires cargo degradation, the actin and microtubule cytoskeletons, and clathrin. We provide evidence that lysosome reformation occurs during phagosome resolution since the majority of phagosome-derived vesicles displayed lysosomal properties. Importantly, we show that clathrin-dependent phagosome resolution is important to maintain the degradative capacity of macrophages challenged with two waves of phagocytosis. Overall, our work suggests that phagosome resolution contributes to lysosome recovery and to maintaining the degradative power of macrophages to handle multiple waves of phagocytosis. 
Migration through physical constraints is enabled by MAPK-induced cell softening via actin cytoskeleton re-organization
Authors: Rudzka Dominika A , Spennati Giulia , McGarry David J. , Chim Ya Hua , Neilson Matthew , Ptak Aleksandra , Munro June , Kalna Gabriela , Hedley Ann , Moralli Daniela , Green Catherine , Mason Susan , Blyth Karen , Mullin Margaret , Yin Huabing , Olson Michael
Published: January 2023

Cancer cells are softer than the normal cells, and metastatic cells are even softer. These changes in biomechanical properties contribute to cancer progression by facilitating cell movement through physically constraining environments. To identify properties that enabled passage through physical constraints, cells that were more efficient at moving through narrow membrane micropores were selected from established cell lines. By examining micropore-selected human MDA MB 231 breast cancer and MDA MB 435 melanoma cancer cells, membrane fluidity and nuclear elasticity were excluded as primary contributors. Instead, reduced actin cytoskeleton anisotropy, focal adhesion density and cell stiffness were characteristics associated with efficient passage through constraints. By comparing transcriptomic profiles between the parental and selected populations, increased Ras/MAPK signalling was linked with cytoskeleton rearrangements and cell softening. MEK inhibitor treatment reversed the transcriptional, cytoskeleton, focal adhesion and elasticity changes. Conversely, expression of oncogenic KRas in parental MDA MB 231 cells, or oncogenic BRaf in parental MDA MB 435 cells, significantly reduced cell stiffness. These results reveal that MAPK signalling, in addition to tumour cell proliferation, has a significant role in regulating cell biomechanics.This article has an associated First Person interview with the first author of the paper.
The Study of Living Qur'an on Al-Ma’tsurat Recitation Tradition at Darul Qur'an Islamic Boarding School Pendung Talang Genting
Authors: Munawaroh Munawaroh , Ravico Ravico
Published: January 2023

It takes calm in everything that we will do, especially when the students study religious knowledge, study Qur’an and memorize Qur’an. This gave birth to a thought to create a peaceful and serene atmosphere in the pesantren environment and the hearts of students. This study aims to find out how the tradition of reading al-Ma’tsurat in the Darul Qur'an Islamic boarding school; Second, to see how the meaning of al-Ma’tsurat is in the lives of the students of the Darul Qur'an Islamic boarding school; Third, to see the impact of reading al-Ma’tsurat on the students at Darul Qur'an Islamic Boarding School. This study uses the Living Qur'an method, where this method looks at how social phenomena are present because of the Qur'an in certain places and at certain times. From this study, it was found that the tradition of reading al-Ma’tsurat in Darul Qur'an is a daily activity that is routinely carried out in the morning and evening by the students. Al-Ma’tsurat has the meaning of a form of closeness to Allah and a form of gratitude for the blessings that Allah has given. Reading al-Ma’tsurat can have an impact both on the environment and on the mind of a student or reader.
The Legal and Practical Issues Related to the System of Two High Courts in Malaysia
Authors: Ramalingam Sheila , Sabaruddin Johan Shamsuddin , Dhanapal Saroja
Published: January 2023

Malaysia was formed on 16 September 1963 when among others, the two states in East Malaysia (Sabah and Sarawak) were federated with West Malaysia or Peninsula Malaysia (then known as the Federation of Malaya). The Federal Constitution of the Federation of Malaya was then extensively amended to accommodate the creation of the new Federation of Malaysia. However, as a compromise for the states of Sabah and Sarawak to join Malaya and become the Federation of Malaysia, many aspects of the judicial and legal system, as it was before the formation of Malaysia, were maintained. This included, among others, having two High Courts of co-ordinate jurisdiction and status, namely the High Court in Malaya for West Malaysia and the High Court in Sabah and Sarawak for East Malaysia, the use of different languages in both these courts, separate legal profession for West Malaysia, Sabah and Sarawak respectively, and different laws on the same subject matter between East and West Malaysia. Although this system has been in place now for over five decades, it has given rise to various legal and practical issues which have remained unresolved up till now. This paper seeks to highlight some of these issues.
Israeli Government Policy on Non-Israeli Construction Workers
Authors: Ida Yoram , Talit Gal
Published: January 2023

In Israel, there has been a severe shortage of housing units for several decades, due, among other things, to a shortage of skilled construction workers. The industry employs Palestinian labourers (since 1967) and migrant workers, mainly from Eastern Europe and China (since the 1990s). The Israeli government has changed its policy on the employment of non-Israeli workers several times. This article reviews these changes and discusses their successes and failures. The findings show that the shortage of workers in the construction industry in Israel might justify an increase in the quota of non-Israeli workers in the short term. However, in the medium and long term, measures must be taken to ensure implementation of planned reforms to reduce Israel's dependence on non-Israelis and encourage the integration of Israeli workers in the industry. This should be achieved mainly through technological improvements and a transition to industrialized construction.
Successful treatment of generalized subcorneal pustular dermatosis involving mucosa with cyclosporine: a case report
Authors: SALICI Nazmiye Selin , ERTEKİN Sümeyre Seda , DEMİRKESEN Cuyan , VURAL Seçil
Published: January 2023

Subcorneal pustular dermatosis (SPD), is rare, chronic, and relapsing pustuler eruption. Mostly, it affects middle-aged and elderly women. Mucosal involvement is extremely rare. Here we report a 31-year-old woman with generalized SPD with lip involvement. The patient had annular or serpiginous patterned well-demarcated plaques on the trunk, intertriginous areas and flexor aspects of the limbs, palmoplantar areas, face, and lip mucosa. The bullous lesions exhibited the typical half and half sign. The patient was treated successfully with systemic steroids and cyclosporine.
Analisis Ekonomis, Efisiensi dan Efektivitas Anggaran Pendapatan dan Belanja
Authors: Lona Sumartin Selfina , Perseveranda M. E. , Manafe Henny A.
Published: January 2023

The objective of this study was to understand the economical, efficient and effective implementation of the State Revenue and Expenditure Budget at the government institution. Data sources used in this study are financial reports especially budget ceiling and budget realization between the period of 2017 and 2021 fiscal year was obtained  from The Online Monitoring of the State Accounting Treasury System, the Ministry of Finance of the Republic of Indonesia. The descriptive and comparative analyses were employed in this study. The results of the research show that Economic level in 2017-2021 fiscal year utilisation felt into the economical category as shown by  the percentage of budget realization was less than 100% (<100%). The effective level of achievement for non-tax state income realisation between 2017 and 2021 fiscal year felt into a very effective criteria with the effective ratio was 103.62%; while that for the expenditure felt into a sufficient effective criteria with an average effective ratio was 91.30%. Cost efficiency ratio/expenditure realization to achieve the maximum revenue in the period of 2017 – 2021 suits for a very efficient category with the ratio for each fiscal year was less than 19%; thus economical, efficient and effective implementation of State Revenue and Expenditure Budget must continue to be improved
Personalised Approach to Atherosclerotic Cardiovascular Disease: The Future is Here
Authors: Humphry Nicola
Published: January 2023

This plenary session began with a focus on cutting edge research into the role of the immune system in atherosclerotic cardiovascular disease (ASCVD). Firstly, Chiara Giannerelli, New York University (NYU) Langone Health and NYU Grossman School of Medicine, New York, USA, emphasised the value of deep phenotyping of atherosclerotic disease to understand the immune mechanisms involved in cardiovascular (CV) risk. She presented data demonstrating an enrichment of phenotypically distinct cluster of differentiation (CD) 4+ and CD8+ T cells in advanced atherosclerotic plaque compared with paired blood and explained how this data can be used to identify drugs with the potential to be repurposed to reduce CV risk.

Secondly, Eicke Latz, Institute of Innate Immunity, University of Bonn, Germany, presented data from his research team that begins to explain how the Western diet might lead to chronic inflammation and atherogenesis, implicating cholesterol crystals and short-chain sphingomyelins in the reprogramming of granulocyte-monocyte precursor cells (GMP) in this process. The arguments for greater use of imaging and molecular biomarkers in clinical practice were presented by Wolfgang Koenig, German Heart Center Munich, Technical University of Munich, Germany, who speculated that the assessment of CV risk in the future is likely to harness big data and machine learning to achieve accurate risk assessment in individual patients.

Finally, Amit Khera, Massachusetts General Hospital, Boston, USA, covered the role of genetic factors in the prediction of CV disease (CVD), explaining that a combination of traditional risk factors and polygenic scoring techniques provides the most accurate estimation of CVD risk.
Resistance to Targeted Therapies in Melanoma: New Insights
Authors: Palmieri Giuseppe , Colombino Maria , Sini Maria Cristina , Manca Antonella , Ascierto Paolo Antonio , Cossu Antonio
Published: January 2023

Several molecular mechanisms are involved in melanoma genesis and progression. Molecular targets for effective therapeutic intervention have been identified within the RAS-RAF-MEK-ERK and, to a less extent, PI3K-AKT pathways. The development of inhibitors of key effectors (mainly BRAF mutant, MEK, and KIT) into such pathways has significantly improved the treatment of patients with advanced melanoma. However, emerging data indicate that a large variety of acquired and intrinsic mechanisms may drive resistance to the main targeted inhibitors. All the evidence suggests that in melanoma, as probably in all types of cancer, it is unlikely that targeting a single component in pathogenetic signalling pathways could yield significant antitumour responses. Therefore, knowledge of the multiple altered signalling events involved in response and resistance to targeted treatments will allow for the development of more effective combination therapies, which may represent the next challenge for the management of patients with such a disease.
Practical Evaluation and Handling of Patients with Irritable Bowel Syndrome
Authors: Ohlsson Bodil
Published: January 2023

Irritable bowel syndrome (IBS) is a functional bowel disorder by unknown aetiology. Several reviews are written about pharmacological and psychological treatment of the disease. Nevertheless, healthcare professionals consider these patients difficult to handle in daily practice. There is an uncertainty about how to measure symptoms and to evaluate the effect of any given treatment. In the absence of objective markers, professionals feel unsure of how to manage the condition and the patients do not feel that they are taken seriously. The development of the short, self-reported questionnaire, Visual Analogue Scale for Irritable Bowel Syndrome (VAS-IBS), offers a practical guide to objective measurement of symptoms and effect of given treatments into numerical values in the daily practice.
Adipose Tissue, Metabolic Syndrome, and Non-Alcoholic Fatty Liver Disease – A Short Review
Authors: Kouis Panayiotis , Pampaka Despina , Panayiotou Andrie G
Published: January 2023

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease globally, and it is expected to rise even further as a result of the increase in obesity and related risk factors. This short review summarises current evidence on the role of adipose tissue and insulin resistance in NAFLD and the interrelationship between NAFLD and the metabolic syndrome (MetS), considering central adiposity is a major feature of both the MetS and NAFLD, and that NAFLD has been previously described as the hepatic manifestation of the MetS. In addition, genetic studies of NAFLD with relation to adiposity and insulin resistance are reviewed, and up-to-date diagnostic and therapeutic tools are also discussed.
Paediatric Acute-on-Chronic Liver Failure: A Review of Current Evidence in Children
Authors: Go Lynette , Kuan Chiou Fang
Published: January 2023

Acute-on-chronic liver failure (ACLF) is a syndrome that describes acute decompensation of chronic liver disease with differing definitions worldwide, but is universally associated with high short-term mortality. This is becoming increasingly recognised as a unique entity that affects both adults and children. This narrative review summarises the current available evidence from paediatric studies on definition, incidence, pathophysiology, and outcome, with reference to data on ACLF from adult literature. Paediatric data remain scarce, and study groups have used differing inclusion criteria that have limited generalisability of data. There is a crucial need for a consensus definition for paediatric ACLF so that future collaborative research may provide better understanding on the epidemiology, pathophysiology, risk factors, and outcome of this clinical entity.
New Generations of Drug-Eluting Stents – A Brief Review
Authors: Ernst Aleksander , Bulum Joško
Published: January 2023

This review focuses on describing new generations of drug-eluting stents (DES) based on the use of novel stent platforms, coatings, and carrier systems, developed to enhance DES safety. Examples of various DES classes among the most clinically-used DES are briefly discussed.
Multivariate Analysis and Outcomes in Percutaneous Coronary Intervention; from Statistics to Cath Lab
Authors: D’Ascenzo Fabrizio , Biondi Zoccai Giuseppe , Cavallero Erika , Omedè Pierluigi , Giacomo Presutti Davide , Sciuto Filippo , Cerrato Enrico , Ballocca Flavia , Bisi Marta , Quadri Giorgio , Meynet Ilaria , Barbero Umberto , Vicentini Silvia , Gasparini Mauro , Agostoni Pierfrancesco , Capodanno Davide , Moretti Claudio , Gaita Fiorenzo
Published: January 2023

High quality randomised clinical trials (RCTs) and meta-analysis represent the highest levels of evidence, but in everyday clinical practice, observational studies are often exploited as a quick and easy way to understand the performance of clinical and interventional strategies. In this setting, multivariate analyses are exploited to drive useful and independent information, but due to potentially confounding messages, should be critically appraised and used in everyday clinical practice.
HOW WE MANAGE TO DIVERSITY: DIVERSITY CLIMATE EFFECT OF JOB SATISFACTION
Authors: GÜNER KİBAROĞLU Gamze
Published: January 2023

This study was examined in order to manage diversity by revealing the effect of a diversity climate on job satisfaction. The study was conducted with female participants working as blue-collar workers. In this context, 392 blue-collar female employees were reached. According to the results of the study, diversity climate has a significant effect on job satisfaction in the same direction. To put it more clearly, job satisfaction will increase with the increase in the diversity climate level of blue-collar women. In other words, job satisfaction levels will increase when blue-collar employees are treated more fairly by their companies, have a friendly working environment, and respect the opinions of the company regardless of race, language or religion. According to these results of the study, suggestions were presented to practitioners and academicians. In addition, within the scope of the study, the diversity climate scale was adapted into Turkish. In this implementation study, the cultural compatibility of the scale was analyzed with construct validity and concurrent validity according to scale variance structure and covariance relations. For reliability, internal consistency tests of the questions were made, and the education difference of the scale was calculated. As a result of all analyzes, sufficient evidence has been obtained that the scale is valid and reliable.
AMERİKAN DOLARI KURUNUN YAPAY SİNİR AĞLARI YÖNTEMİYLE TAHMİNLENMESİ: 2009 – 2021 DÖNEMİ
Authors: TEKİN Tahsin Galip , PATIR Sait
Published: January 2023

Bu çalışmada Türk Lirası cinsinden Amerikan Doları (çalışmanın geri kalan kısmında dolar olarak anılacaktır) kuru değerinin yapay sinir ağları yöntemiyle tahminlenmesi ve yapay sinir ağları yönteminin dolar kuru tahminlemesinde başarılı olup olmadığının tespitinin yapılması hedeflenmektedir. Bu amaçla yapay sinir ağı, 2009 - 2021 dönemindeki yedi ayrı zaman serisine ait verilerle eğitilerek aynı dönem tahminlenmiştir. Tahmin değerleri gerçek değerlerle karşılaştırılmış ve hata metrikleri hesaplanmıştır. Çalışmada kullanılan tüm veriler Türkiye Cumhuriyet Merkez Bankası Elektronik Veri Dağıtım Sistemi’nden alınmıştır. Veriler MATLAB 2013 programı aracılığıyla analiz edilmiştir. Yapılan analiz sonrası MAE, MSE ve MAPE hata metrikleri hesaplanmıştır. Elde edilen sonuçlara göre MSE değeri 0,0019355, MAE değeri 0,01738, MAPE değeri ise 0,5137 olarak hesaplanmıştır. Bu bulgu kurulan modelin % 0,5137 (yaklaşık binde beş) hata oranı ile dolar kurunu tahmin ettiğini göstermektedir.
Alginate oligosaccharides enhance the antifungal activity of nystatin against candidal biofilms
Authors: Powell Lydia C. , Adams Jennifer Y. M. , Quoraishi Sadik , Py Charlène , Oger Anaϊs , Gazze Salvatore A. , Francis Lewis W. , von Ruhland Christopher , Owens David , Rye Philip D. , Hill Katja E. , Pritchard Manon F. , Thomas David W.
Published: January 2023

Background

The increasing prevalence of invasive fungal infections in immuno-compromised patients is a considerable cause of morbidity and mortality. With the rapid emergence of antifungal resistance and an inadequate pipeline of new therapies, novel treatment strategies are now urgently required.

Methods

The antifungal activity of the alginate oligosaccharide OligoG in conjunction with nystatin was tested against a range of Candida spp. (C. albicans, C. glabrata, C. parapsilosis, C. auris, C. tropicalis and C. dubliniensis), in both planktonic and biofilm assays, to determine its potential clinical utility to enhance the treatment of candidal infections. The effect of OligoG (0-6%) ± nystatin on Candida spp. was examined in minimum inhibitory concentration (MIC) and growth curve assays. Antifungal effects of OligoG and nystatin treatment on biofilm formation and disruption were characterized using confocal laser scanning microscopy (CLSM), scanning electron microscopy (SEM) and ATP cellular viability assays. Effects on the cell membrane were determined using permeability assays and transmission electron microscopy (TEM).

Results

MIC and growth curve assays demonstrated the synergistic effects of OligoG (0-6%) with nystatin, resulting in an up to 32-fold reduction in MIC, and a significant reduction in the growth of C. parapsilosis and C. auris (minimum significant difference = 0.2 and 0.12 respectively). CLSM and SEM imaging demonstrated that the combination treatment of OligoG (4%) with nystatin (1 µg/ml) resulted in significant inhibition of candidal biofilm formation on glass and clinical grade silicone surfaces (p < 0.001), with increased cell death (p < 0.0001). The ATP biofilm disruption assay demonstrated a significant reduction in cell viability with OligoG (4%) alone and the combined OligoG/nystatin (MIC value) treatment (p < 0.04) for all Candida strains tested. TEM studies revealed the combined OligoG/nystatin treatment induced structural reorganization of the Candida cell membrane, with increased permeability when compared to the untreated control (p < 0.001).

Conclusions

Antimicrobial synergy between OligoG and nystatin against Candida spp. highlights the potential utility of this combination therapy in the prevention and topical treatment of candidal biofilm infections, to overcome the inherent tolerance of biofilm structures to antifungal agents.
The role of FOXA family transcription factors in glucolipid metabolism and NAFLD
Authors: Yu Chuchu , Li Xiaojing , Zhao Yu , Hu Yiyang
Published: January 2023

Abnormal glucose metabolism and lipid metabolism are common pathological processes in many metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD). Many studies have shown that the forkhead box (FOX) protein subfamily FOXA has a role in regulating glucolipid metabolism and is closely related to hepatic steatosis and NAFLD. FOXA exhibits a wide range of functions ranging from the initiation steps of metabolism such as the development of the corresponding metabolic organs and the differentiation of cells, to multiple pathways of glucolipid metabolism, to end-of-life problems of metabolism such as age-related obesity. The purpose of this article is to review and discuss the currently known targets and signal transduction pathways of FOXA in glucolipid metabolism. To provide more experimental evidence and basis for further research and clinical application of FOXA in the regulation of glucolipid metabolism and the prevention and treatment of NAFLD.
Optimal configuration method of wind farm hybrid energy storage based on EEMD-EMD and grey relational degree analysis
Authors: Shen Jiangbo , Huang Sujuan , Liu Chunjing , Li Shaodong , Wu Jinwen
Published: January 2023

The large-scale grid connection of new energy wind power generation has caused serious challenges to the power quality of the power system. The hybrid energy storage system (HESS) is an effective means to smooth the fluctuation of wind power and improve the economy of the system. In order to determine the optimal capacity configuration of the hybrid energy storage system, first, a decomposition method which combines ensemble empirical mode decomposition (EEMD) and empirical mode decomposition (EMD) is proposed, and a series of intrinsic mode functions are obtained, the grey correlation analysis method is used to analyze the similarity, and the components with similar correlation values are reconstructed to obtain high-frequency and low-frequency components; second, considering the battery life loss of the hybrid energy storage system, with the goal of minimizing the entire life cycle cost, the optimal configuration model of hybrid energy storage capacity is established, and different energy storage schemes are analyzed to obtain the energy storage configuration scheme with the best economy; finally, based on the typical daily historical data of a wind farm, the effectiveness and economy of the proposed method are verified.
Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies
Authors: Wan Shanshan , Zhao Ende , Freeman Daniel , Weissinger Daniel , Krantz Benjamin A. , Werba Gregor , Khanna Lauren G. , Siolas Despina , Oberstein Paul E. , Chattopadhyay Pratip K. , Simeone Diane M. , Welling Theodore H.
Published: January 2023

Hepato-pancreatico-biliary (HPB) malignancies are difficult-to-treat and continue to to have a high mortality and significant therapeutic resistance to standard therapies. Immune oncology (IO) therapies have demonstrated efficacy in several solid malignancies when combined with chemotherapy, whereas response rates in pancreatic ductal adenocarcinoma (PDA) are poor. While promising in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), there remains an unmet need to fully leverage IO therapies to treat HPB tumors. We therefore defined T cell phenotypic states, particularly in terms of immune checkpoint receptor expression, in the tumor microenvironment of HPB patients utilizing novel, multiparameter flow cytometry and bioinformatics analysis. We demonstrate the presence of CD103+ tissue resident memory T cells (TRM), CCR7+ central memory T cells, and CD57+ terminally differentiated effector cells across all HPB cancers, with simultaneous expression of multiple co-inhibitory checkpoint receptors. Terminally differentiated T cells lacking co-stimulatory receptors were more prevalent in PDA, whereas T cells expressing both co-inhibitory and co-stimulatory receptors were most prevalent in HCC, especially in early stage. HCC patients had significantly higher TRM with a phenotype that might confer restored activation in response to immune checkpoint therapies. Further, T-cell activation state and checkpoint expression did not change robustly in response to chemotherapy in PDA patients. These results support that HCC patients might benefit most from combined checkpoint therapies, whereas efforts other than cytotoxic chemotherapy will likely be necessary to increase overall T cell activation in CCA and PDA for future clinical development.
Analysis of IGH allele content in a sample group of rheumatoid arthritis patients demonstrates unrevealed population heterogeneity
Authors: Hardt Uta , Corcoran Martin M. , Narang Sanjana , Malmström Vivianne , Padyukov Leonid , Karlsson Hedestam Gunilla B.
Published: January 2023

Immunoglobulin heavy chain (IGH) germline gene variations influence the B cell receptor repertoire, with resulting biological consequences such as shaping our response to infections and altering disease susceptibilities. However, the lack of information on polymorphism frequencies in the IGH loci at the population level makes association studies challenging. Here, we genotyped a pilot group of 30 individuals with rheumatoid arthritis (RA) to examine IGH allele content and frequencies in this group. Eight novel IGHV alleles and one novel IGHJ allele were identified in the study. 15 cases were haplotypable using heterozygous IGHJ6 or IGHD anchors. One variant, IGHV4-34*01_S0742, was found in three out of 30 cases and included a single nucleotide change resulting in a non-canonical recombination signal sequence (RSS) heptamer. This variant allele, shown by haplotype analysis to be non-expressed, was also found in three out of 30 healthy controls and matched a single nucleotide polymorphism (SNP) described in the 1000 Genomes Project (1KGP) collection with frequencies that varied between population groups. Our finding of previously unreported alleles in a relatively small group of individuals with RA illustrates the need for baseline information about IG allelic frequencies in targeted study groups in preparation for future analysis of these genes in disease association studies.
Inhibition of sphingosine-1-phosphate receptor 3 suppresses ATP-induced NLRP3 inflammasome activation in macrophages via TWIK2-mediated potassium efflux
Authors: Wang Yingqin , Wang Chen , He Qiaolan , Chen Guannan , Yu Jie , Cang Jing , Zhong Ming
Published: January 2023

Background

Inhibition of sphingosine kinase 1 (SphK1), which catalyzes bioactive lipid sphingosine-1–phosphate (S1P), attenuates NLRP3 inflammasome activation. S1P exerts most of its function by binding to S1P receptors (S1PR1-5). The roles of S1P receptors in NLRP3 inflammasome activation remain unclear.

Materials and methods

The mRNA expressions of S1PRs in bone marrow-derived macrophages (BMDMs) were measured by real-time quantitative polymerase chain reaction (qPCR) assays. BMDMs were primed with LPS and stimulated with NLRP3 activators, including ATP, nigericin, and imiquimod. Interleukin-1β (IL-1β) in the cell culture supernatant was detected by enzyme-linked immunosorbent assay (ELISA). Intracellular potassium was labeled with a potassium indicator and was measured by confocal microscopy. Protein expression in whole-cell or plasma membrane fraction was measured by Western blot. Cecal ligation and puncture (CLP) was induced in C57BL/6J mice. Mortality, lung wet/dry ratio, NLRP3 activation, and bacterial loads were measured.

Results

Macrophages expressed all five S1PRs in the resting state. The mRNA expression of S1PR3 was upregulated after lipopolysaccharide (LPS) stimulation. Inhibition of S1PR3 suppressed NLRP3 and pro-IL-1β in macrophages primed with LPS. Inhibition of S1PR3 attenuated ATP-induced NLRP3 inflammasome activation, enhanced nigericin-induced NLRP3 activation, and did not affect imiquimod-induced NLRP3 inflammasome activation. In addition, inhibition of S1PR3 suppressed ATP-induced intracellular potassium efflux. Inhibition of S1PR3 did not affect the mRNA or protein expression of TWIK2 in LPS-primed BMDMs. ATP stimulation induced TWIK2 expression in the plasma membrane of LPS-primed BMDMs, and inhibition of S1PR3 impeded the membrane expression of TWIK2 induced by ATP. Compared with CLP mice treated with vehicle, CLP mice treated with the S1PR3 antagonist, TY52156, had aggravated pulmonary edema, increased bacterial loads in the lung, liver, spleen, and blood, and a higher seven-day mortality rate.

Conclusions

Inhibition of S1PR3 suppresses the expression of NLRP3 and pro-IL-1β during LPS priming, and attenuates ATP-induced NLRP3 inflammasome activation by impeding membrane trafficking of TWIK2 and potassium efflux. Although inhibition of S1PR3 decreases IL-1β maturation in the lungs, it leads to higher bacterial loads and mortality in CLP mice.
Natural and synthetic microfibers alter growth and behavior in early life stages of estuarine organisms
Authors: Siddiqui S. , Hutton S. J. , Dickens J. M. , Pedersen E. I. , Harper S. L. , Brander S. M.
Published: January 2023

Increasing shares of microfibers are being detected in environmental samples and a closer look to identify the risk associated with them using ecologically relevant endpoints, especially at sensitive early life stages, is needed. To assess exposure hazards, we used rope samples representative of fiber types ubiquitous in coastal systems, where microfibers are often the most common debris type found in the water column. To compare responses to natural vs. synthetic microfibers, we used rinsed “natural” cotton, polyester, and polypropylene microfibers (80-150 µm length, 8-20 µm width) created from the rope. Larval and juvenile estuarine indicator species Inland Silverside (Menidia beryllina) and mysid shrimp (Americamysis bahia), respectively, were exposed to these three microfiber types at three concentrations (3, 10, 30 particles/ml) along a 5-25 PSU salinity gradient to mimic estuarine conditions. Behavioral responses, growth, and ingestion were measured. The cotton microfibers were not detected in the digestive tracts of Silversides, however, both the polyester and polypropylene microfibers were detected in the Silversides’ stomach and gut lining. None of the fiber types were detected in mysid shrimps. Mysids exposed to cotton microfibers had fewer behavioral effects compared to Silversides, who responded more to cotton. Cotton exerted no effect on growth in Silversides but did cause reduced growth in the mysids at the two lower salinities. In contrast, polyester and polypropylene were identified to have a significant dose dependent effect on mysid and Silverside behavior as well as growth was affected in at least one of the three salinities at concentrations as low as 3 particles/ml. Cotton impacted both the organism’s behavior more at higher salinities, whereas polyester and polypropylene had more impacts at lower salinities. This raises concerns for microfiber impacts on estuarine ecosystems and the need for policies to limit microfiber production and outfall into the aquatic environment.
Spatial comparison and temporal evolution of two marine iron-rich microbial mats from the Lucky Strike Hydrothermal Field, related to environmental variations
Authors: Astorch-Cardona Aina , Guerre Mathilde , Dolla Alain , Chavagnac Valérie , Rommevaux Céline
Published: January 2023

In hydrothermal environments, diffuse fluids emanations provide optimal conditions for the development of iron-rich microbial mats. Here, we present a unique spatial and temporal study of phylogenetic and chemical data from this type of mats and their associated hydrothermal fluids from two sites of the Lucky Strike Hydrothermal Field (EMSO-Azores deep-sea observatory), collected annually from 2016 to 2020. Our metabarcoding analyses reveal a completely different microbial community at each site, linked to the distinctive chemical composition of the diffuse fluids nourishing the mats. Capelinhos site is dominated by microorganisms with metabolisms related to iron, methane, and reduced sulphur compounds, coming from hydrothermal fluids, while North Tour Eiffel site presents higher abundances of microorganisms with metabolisms related to nitrogen, organic and oxidized sulphur compounds, coming from seawater. We present for the first time the yearly evolution of these mats over a five-year period. This analysis reveals similar variations of the microbial communities over time at both sites, indicating a regional Lucky Strike influence on the temporal scale. We also highlight more diversified microbial communities at both sites in 2016, pointing out the occurrence of a geological event that could have affected them during this specific year. Except for this year, our study shows that the communities of iron-rich microbial mats remain stable over time at both sites.
Silver nanoparticles enhance the efficacy of aminoglycosides against antibiotic-resistant bacteria
Authors: Dove Autumn S. , Dzurny Dominika I. , Dees Wren R. , Qin Nan , Nunez Rodriguez Carmen C. , Alt Lauren A. , Ellward Garrett L. , Best Jacob A. , Rudawski Nicholas G. , Fujii Kotaro , Czyż Daniel M.
Published: January 2023

As the threat of antimicrobial-resistant bacteria compromises the safety and efficacy of modern healthcare practices, the search for effective treatments is more urgent than ever. For centuries, silver (Ag) has been known to have antibacterial properties and, over the past two decades, Ag-based nanoparticles have gained traction as potential antimicrobials. The antibacterial efficacy of Ag varies with structure, size, and concentration. In the present study, we examined Ag nanoparticles (AgNPs) for their antimicrobial activity and safety. We compared different commercially-available AgNPs against gram-negative Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, and gram-positive Staphylococcus aureus methicillin-resistant and susceptible strains. The most effective formula of AgNPs tested had single-digit (μg/mL) minimum inhibitory concentrations against gram-negative multidrug-resistant clinical bacterial isolates with novel and emerging mechanisms of resistance. The mode of killing was assessed in E. coli and was found to be bactericidal, which is consistent with previous studies using other AgNP formulations. We evaluated cytotoxicity by measuring physiological readouts using the Caenorhabditis elegans model and found that motility was affected, but not the lifespan. Furthermore, we found that at their antibacterial concentrations, AgNPs were non-cytotoxic to any of the mammalian cell lines tested, including macrophages, stem cells, and epithelial cells. More interestingly, our experiments revealed synergy with clinically relevant antibiotics. We found that a non-toxic and non-effective concentration of AgNPs reduced the minimum inhibitory concentrations of aminoglycoside by approximately 22-fold. Because both aminoglycosides and Ag are known to target the bacterial ribosome, we tested whether Ag could also target eukaryotic ribosomes. We measured the rate of mistranslation at bactericidal concentration and found no effect, indicating that AgNPs are not proteotoxic to the host at the tested concentrations. Collectively, our results suggest that AgNPs could have a promising clinical application as a potential stand-alone therapy or antibiotic adjuvants.
Versatile and active THz wave polarization modulators using metamaterial/graphene resonators
Authors: Zaman Abdullah M. , Lu Yuezhen , Almond Nikita W. , Burton Oliver J. , Alexander-Webber Jack , Hofmann Stephan , Mitchell Thomas , Griffiths Jonathan D. P. , Beere Harvey E. , Ritchie David A. , Degl’Innocenti Riccardo
Published: January 2023

Active modification of the polarization state is a key feature for the next-generation of wireless communications, sensing, and imaging in the THz band. The polarization modulation performance of an integrated metamaterial/graphene device is investigated via a modified THz time domain spectroscopic system. Graphene’s Fermi level is modified through electrostatic gating, thus modifying the device’s overall optical response. Active tuning of ellipticity by >0.3 is reported at the resonant frequency of 0.80 THz. The optical activity of transmitted THz radiations is continuously modified by >21.5o at 0.71 THz. By carefully selecting the transmitted frequency with the relative angle between the incoming linear polarization and the device’s symmetry axis, active circular dichroism and optical activity are almost independently exploited. Finally, this all-electronically tuneable versatile polarization device can be used in all applications requiring an ultrafast modulation such as polarization spectroscopy, imaging, and THz wireless generation.
Tanshinone IIA and hepatocellular carcinoma: A potential therapeutic drug
Authors: Li Hu , Hu Pengbo , Zou Yajun , Yuan Lijuan , Xu Yucheng , Zhang Xiaohui , Luo Xiaoyan , Zhang Zhiqiang
Published: January 2023

Because of its high prevalence and poor long-term clinical treatment effect, liver disease is regarded as a major public health problem around the world. Among them, viral hepatitis, fatty liver, cirrhosis, non-alcoholic fatty liver disease (NAFLD), and autoimmune liver disease are common causes and inducements of liver injury, and play an important role in the occurrence and development of hepatocellular carcinoma (HCC). Tanshinone IIA (TsIIA) is a fat soluble polyphenol of Salvia miltiorrhiza that is extracted from Salvia miltiorrhiza. Because of its strong biological activity (anti-inflammatory, antioxidant), it is widely used in Asia to treat cardiovascular and liver diseases. In addition, TsIIA has shown significant anti-HCC activity in previous studies. It not only has significant anti proliferation and pro apoptotic properties. It can also play an anti-cancer role by mediating a variety of signal pathways, including phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/rapamycin (mTOR), mitogen-activated protein kinase (MAPK), and nuclear factor kappa-B (NF-κB). This review not only reviews the existing evidence and molecular mechanism of TsIIA’s anti-HCC effect but also reviews the liver-protective effect of TsIIA and its impact on liver fibrosis, NAFLD, and other risk factors for liver cancer. In addition, we also conducted network pharmacological analysis on TsIIA and HCC to further screen and explore the possible targets of TsIIA against hepatocellular carcinoma. It is expected to provide a theoretical basis for the development of anti-HCC-related drugs based on TsIIA.
Notch signaling, hypoxia, and cancer
Authors: Guo Mingzhou , Niu Yang , Xie Min , Liu Xiansheng , Li Xiaochen
Published: January 2023

Notch signaling is involved in cell fate determination and deregulated in human solid tumors. Hypoxia is an important feature in many solid tumors, which activates hypoxia-induced factors (HIFs) and their downstream targets to promote tumorigenesis and cancer development. Recently, HIFs have been shown to trigger the Notch signaling pathway in a variety of organisms and tissues. In this review, we focus on the pro- and anti-tumorigenic functions of Notch signaling and discuss the crosstalk between Notch signaling and cellular hypoxic response in cancer pathogenesis, including epithelia-mesenchymal transition, angiogenesis, and the maintenance of cancer stem cells. The pharmacological strategies targeting Notch signaling and hypoxia in cancer are also discussed in this review.
Case report: A unique presentation of a high-grade neuroepithelial tumor with EWSR1::PATZ1 fusion with diagnostic, molecular, and therapeutic insights
Authors: Ene Andre , Di Jing , Neltner Janna H. , Pittman Thomas , Arnold Susanne M. , Kolesar Jill M. , Villano John L. , Bachert Sara E. , Allison Derek B.
Published: January 2023

Background

EWSR1::PATZ1 fusion tumors are exceedingly rare in the central nervous system with only 14 prior cases documented. PATZ1 fusion neuroepithelial tumors are beginning to be recognized as a distinct molecular class of neoplasms that most often occur in children and young adults. These tumors are polyphenotypic, show diverse morphologic features, may be low- or high-grade, and tend to have an intermediate prognosis.

Case presentation

Herein, we present an unusual case of a high-grade neuroepithelial tumor in a young man with an EWSR1::PATZ1 fusion. This case is unique because the tumor appears to have undergone high-grade transformation from a persistent low-grade glioma, which has yet to be reported. Furthermore, this case is the first to document concurrent RB1 loss, SMAD4 loss, and TP53 inactivation in this tumor type, which correlates with high-grade transformation. Fortunately, this patient is alive 2.5 years after treatment and 18.5 years after initial presentation, which provides a unique window into how these tumors clinically behave over a long follow-up period. Finally, we discuss the altered molecular pathways that are a result of the EWSR1::PATZ1 fusion and discuss potential therapeutic targets.

Conclusion

Awareness of the emerging entity of PATZ1 fusion neuroepithelial tumors is important not only for accurate diagnostic and prognostic purposes but also for predicting response to therapy.