bluuebunny/crossref_metadata_2025 huggingface dataset:
The Electric Vehicle Traveling Salesman Problem on Digital Elevation Models for Traffic-Aware Urban Logistics
Authors: Ahsini Yusef , Díaz-Masa Pablo , Inglés Belén , Rubio Ana , Martínez Alba , Magraner Aina , Conejero J. Alberto
Published: August 2023

With the increasing demand for online shopping and home delivery services, optimizing the routing of electric delivery vehicles in urban areas is crucial to reduce environmental pollution and improve operational efficiency. To address this opportunity, we optimize the Steiner Traveling Salesman Problem (STSP) for electric vehicles (EVs) in urban areas by combining city graphs with topographic and traffic information. The STSP is a variant of the traditional Traveling Salesman Problem (TSP) where it is not mandatory to visit all the nodes present in the graph. We train an artificial neural network (ANN) model to estimate electric consumption between nodes in the route using synthetic data generated with historical traffic simulation and topographical data. This allows us to generate smaller-weighted graphs that transform the problem from an STSP to a normal TSP where the 2-opt optimization algorithm is used to solve it with a Nearest Neighbor (NN) initialization. Compared to the approach of optimizing routes based on distance, our proposed algorithm offers a fast solution to the STSP for EVs (EV-STSP) with routes that consume 17.34% less energy for the test instances generated.
The Potential Role of Fecal Microbiota Transplantation in Parkinson’s Disease: A Systematic Literature Review
Authors: Vongsavath Tahne , Laeeq Tooba , Tun Kyaw Min , Hong Annie S.
Published: August 2023

Background and Aims: Parkinson’s disease (PD) is a multifaceted disease that can cause symptoms in multiple body systems, including the gastrointestinal (GI) tract. Fecal microbiota transplantation (FMT) is a proposed treatment to address dysregulation in the microbiome, with neurologic and GI symptoms as theoretic effects. The complex relationship between gut dysbiosis and PD symptoms suggests that FMT may have a role in therapy. Methods: A total of 124 articles with information pertaining to PD and FMT were reviewed. PD adult patients with neuromotor or GI symptoms who received FMT with moderate levels of evidence were examined. Data using self-reporting symptom scales were compared at baseline and following FMT. Results: An overall improvement was seen in patients’ neuromotor or GI symptoms, when compared to the baseline after FMT. After FMT, the patients reported improved constipation and decreased time to stool. Overall satisfaction differed between groups receiving differing routes of FMT administration and the severity of their baseline symptoms. Conclusions: FMT shows promising utility for PD patients with neuromotor and/or GI symptoms. Our results are limited by need to evaluate routes of administration, the chronicity of inflammation, and acidity’s role in colonization and efficacy. FMT has been illustrated as a well-tolerated non-pharmacologic treatment method for PD with refractory symptoms.
Exploring the Role of microRNAs in Glioma Progression, Prognosis, and Therapeutic Strategies
Authors: Tluli Omar , Al-Maadhadi Mazyona , Al-Khulaifi Aisha Abdulla , Akomolafe Aishat F. , Al-Kuwari Shaikha Y. , Al-Khayarin Roudha , Maccalli Cristina , Pedersen Shona
Published: August 2023

Gliomas, which arise from glial cells in the brain, remain a significant challenge due to their location and resistance to traditional treatments. Despite research efforts and advancements in healthcare, the incidence of gliomas has risen dramatically over the past two decades. The dysregulation of microRNAs (miRNAs) has prompted the creation of therapeutic agents that specially target them. However, it has been reported that they are involved in complex signaling pathways that contribute to the loss of expression of tumor suppressor genes and the upregulation of the expression of oncogenes. In addition, numerous miRNAs promote the development, progression, and recurrence of gliomas by targeting crucial proteins and enzymes involved in metabolic pathways such as glycolysis and oxidative phosphorylation. However, the complex interplay among these pathways along with other obstacles hinders the ability to apply miRNA targeting in clinical practice. This highlights the importance of identifying specific miRNAs to be targeted for therapy and having a complete understanding of the diverse pathways they are involved in. Therefore, the aim of this review is to provide an overview of the role of miRNAs in the progression and prognosis of gliomas, emphasizing the different pathways involved and identifying potential therapeutic targets.
Locoregional Treatment in Intrahepatic Cholangiocarcinoma: Which Treatment for Which Patient?
Authors: Bourien Héloïse , Pircher Chiara Carlotta , Guiu Boris , Lamarca Angela , Valle Juan W , Niger Monica , Edeline Julien
Published: August 2023

For unresectable intrahepatic cholangiocarcinoma (iCC), different locoregional treatments (LRT) could be proposed to patients, including radiofrequency ablation (RFA) and microwave ablation (MWA), external beam radiotherapy (EBRT) or transarterial treatments, depending on patient and tumor characteristics and local expertise. These different techniques of LRT have not been compared in a randomized clinical trial; most of the relevant studies are retrospective and not comparative. The aim of this narrative review is to help clinicians in their everyday practice discuss the pros and cons of each LRT, depending on the individual characteristics of their patients.
A Case-Only Genome-Wide Interaction Study of Smoking and Bladder Cancer Risk: Results from the COBLAnCE Cohort
Authors: Karimi Maryam , Mendez-Pineda Sebastian , Blanché Hélène , Boland Anne , Besse Céline , Deleuze Jean-François , Meng Xiang-Yu , Sirab Nanor , Groussard Karine , Lebret Thierry , Bonastre Julia , Allory Yves , Radvanyi François , Benhamou Simone , Michiels Stefan
Published: August 2023

Bladder cancer (BC) is the 6th most common cancer worldwide, with tobacco smoking considered as its main risk factor. Accumulating evidence has found associations between genetic variants and the risk of BC. Candidate gene-environment interaction studies have suggested interactions between cigarette smoking and NAT2/GSTM1 gene variants. Our objective was to perform a genome-wide association case-only study using the French national prospective COBLAnCE cohort (COhort to study BLAdder CancEr), focusing on smoking behavior. The COBLAnCE cohort comprises 1800 BC patients enrolled between 2012 and 2018. Peripheral blood samples collected at enrolment were genotyped using the Illumina Global Screening Array with a Multi-Disease drop-in panel. Genotyping data (9,719,614 single nucleotide polymorphisms (SNP)) of 1674, 1283, and 1342 patients were analyzed for smoking status, average tobacco consumption, and age at smoking initiation, respectively. A genome-wide association study (GWAS) was conducted adjusting for gender, age, and genetic principal components. The results suggest new candidate loci (4q22.1, 12p13.1, 16p13.3) interacting with smoking behavior for the risk of BC. Our results need to be validated in other case-control or cohort studies.
Optimized Conformal Total Body Irradiation with VMAT Using a Linear-Accelerator-Based Radiosurgery Treatment System in Comparison to the Golden Standard Helical TomoTherapy
Authors: Köksal Mümtaz , Özkan Oğuzhan , Holderried Tobias , Heine Annkristin , Brossart Peter , Gawish Ahmed , Scafa Davide , Sarria Gustavo R. , Leitzen Christina , Schmeel Leonard C. , Müdder Thomas
Published: August 2023

Modern irradiation techniques for optimized conformal TBI can be realized by Helical Tomotherapy (HT) or Volumetric Modulated Arc Therapy (VMAT), depending on the availability of suitable specialized equipment. In this dosimetric planning study, we compared both modalities and addressed the question of whether VMAT with small field sizes is also suitable as a backup in case of HT equipment malfunctions. For this purpose, we retrospectively used planning computed tomography (CT) data from 10 patients treated with HT with a total dose of 8 Gy (n = 5) or 12 Gy (n = 5) for treatment planning for VMAT with a small field size (36 × 22 cm). The target volume coverage, dose homogeneity at target volume, and dose reduction in organs at risk (OAR) (lungs, kidneys, lenses) were analyzed and compared. One patient was irradiated with both modalities due to a device failure of the HT equipment during the study, which facilitated a comparison in a real clinical setting. The findings indicate that in addition to a higher mean dose to the lenses in the 12 Gy group for VMAT and a better dose homogeneity in the target volume for HT, comparably good and adequate target dose coverage and dose reduction in the other OAR could be achieved for both modalities, with significantly longer treatment times for VMAT. In conclusion, after appropriate optimization of the treatment times, VMAT using linear accelerator radiosurgery technology can be used both as a backup in addition to HT and in clinical routines to perform optimized conformal TBI.
Long-Term Outcomes of Liver Transplantation in Hepatocellular Carcinoma with Bile Duct Tumor Thrombus: A Comparison with Portal Vein Tumor Thrombus
Authors: Lee Ji Soo , Kim Jongman , Rhu Jinsoo , Choi Gyu-Seong , Joh Jae-Won
Published: August 2023

Liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) with bile duct tumor thrombus (BDTT) remains controversial. This study analyzed the recurrence and overall survival rates through long-term results after LT in HCC patients with BDTT and compared the results after LT in HCC patients with portal vein tumor thrombus (PVTT). We performed a retrospective study of 45 patients with PVTT, 16 patients with BDTT, and 11 patients with coexisting PVTT and BDTT among HCC patients who underwent LT at a single center from 1999 to 2020. The HCC recurrence rates were 40.4% at 1 year, 30.3.3% at 2 years, and 27.6% at 3 years in the PVTT group; 66.7%, 53.3%, and 46.7% in the BDTT group; and 22.2%, 22.2%, and 0% in the coexisting group (p = 0.183). Overall patient survival rates were 68.4% at 1 year, 54.3% at 2 years, and 41.7% at 3 years in the PVTT group; 81.3%, 62.5%, and 48.2% in the BDTT group; and 63.6%, 27.3%, and 0% in the coexisting group (p = 0.157). In the multivariate analysis, the pre-transplantation model for tumor recurrence after liver transplantation (MoRAL) score and model for end-stage liver disease (MELD) score were found to be independent risk factors for recurrence and survival in all groups. HCC patients with BDTT showed no difference in recurrence and survival compared with HCC patients with PVTT at the long-term follow-up after LT.
Adiabatic Shortcuts Completion in Quantum Field Theory: Annihilation of Created Particles
Authors: Del Grosso Nicolás F. , Lombardo Fernando C. , Mazzitelli Francisco D. , Villar Paula I.
Published: August 2023

Shortcuts to adiabaticity (STA) are relevant in the context of quantum systems, particularly regarding their control when they are subjected to time-dependent external conditions. In this paper, we investigate the completion of a nonadiabatic evolution into a shortcut to adiabaticity for a quantum field confined within a one-dimensional cavity containing two movable mirrors. Expanding upon our prior research, we characterize the field’s state using two Moore functions that enables us to apply reverse engineering techniques in constructing the STA. Regardless of the initial evolution, we achieve a smooth extension of the Moore functions that implements the STA. This extension facilitates the computation of the mirrors’ trajectories based on the aforementioned functions. Additionally, we draw attention to the existence of a comparable problem within nonrelativistic quantum mechanics.
Combination of Fast Finite Shear Wave Transform and Optimized Deep Convolutional Neural Network: A Better Method for Noise Reduction of Wetland Test Images
Authors: Cui Xiangdong , Bai Huajun , Zhao Ying , Wang Zhen
Published: August 2023

Wetland experimental images are often affected by factors such as waves, weather conditions, and lighting, resulting in severe noise in the images. In order to improve the quality and accuracy of wetland experimental images, this paper proposes a wetland experimental image denoising method based on the fast finite shearlet transform (FFST) and a deep convolutional neural network model. The FFST is used to decompose the wetland experimental images, which can capture the features of different frequencies and directions in the images. The network model has a deep network structure and powerful feature extraction capabilities. By training the model, it can learn the relevant features in the wetland experimental images, thereby achieving denoising effects. The experimental results show that, compared to traditional denoising methods, the proposed method in this paper can effectively remove noise from wetland experimental images while preserving the details and textures of the images. This is of great significance for improving the quality and accuracy of wetland experimental images.
Timing-Driven Simulated Annealing for FPGA Placement in Neural Network Realization
Authors: Yu Le , Guo Baojin
Published: August 2023

The simulated annealing algorithm is an extensively utilized heuristic method for heterogeneous FPGA placement. As the application of neural network models on FPGAs proliferates, new challenges emerge for the traditional simulated annealing algorithm in terms of timing. These challenges stem from large circuit sizes and high heterogeneity in the block proportions typical in neural networks. To address these challenges, this study introduces a timing-driven simulated annealing placement algorithm. This algorithm integrates cluster criticality identification during the cluster selection phase, which enhances the probability of high-criticality cluster selection. In the cluster movement phase, the proposed method employs an improved weighted center movement for high-criticality clusters and a random movement strategy for other clusters. Experimental evidence demonstrates that the proposed placement algorithm decreases the average wire length by 1.52% and the average critical path delay by 5.03%. This improvement in performance is achieved with a marginal increase of 5.01% in runtime, as compared to VTR8.0.
Enhanced Density Peak-Based Power Grid Reactive Voltage Partitioning
Authors: Deng Xingye , Liu Canwei , Liu Hualiang , Chen Lei , Guo Yuyan , Zhen Heding
Published: August 2023

Clustering-based reactive voltage partitioning is successful in reducing grid cascading faults, by using clustering methods to categorize different power-consuming entities in the power grid into distinct regions. In reality, each power-consuming entity has different electrical characteristics. Additionally, due to the irregular and uneven distribution of the population, the distribution of electricity consumption is also irregular and uneven. However, the existing method neglects the electrical difference among each entity and the irregular and uneven density distribution of electricity consumption, resulting in poor accuracy and adaptability of these methods. To address these problems, an enhanced density peak model-based power grid reactive voltage partitioning method is proposed in this paper, called EDPVP. First, the power grid is modeled as a weighted reactive network to consider entity electrical differences. Second, the novel local density and density following distance are designed to enhance the density peak model to address the problem that the traditional density peak model cannot adapt to weighted networks. Finally, the enhanced density peak model is further equipped with an optimized cluster centers selection strategy and an updated remaining node assignment strategy, to better identify irregular and uneven density distribution of electricity consumption, and to achieve fast and accurate reactive voltage partition. Experiments on two real power grids demonstrate the effectiveness of the EDPVP.
Experimental Treatment of Solar Chimney Power Plant—A Comprehensive Review
Authors: Biswas Nirmalendu , Mandal Dipak Kumar , Bose Sharmistha , Manna Nirmal K. , Benim Ali Cemal
Published: August 2023

Solar chimney power plants (SCPPs) are encouraging sustainable energy sources due to their low cost, abundance, low maintenance, and eco-friendliness. However, despite significant efforts to optimize SCPP design, their efficiency and power generation capabilities remain limited. Researchers have explored modifications in plant geometry and hybridization to improve efficiency. Despite extensive work in this area, commercialization of SCPPs has not yet been achieved. Most of the research is numerical and may differ from real-world practical use. The number of experimental studies is also relatively small. To facilitate commercialization, further investigation with practical and feasible dimensions is required. This comprehensive review paper aims to provide an in-depth analysis of experimental approaches and advancements in the field of SCPPs. The paper begins with an introduction, highlighting the background, significance, and objectives of the review. It provides an overview of the plants, discussing their principles and operation as innovative renewable energy systems. The historical development and evolution of solar chimneys are explored, shedding light on their progression over time. Case studies of operational hybrid SCPPs are examined to showcase real-world applications and performance. The paper also addresses environmental impacts and sustainability considerations associated with SCPPs. Furthermore, recommendations for future research and development in this field are provided to guide researchers and industry professionals. This study focuses on the possibility of commercialization of both standalone and hybrid SCPPs.
Examining the Role of Renewable Energy, Technological Innovation, and the Insurance Market in Environmental Sustainability in the United States: A Step toward COP26 Targets
Authors: Samour Ahmed , Mehmood Usman , Radulescu Magdalena , Budu Radu Alexandru , Nitu Rares Mihai
Published: August 2023

Investigating the determinants of environmental sustainability has become a very attractive and popular area of research in response to the United Nations’ sustainable development goals (SDGs) and COP26 targets. Against this backdrop, this paper aims to explore the effects of renewable energy, technological innovation, and the insurance market on environmental sustainability in the United States (US). This work contributes to the extant body of knowledge by exploring the effect of the insurance market on the load capacity factor (LC), specifically regarding the US. The LC tracks a certain ecological threshold by simultaneously comparing biocapacity and ecological footprint (EF), thereby providing a comprehensive empirical analysis of ecological sustainability determinants. However, this proxy includes the combined attributes of the demand and supply sides of ecological sustainability. Using the recently developed autoregressive distributed lag method, this research reveals that the insurance market adversely affects the LC in the US. The overall outcomes highlight the positive role of renewable energy, technological innovation, and the insurance market in achieving the SDGs and COP26 targets. Policy recommendations for policymakers concerning promoting renewable energy, green innovation activities, the green insurance market, and ecological regulations are also discussed.
Exploring the Transcriptome Dynamics of In Vivo Theileria annulata Infection in Crossbred Cattle
Authors: Ahlawat Sonika , Choudhary Vikas , Arora Reena , Kumar Ashish , Kaur Mandeep , Chhabra Pooja
Published: August 2023

The molecular changes occurring in the host in response to in vivo Theileria annulata parasitic infection are not well understood. Therefore, the present study investigated the differential expression profiles of peripheral blood mononuclear cells (PBMCs) across Theileria annulata-infected and non-infected crossbred cows. The differential expression profiles from PBMCs of infected and non-infected crossbred cows were generated by RNA sequencing. A marked difference in the expression of genes associated with innate immunity (FTH1, ACTB, ISG15) was observed between the two groups. The over-represented pathways in Theileria annulata-infected cows were associated with the immune system and regulation of the mitotic cycle. Enriched genes and pathways in non-infected animals were associated with the maintenance of chromatin integrity and cell structure. The highly connected genes identified in this study form potential candidates for further investigation into host–parasite interactions in cattle. An improved understanding of the transcriptomic dynamics during theileriosis would lead to underpinning molecular level differences related to the health status of cattle.
Snijders Blok–Campeau Syndrome: Description of 20 Additional Individuals with Variants in CHD3 and Literature Review
Authors: Pascual Patricia , Tenorio-Castano Jair , Mignot Cyril , Afenjar Alexandra , Arias Pedro , Gallego-Zazo Natalia , Parra Alejandro , Miranda Lucia , Cazalla Mario , Silván Cristina , Heron Delphine , Keren Boris , Popa Ioana , Palomares María , Rikeros Emi , Ramos Feliciano J. , Almoguera Berta , Ayuso Carmen , Swafiri Saoud Tahsin , Barbero Ana Isabel Sánchez , Srinivasan Varunvenkat M. , Gowda Vykuntaraju K. , Morleo Manuela , Nigro Vicenzo , D’Arrigo Stefano , Ciaccio Claudia , Martin Mesa Carmen , Paumard Beatriz , Guillen Gema , Anton Ana Teresa Serrano , Jimenez Marta Domínguez , Seidel Veronica , Suárez Julia , Cormier-Daire Valerie , Consortium The SOGRI , Nevado Julián , Lapunzina Pablo
Published: August 2023

Snijders Blok–Campeau syndrome (SNIBCPS, OMIM# 618205) is an extremely infrequent disease with only approximately 60 cases reported so far. SNIBCPS belongs to the group of neurodevelopmental disorders (NDDs). Clinical features of patients with SNIBCPS include global developmental delay, intellectual disability, speech and language difficulties and behavioral disorders like autism spectrum disorder. In addition, patients with SNIBCPS exhibit typical dysmorphic features including macrocephaly, hypertelorism, sparse eyebrows, broad forehead, prominent nose and pointed chin. The severity of the neurological effects as well as the presence of other features is variable among subjects. SNIBCPS is caused likely by pathogenic and pathogenic variants in CHD3 (Chromodomain Helicase DNA Binding Protein 3), which seems to be involved in chromatin remodeling by deacetylating histones. Here, we report 20 additional patients with clinical features compatible with SNIBCPS from 17 unrelated families with confirmed likely pathogenic/pathogenic variants in CHD3. Patients were analyzed by whole exome sequencing and segregation studies were performed by Sanger sequencing. Patients in this study showed different pathogenic variants affecting several functional domains of the protein. Additionally, none of the variants described here were reported in control population databases, and most computational predictors suggest that they are deleterious. The most common clinical features of the whole cohort of patients are global developmental delay (98%) and speech disorder/delay (92%). Other frequent features (51–74%) include intellectual disability, hypotonia, hypertelorism, abnormality of vision, macrocephaly and prominent forehead, among others. This study expands the number of individuals with confirmed SNIBCPS due to pathogenic or likely pathogenic variants in CHD3. Furthermore, we add evidence of the importance of the application of massive parallel sequencing for NDD patients for whom the clinical diagnosis might be challenging and where deep phenotyping is extremely useful to accurately manage and follow up the patients.
MiRNAs Expression Modulates Osteogenesis in Response to Exercise and Nutrition
Authors: Proia Patrizia , Rossi Carlo , Alioto Anna , Amato Alessandra , Polizzotto Caterina , Pagliaro Andrea , Kuliś Szymon , Baldassano Sara
Published: August 2023

In recent years, many articles have been published describing the impact of physical activity and diet on bone health. This review has aimed to figure out the possible epigenetic mechanisms that influence bone metabolism. Many studies highlighted the effects of macro and micronutrients combined with exercise on the regulation of gene expression through miRs. The present review will describe how physical activity and nutrition can prevent abnormal epigenetic regulation that otherwise could lead to bone-metabolism-related diseases, the most significant of which is osteoporosis. Nowadays, it is known that this effect can be carried out not only by endogenously produced miRs, but also through those intakes through the diet. Indeed, they have also been found in the transcriptome of animals and plants, and it is possible to hypothesise an interaction between miRNAs produced by different kingdoms and epigenetic influences on human gene expression. In particular, the key to the activation pathways triggered by diet and physical activity appears to be the activation of Runt-related transcription factor 2 (RUNX2), the expression of which is regulated by several miRs. Among the main miRs involved are exercise-induced miR21 and 21-5p, and food-induced miR 221-3p and 222-3p.
“Embracing the Inner Strength and Staying Strong”: Exploring Self-Care Preparedness among Nurses for Enhancing Their Psychological Well-Being against the Long-Term Effect of COVID-19 Pandemic in Brunei Darussalam
Authors: Abdul-Mumin Khadizah H. , Maideen Aminol Azrin , Lupat Agong , Mohd-Alipah Siti Nur-Diyana , Mohammad-Alli Roziah H. , Abd-Manaf Hajah-Noraini H. , Osman Abd-Rani , Abd. Fata Haji Mohd Reduan , Busrah Nani , Darling-Fisher Cynthia , Idris Deeni Rudita
Published: August 2023

During three years of the unprecedented, massive COVID-19 pandemic that affected the world, nurse front liners faced substantial challenges and experienced long-term adverse mental health. This study explored psychological self-care practices undertaken by nurses to strengthen their mental health and develop resilience in their professional care role while addressing the challenges of the COVID-19 era. A qualitative descriptive exploratory study was conducted on 40 nurses who worked in providing COVID-19 care across Brunei using focus groups aided by semi-structured open-ended questions. Data were thematically analyzed using constructivist grounded theory. Four themes emerged: (1) ‘Care of the mind, heart and soul’; (2) ‘Physical care for the psychological well-being’; (3) ‘Venting out and distraction’; (4) ‘Have faith, think and stay positive’. The challenges of dealing with a worldwide pandemic unintentionally placed nurses’ mental well-being at risk while the government strategized and prioritized containing and preventing the spread of and death from COVID-19. Health administrators, as well as nursing educators, need to promote and develop resources to strengthen nurses’ psychological self-care practices. This will not only benefit individual nurses but will help promote the well-being of patients and employees, improve the health of all, and counteract any unintended stressful situations, even beyond the COVID-19 pandemic.
Use and Quality of Blood Cultures for the Diagnosis of Bloodstream Infections: A Cross-Sectional Study in the Ho Teaching Hospital, Ghana, 2019–2021
Authors: Boakye-Yiadom Emily , Najjemba Robinah , Thekkur Pruthu , Labi Appiah-Korang , Gil-Cuesta Julita , Asafo-Adjei Karikari , Mensah Prosper , van Boetzelaer Elburg , Jessani Nasreen S. , Orish Verner Ndudri
Published: August 2023

Blood Culture and Drug Susceptibility Testing (CDST) remains vital for the diagnosis and management of bloodstream infections (BSIs). While the Ghana National Standard Treatment Guidelines require CDST to be performed in each case of suspected or clinically diagnosed BSI, these are poorly adhered to in the Ho Teaching Hospital (HTH). This study used secondary medical and laboratory records to describe blood CDST requests by clinicians and the quality of CDST processes for the diagnosis of BSI among patients admitted to HTH from 2019 to 2021. Of 4278 patients, 33% were infants. Pneumonia and neonatal sepsis cases were 40% and 22%, respectively. Only 8% (351/4278) had blood CDST requested. Of 94% (329/351) blood CDST processed and reported, only 7% (22/329) were culture-positive, with likely contaminants being recovered from 16% (52/329) of the specimens. The duration from admission to request was 2 days (IQR: 0–5), and Further qualitative studies must be conducted to understand the reasons for low blood CDST utilisation among clinicians and the patient outcomes. Targeted interventions are required to enhance the utilisation of blood CDST by clinicians and the quality of laboratory processes.
Canagliflozin Inhibited the Activity of Hemolysin and Reduced the Inflammatory Response Caused by Streptococcus suis
Authors: Li Xiaodan , Li Qingyuan , Zhang Zhaoran , Wang Chenchen , Huo Xinyu , Lai Hongjiang , Lu Hao , Lu Wenjia , Qian Yulin , Dong Wenqi , Tan Chen , Liu Manli
Published: August 2023

Highly virulent Streptococcus suis (S. suis) infections can cause Streptococcal toxic shock-like syndrome (STSLS) in pigs and humans, in which an excessive inflammatory response causes severe damage. Hemolysin (SLY) is a major virulence factor of S. suis serotype 2 that produces pores in the target cell membrane, leading to cytoplasmic K+ efflux and activation of the NLRP3 inflammasome, ultimately causing STSLS. The critical aspect of hemolysin in the pathogenesis of S. suis type 2 makes it an attractive target for the development of innovative anti-virulence drugs. Here, we use the S. suis toxin protein (SLY) as a target for virtual screening. A compound called canagliflozin, a hypoglycemic agent, was identified through screening. Canagliflozin significantly inhibits the hemolytic activity of hemolysin. The results combined with molecular dynamics simulation, surface plasmon resonance, and nano differential scanning fluorimetry show that canagliflozin inhibits the hemolytic activity of SLY by binding to SLY. In addition, canagliflozin markedly reduced the release of SC19-induced inflammatory factors at the cellular level and in mice. Importantly, the combination of canagliflozin and ampicillin had a 90% success rate in mice, significantly greater than the therapeutic effect of ampicillin. The findings suggest that canagliflozin may be a promising new drug candidate for S. suis infections.
Real-World Data on Combined EGFR-TKI and Crizotinib Treatment for Acquired and De Novo MET Amplification in Patients with Metastatic EGFR-Mutated NSCLC
Authors: Urbanska Edyta M. , Grauslund Morten , Koffeldt Peter R. , Truelsen Sarah L. B. , Löfgren Johan O. , Costa Junia C. , Melchior Linea C. , Sørensen Jens B. , Santoni-Rugiu Eric
Published: August 2023

Amplification of the mesenchymal epithelial transition (MET) gene is a mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine-kinase-inhibitors (TKIs) in over 20% of patients with advanced EGFR-mutated (EGFRm+) non-small lung cancer (NSCLC). However, it may also occur de novo in 2–8% of EGFRm+ NSCLC cases as a potential mechanism of intrinsic resistance. These patients represent a group with unmet needs, since there is no standard therapy currently approved. Several new MET inhibitors are being investigated in clinical trials, but the results are awaited. Meanwhile, as an alternative strategy, combinations of EGFR-TKIs with the MET/ALK/ROS1-TKI Crizotinib may be used in this setting, despite this use is principally off-label. Thus, we studied five of these MET amplified cases receiving EGFR-TKI and Crizotinib doublet after progression on EGFR-TKI treatment to assess the benefits and challenges related to this combination and the possible occurrence of genomic and phenotypic co-alterations. Furthermore, we compared our cases with other real-world reports on Crizotinib/EGFR-TKI combinations, which appeared effective, especially in patients with high-level MET amplification. Yet, we observed that the co-occurrence of other genomic and phenotypical alterations may affect the response to combined EGFR-TKI and Crizotinib. Finally, given the heterogeneity of MET amplification, the diagnostic methods for assessing it may be discrepant. In this respect, we observed that for optimal detection, immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing should be used together, as these methods possess different sensitivities and complement each other in characterizing MET amplification. Additionally, we addressed the issue of managing EGFR-mutated NSCLC patients with de novo MET amplification causing primary EGFR-TKI resistance. We conclude that, while data from clinical trials with new MET inhibitors are still pending, adding Crizotinib to EGFR-TKI in NSCLC patients acquiring MET amplification at progression on EGFR-TKI monotherapy is a reasonable approach, with a progression-free survival of 3–19 months.
Revisiting Retinal Degeneration Hallmarks: Insights from Molecular Markers and Therapy Perspectives
Authors: Rosa João Gabriel Santos , Disner Geonildo Rodrigo , Pinto Felipe Justiniano , Lima Carla , Lopes-Ferreira Monica
Published: August 2023

Visual impairment and blindness are a growing public health problem as they reduce the life quality of millions of people. The management and treatment of these diseases represent scientific and therapeutic challenges because different cellular and molecular actors involved in the pathophysiology are still being identified. Visual system components, particularly retinal cells, are extremely sensitive to genetic or metabolic alterations, and immune responses activated by local insults contribute to biological events, culminating in vision loss and irreversible blindness. Several ocular diseases are linked to retinal cell loss, and some of them, such as retinitis pigmentosa, age-related macular degeneration, glaucoma, and diabetic retinopathy, are characterized by pathophysiological hallmarks that represent possibilities to study and develop novel treatments for retinal cell degeneration. Here, we present a compilation of revisited information on retinal degeneration, including pathophysiological and molecular features and biochemical hallmarks, and possible research directions for novel treatments to assist as a guide for innovative research. The knowledge expansion upon the mechanistic bases of the pathobiology of eye diseases, including information on complex interactions of genetic predisposition, chronic inflammation, and environmental and aging-related factors, will prompt the identification of new therapeutic strategies.
Macrophage-Derived Chemokine MDC/CCL22: An Ambiguous Finding in COVID-19
Authors: Korobova Zoia R. , Arsentieva Natalia A. , Totolian Areg A.
Published: August 2023

Macrophage-derived chemokine (MDC/CCL22) is a chemokine of the C-C subfamily. It is involved in T-cellular maturation and migration. Our previous research shows that plasma CCL22/MDC tends to show a statistically significant depletion of concentrations in acute patients and convalescents when compared to healthy donors. In the current work, we investigate existing views on MDC/CCL22 dynamics in association with various pathologies, including respiratory diseases and, specifically, COVID-19. Additionally, we present our explanations for the observed decrease in MDC/CCL22 concentrations in COVID-19. The first hypothesis we provide implies that viral products bind to MDC/CCL22 and block its activity. Another explanation for this phenomenon is based on dendritic cells population and the inhibition of their function.
Differential Epigenetic Changes in the Dorsal Hippocampus of Male and Female SAMP8 Mice: A Preliminary Study
Authors: Ravanelli Federico , Musazzi Laura , Barbieri Silvia Stella , Rovati Gianenrico , Popoli Maurizio , Barbon Alessandro , Ieraci Alessandro
Published: August 2023

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease characterized by memory loss and cognitive impairment. The causes of the disease are not well understood, as it involves a complex interaction between genetic, environmental, and epigenetic factors. SAMP8 mice have been proposed as a model for studying late-onset AD, since they show age-related learning and memory deficits as well as several features of AD pathogenesis. Epigenetic changes have been described in SAMP8 mice, although sex differences have never been evaluated. Here we used western blot and qPCR analyses to investigate whether epigenetic markers are differentially altered in the dorsal hippocampus, a region important for the regulation of learning and memory, of 9-month-old male and female SAMP8 mice. We found that H3Ac was selectively reduced in male SAMP8 mice compared to male SAMR1 control mice, but not in female mice, whereas H3K27me3 was reduced overall in SAMP8 mice. Moreover, the levels of HDAC2 and JmjD3 were increased, whereas the levels of HDAC4 and Dnmt3a were reduced in SAMP8 mice compared to SAMR1. In addition, levels of HDAC1 were reduced, whereas Utx and Jmjd3 were selectively increased in females compared to males. Although our results are preliminary, they suggest that epigenetic mechanisms in the dorsal hippocampus are differentially regulated in male and female SAMP8 mice.
Semaphorins and Their Roles in Breast Cancer: Implications for Therapy Resistance
Authors: Aiyappa-Maudsley Radhika , McLoughlin Louis F. V. , Hughes Thomas A.
Published: August 2023

Breast cancer is the most common cancer worldwide and a leading cause of cancer-related deaths in women. The clinical management of breast cancer is further complicated by the heterogeneous nature of the disease, which results in varying prognoses and treatment responses in patients. The semaphorins are a family of proteins with varied roles in development and homoeostasis. They are also expressed in a wide range of human cancers and are implicated as regulators of tumour growth, angiogenesis, metastasis and immune evasion. More recently, semaphorins have been implicated in drug resistance across a range of malignancies. In breast cancer, semaphorins are associated with resistance to endocrine therapy as well as breast cancer chemotherapeutic agents such as taxanes and anthracyclines. This review will focus on the semaphorins involved in breast cancer progression and their association with drug resistance.
Sex Differences in Neurovascular Control: Implications for Obstructive Sleep Apnea
Authors: Bock Joshua M. , Greenlund Ian M. , Somers Virend K. , Baker Sarah E.
Published: August 2023

Patients with obstructive sleep apnea (OSA) have a heightened risk of developing cardiovascular diseases, namely hypertension. While seminal evidence indicates a causal role for sympathetic nerve activity in the hypertensive phenotype commonly observed in patients with OSA, no studies have investigated potential sex differences in the sympathetic regulation of blood pressure in this population. Supporting this exploration are large-scale observational data, as well as controlled interventional studies in healthy adults, indicating that sleep disruption increases blood pressure to a greater extent in females relative to males. Furthermore, females with severe OSA demonstrate a more pronounced hypoxic burden (i.e., disease severity) during rapid eye movement sleep when sympathetic nerve activity is greatest. These findings would suggest that females are at greater risk for the hemodynamic consequences of OSA and related sleep disruption. Accordingly, the purpose of this review is three-fold: (1) to review the literature linking sympathetic nerve activity to hypertension in OSA, (2) to highlight recent experimental data supporting the hypothesis of sex differences in the regulation of sympathetic nerve activity in OSA, and (3) to discuss the potential sex differences in peripheral adrenergic signaling that may contribute to, or offset, cardiovascular risk in patients with OSA.
Glucagon-like Peptide-1 Receptor Activation Reduces Pulmonary Vein Arrhythmogenesis and Regulates Calcium Homeostasis
Authors: Chan Chao-Shun , Lin Fong-Jhih , Chen Yao-Chang , Lin Yung-Kuo , Higa Satoshi , Chen Shih-Ann , Chen Yi-Jen
Published: August 2023

Glucagon-like peptide-1 (GLP-1) receptor agonists are associated with reduced atrial fibrillation risk, but the mechanisms underlying this association remain unclear. The GLP-1 receptor agonist directly impacts cardiac Ca2+ homeostasis, which is crucial in pulmonary vein (PV, the initiator of atrial fibrillation) arrhythmogenesis. This study investigated the effects of the GLP-1 receptor agonist on PV electrophysiology and Ca2+ homeostasis and elucidated the potential underlying mechanisms. Conventional microelectrodes and whole-cell patch clamp techniques were employed in rabbit PV tissues and single PV cardiomyocytes before and after GLP-1 (7-36) amide, a GLP-1 receptor agonist. Evaluations were conducted both with and without pretreatment with H89 (10 μM, an inhibitor of protein kinase A, PKA), KN93 (1 μM, an inhibitor of Ca2+/calmodulin-dependent protein kinase II, CaMKII), and KB-R7943 (10 μM, an inhibitor of Na+/Ca2+ exchanger, NCX). Results showed that GLP-1 (7-36) amide (at concentrations of 1, 10, and 100 nM) reduced PV spontaneous activity in a concentration-dependent manner without affecting sinoatrial node electrical activity. In single-cell experiments, GLP-1 (7-36) amide (at 10 nM) reduced L-type Ca2+ current, NCX current, and late Na+ current in PV cardiomyocytes without altering Na+ current. Additionally, GLP-1 (7-36) amide (at 10 nM) increased sarcoplasmic reticulum Ca2+ content in PV cardiomyocytes. Furthermore, the antiarrhythmic effects of GLP-1 (7-36) amide on PV automaticity were diminished when pretreated with H89, KN93, or KB-R7943. This suggests that the GLP-1 receptor agonist may exert its antiarrhythmic potential by regulating PKA, CaMKII, and NCX activity, as well as modulating intracellular Ca2+ homeostasis, thereby reducing PV arrhythmogenesis.
Overexpression of RAB27A in Oral Squamous Cell Carcinoma Promotes Tumor Migration and Invasion via Modulation of EGFR Membrane Stability
Authors: Huang Jue , Yang Jie-Gang , Ren Jian-Gang , Xia Hou-Fu , Chen Gao-Hong , Fu Qiu-Yun , Zhang Lin-Zhou , Liu Hai-Ming , Wang Kui-Ming , Xie Qi-Hui , Chen Gang
Published: August 2023

Oral squamous cell carcinoma (OSCC) is the most prevalent subtype of head and neck tumors, highly prone to lymph node metastasis. This study aims to examine the expression pattern of Ras-related protein Rab-27A (RAB27A) and explore its potential implications in OSCC. The expression of RAB27A was assessed through immunohistochemical analysis utilizing tissue microarrays. In vitro experiments were conducted using RAB27A-knockdown cells to investigate its impact on OSCC tumor cells. Additionally, transcriptome sequencing was performed to elucidate potential underlying mechanisms. RAB27A was significantly overexpressed in OSCC, and particularly in metastatic lymph nodes. It was positively correlated with the clinical progression and poor survival prognosis. Silencing RAB27A notably decreased the proliferation, migration, and invasion abilities of OSCC cells in vitro. A Gene Ontology (GO) enrichment analysis indicated a strong association between RAB27A and the epidermal growth factor receptor (EGFR) signaling pathway. Further investigations revealed that RAB27A regulated the palmitoylation of EGFR via zinc finger DHHC-type containing 13 (ZDHHC13). These findings provide insights into OSCC progression and highlight RAB27A as a potential therapeutic target for combating this aggressive cancer.
HIV Infection: Shaping the Complex, Dynamic, and Interconnected Network of the Cytoskeleton
Authors: Cabrera-Rodríguez Romina , Pérez-Yanes Silvia , Lorenzo-Sánchez Iria , Trujillo-González Rodrigo , Estévez-Herrera Judith , García-Luis Jonay , Valenzuela-Fernández Agustín
Published: August 2023

HIV-1 has evolved a plethora of strategies to overcome the cytoskeletal barrier (i.e., actin and intermediate filaments (AFs and IFs) and microtubules (MTs)) to achieve the viral cycle. HIV-1 modifies cytoskeletal organization and dynamics by acting on associated adaptors and molecular motors to productively fuse, enter, and infect cells and then traffic to the cell surface, where virions assemble and are released to spread infection. The HIV-1 envelope (Env) initiates the cycle by binding to and signaling through its main cell surface receptors (CD4/CCR5/CXCR4) to shape the cytoskeleton for fusion pore formation, which permits viral core entry. Then, the HIV-1 capsid is transported to the nucleus associated with cytoskeleton tracks under the control of specific adaptors/molecular motors, as well as HIV-1 accessory proteins. Furthermore, HIV-1 drives the late stages of the viral cycle by regulating cytoskeleton dynamics to assure viral Pr55Gag expression and transport to the cell surface, where it assembles and buds to mature infectious virions. In this review, we therefore analyze how HIV-1 generates a cell-permissive state to infection by regulating the cytoskeleton and associated factors. Likewise, we discuss the relevance of this knowledge to understand HIV-1 infection and pathogenesis in patients and to develop therapeutic strategies to battle HIV-1.
CRISPR/Cas9-Mediated HY5 Gene Editing Reduces Growth Inhibition in Chinese Cabbage (Brassica rapa) under ER Stress
Authors: Lee Ye Rin , Ko Ki Seong , Lee Hye Eun , Lee Eun Su , Han Koeun , Yoo Jae Yong , Vu Bich Ngoc , Choi Ha Na , Lee Yoo Na , Hong Jong Chan , Lee Kyun Oh , Kim Do Sun
Published: August 2023

Various stresses can affect the quality and yield of crops, including vegetables. In this study, CRISPR/Cas9 technology was employed to examine the role of the ELONGATED HYPOCOTYL 5 (HY5) gene in influencing the growth of Chinese cabbage (Brassica rapa). Single guide RNAs (sgRNAs) were designed to target the HY5 gene, and deep-sequencing analysis confirmed the induction of mutations in the bZIP domain of the gene. To investigate the response of Chinese cabbage to endoplasmic reticulum (ER) stress, plants were treated with tunicamycin (TM). Both wild-type and hy5 mutant plants showed increased growth inhibition with increasing TM concentration. However, the hy5 mutant plants displayed less severe growth inhibition compared to the wild type. Using nitroblue tetrazolium (NBT) and 3,3′-diaminobenzidine (DAB) staining methods, we determined the amount of reactive oxygen species (ROS) produced under ER stress conditions, and found that the hy5 mutant plants generated lower levels of ROS compared to the wild type. Under ER stress conditions, the hy5 mutant plants exhibited lower expression levels of UPR- and cell death-related genes than the wild type. These results indicate that CRISPR/Cas9-mediated editing of the HY5 gene can mitigate growth inhibition in Chinese cabbage under stresses, improving the quality and yield of crops.