bluuebunny/crossref_metadata_2025 huggingface dataset:
An Integrated Patient-Centred Medical Home (PCMH) Care Model Reduces Prospective Healthcare Utilisation for Community-Dwelling Older Adults with Complex Needs: A Matched Observational Study in Singapore
Authors: Sum Grace , Sim Silvia Yu Hui , Chay Junxing , Ho Soon Hoe , Ginting Mimaika Luluina , Lim Zoe Zon Be , Yoong Joanne , Wong Chek Hooi
Published: September 2023

The global ageing population is associated with increased health service use. The PCMH care model integrates primary care and home-based care management to deliver comprehensive and personalised healthcare to community-dwelling older adults with bio-psycho-social needs. We examined if an integrated PCMH reduced healthcare utilisation burden of older persons in Singapore. We compared the healthcare utilisation between the intervention group and coarsened exact matched controls for a follow-up of 15 months. Baseline matching covariates included socio-demographics, health status, and past healthcare use. We accounted for COVID-19 social distancing effects on health-seeking behaviour. The intervention group consisted of 165 older adults with complex needs. We analysed national administrative healthcare utilisation data from 2017 to 2020. We applied multivariable zero-inflated regression modelling and presented findings stratified by high (CCI ≥ 5) and low disease burden (CCI < 5). Compared to controls, there were significant reductions in emergency department (β = −0.85; 95%CI = −1.55 to −0.14) and primary care visits (β = −1.70; 95%CI = −2.17 to −1.22) and a decrease in specialist outpatient visits (β = −0.29; 95%CI = −0.64 to 0.07) in the 3-month period immediately after one-year enrolment. The number of acute hospitalisations remained stable. Compared to controls, the intervention group with high and low comorbidity burden had significant decreases in primary care use, while only those with lower comorbidity burden had significant reductions in utilisation of other service types. An integrated PCMH appears beneficial in reducing healthcare utilisation for older persons with complex needs after 1 year in the programme. Future research can explore longer-term utilisation and scalability of the care model.
“Women Friendly”: A Childbirth Preparation Intervention in Israel for Women with Symptoms of Post-Traumatic Stress Disorder
Authors: Bachner-Melman Rachel , Haim-Dahan Racheli , Zohar Ada H.
Published: September 2023

Pregnant women with symptoms of post-traumatic stress disorder (PTSD), who have experienced traumatic events such as sexual abuse and traumatic births, are particularly vulnerable to experiencing extreme fear of childbirth complications during labor and traumatic deliveries. In this commentary, we review the literature on this group of women and their specific needs during pregnancy and childbirth. We present a childbirth preparation intervention for pregnant women with PTSD symptoms, “Women Friendly”, designed in Israel and gradually becoming available in the community and Israeli hospitals. This intervention is intended for women with high levels of fear of childbirth who are unmotivated or unable to undergo traditional psychotherapy that focuses on exposure to and processing of past traumatic event(s). It is based on birth-oriented thinking, principles of positive psychology, and trauma-informed care. In addition to the five sessions offered to pregnant women, medical staff are provided with 19 training sessions on the “Women Friendly” approach. Qualitative and quantitative research should examine the effectiveness of this intervention. Should results be encouraging, this intervention could be more widely implemented in Israel and abroad and applied in broader contexts, such as gynecological check-ups and medical examinations, interventions, and surgery.
What Can One Minute of the Day Tell about Physical Activity?
Authors: Vähä-Ypyä Henri , Husu Pauliina , Sievänen Harri , Vasankari Tommi
Published: September 2023

High cardiorespiratory fitness (CRF) allows individuals to perform daily activities and operate at a higher intensity level. This study investigates the connection between the CRF and peak intensity of physical activity (PA) in absolute and relative terms. A total of 3587 participants (1447 men, 51.9 ± 13.0 years; 2140 women, 50.0 ± 13.0 years) provided substantial accelerometer wear time, and their CRF was estimated via the 6 min walking test. Participants were divided into CRF thirds by age group and sex. Daily one-minute peak intensities were captured in both absolute terms and relative to individual CRF levels. In absolute terms, the highest CRF third had the highest intensity value for men (6.4 ± 1.7 MET; 5.9 ± 1.4 MET; 5.3 ± 1.0 MET) and for women (6.4 ± 1.6 MET; 5.9 ± 1.3 MET; 5.4 ± 1.1 MET). In relative terms, the highest CRF third utilized the least aerobic capacity for men (49 ± 14%; 51 ± 13%; 56 ± 14%) and for women (52 ± 13%; 54 ± 12%; 62 ± 15%). One minute of daily activity offers valuable insights into an individual’s CRF and the effort demanded during PA. Fitter individuals can sustain higher PA intensity levels in absolute terms, whereas individuals with lower CRF utilize a greater fraction of their aerobic capacity. Consequently, heightened CRF not only allows for enhanced intensity levels but also safeguards against strenuous PA during daily routines.
ChineseCTRE: A Model for Geographical Named Entity Recognition and Correction Based on Deep Neural Networks and the BERT Model
Authors: Zhang Wei , Meng Jingtao , Wan Jianhua , Zhang Chengkun , Zhang Jiajun , Wang Yuanyuan , Xu Liuchang , Li Fei
Published: September 2023

Social media is widely used to share real-time information and report accidents during natural disasters. Named entity recognition (NER) is a fundamental task of geospatial information applications that aims to extract location names from natural language text. As a result, the identification of location names from social media information has gradually become a demand. Named entity correction (NEC), as a complementary task of NER, plays a crucial role in ensuring the accuracy of location names and further improving the accuracy of NER. Despite numerous methods having been adopted for NER, including text statistics-based and deep learning-based methods, there has been limited research on NEC. To address this gap, we propose the CTRE model, which is a geospatial named entity recognition and correction model based on the BERT model framework. Our approach enhances the BERT model by introducing incremental pre-training in the pre-training phase, significantly improving the model’s recognition accuracy. Subsequently, we adopt the pre-training fine-tuning mode of the BERT base model and extend the fine-tuning process, incorporating a neural network framework to construct the geospatial named entity recognition model and geospatial named entity correction model, respectively. The BERT model utilizes data augmentation of VGI (volunteered geographic information) data and social media data for incremental pre-training, leading to an enhancement in the model accuracy from 85% to 87%. The F1 score of the geospatial named entity recognition model reaches an impressive 0.9045, while the precision of the geospatial named entity correction model achieves 0.9765. The experimental results robustly demonstrate the effectiveness of our proposed CTRE model, providing a reference for subsequent research on location names.
Fork- and Comb-like Lipophilic Structures: Different Chemical Approaches to the Synthesis of Oligonucleotides with Multiple Dodecyl Residues
Authors: Zharkov Timofey D. , Mironova Ekaterina M. , Markov Oleg V. , Zhukov Sergey A. , Khodyreva Svetlana N. , Kupryushkin Maxim S.
Published: September 2023

Lipophilic oligonucleotide conjugates represent a powerful tool for nucleic acid cellular delivery, and many methods for their synthesis have been developed over the past few decades. In the present study, a number of chemical approaches for the synthesis of different fork- and comb-like dodecyl-containing oligonucleotide structures were performed, including use of non-nucleotide units and different types of phosphate modifications such as alkyl phosphoramidate, phosphoryl guanidine, and triazinyl phosphoramidate. The influence of the number of introduced lipophilic residues, their mutual arrangement, and the type of formed modification backbone on cell penetration was evaluated. The results obtained indicate great potential in the developed chemical approaches, not only for the synthesis of complex oligonucleotide structures but also for the fine-tuning of their properties.
Cold-Temperature Coding with Bursting and Spiking Based on TRP Channel Dynamics in Drosophila Larva Sensory Neurons
Authors: Maksymchuk Natalia , Sakurai Akira , Cox Daniel N. , Cymbalyuk Gennady S.
Published: September 2023

Temperature sensation involves thermosensitive TRP (thermoTRP) and non-TRP channels. Drosophila larval Class III (CIII) neurons serve as the primary cold nociceptors and express a suite of thermoTRP channels implicated in noxious cold sensation. How CIII neurons code temperature remains unclear. We combined computational and electrophysiological methods to address this question. In electrophysiological experiments, we identified two basic cold-evoked patterns of CIII neurons: bursting and spiking. In response to a fast temperature drop to noxious cold, CIII neurons distinctly mark different phases of the stimulus. Bursts frequently occurred along with the fast temperature drop, forming a peak in the spiking rate and likely coding the high rate of the temperature change. Single spikes dominated at a steady temperature and exhibited frequency adaptation following the peak. When temperature decreased slowly to the same value, mainly spiking activity was observed, with bursts occurring sporadically throughout the stimulation. The spike and the burst frequencies positively correlated with the rate of the temperature drop. Using a computational model, we explain the distinction in the occurrence of the two CIII cold-evoked patterns bursting and spiking using the dynamics of a thermoTRP current. A two-parameter activity map (Temperature, constant TRP current conductance) marks parameters that support silent, spiking, and bursting regimes. Projecting on the map the instantaneous TRP conductance, governed by activation and inactivation processes, reflects temperature coding responses as a path across silent, spiking, or bursting domains on the map. The map sheds light on how various parameter sets for TRP kinetics represent various types of cold-evoked responses. Together, our results indicate that bursting detects the high rate of temperature change, whereas tonic spiking could reflect both the rate of change and magnitude of steady cold temperature.
Immune Regulation of Seminal Plasma on the Endometrial Microenvironment: Physiological and Pathological Conditions
Authors: Shen Qiuzi , Wu Xiaoyu , Chen Jin , He Chao , Wang Zehao , Zhou Boyan , Zhang Huiping
Published: September 2023

Seminal plasma (SP) accounts for more than 90% of semen volume. It induces inflammation, regulates immune tolerance, and facilitates embryonic development and implantation in the female reproductive tract. In the physiological state, SP promotes endometrial decidualization and causes changes in immune cells such as macrophages, natural killer cells, regulatory T cells, and dendritic cells. This leads to the secretion of cytokines and chemokines and also results in the alteration of miRNA profiles and the expression of genes related to endometrial tolerance and angiogenesis. Together, these changes modulate the endometrial immune microenvironment and contribute to implantation and pregnancy. However, in pathological situations, abnormal alterations in SP due to advanced age or poor diet in men can interfere with a woman’s immune adaptation to pregnancy, negatively affecting embryo implantation and even the health of the offspring. Uterine pathologies such as endometriosis and endometritis can cause the endometrium to respond negatively to SP, which can further contribute to pathological progress and interfere with conception. The research on the mechanism of SP in the endometrium is conducive to the development of new targets for intervention to improve reproductive outcomes and may also provide new ideas for semen-assisted treatment of clinical infertility.
Applications for Deep Learning in Epilepsy Genetic Research
Authors: Zeibich Robert , Kwan Patrick , J. O’Brien Terence , Perucca Piero , Ge Zongyuan , Anderson Alison
Published: September 2023

Epilepsy is a group of brain disorders characterised by an enduring predisposition to generate unprovoked seizures. Fuelled by advances in sequencing technologies and computational approaches, more than 900 genes have now been implicated in epilepsy. The development and optimisation of tools and methods for analysing the vast quantity of genomic data is a rapidly evolving area of research. Deep learning (DL) is a subset of machine learning (ML) that brings opportunity for novel investigative strategies that can be harnessed to gain new insights into the genomic risk of people with epilepsy. DL is being harnessed to address limitations in accuracy of long-read sequencing technologies, which improve on short-read methods. Tools that predict the functional consequence of genetic variation can represent breaking ground in addressing critical knowledge gaps, while methods that integrate independent but complimentary data enhance the predictive power of genetic data. We provide an overview of these DL tools and discuss how they may be applied to the analysis of genetic data for epilepsy research.
Design, Synthesis, and Potent Anticancer Activity of Novel Indole-Based Bcl-2 Inhibitors
Authors: Almehdi Ahmed M. , Soliman Sameh S. M. , El-Shorbagi Abdel-Nasser A. , Westwell Andrew D. , Hamdy Rania
Published: September 2023

The Bcl-2 family plays a crucial role in regulating cell apoptosis, making it an attractive target for cancer therapy. In this study, a series of indole-based compounds, U1–6, were designed, synthesized, and evaluated for their anticancer activity against Bcl-2-expressing cancer cell lines. The binding affinity, safety profile, cell cycle arrest, and apoptosis effects of the compounds were tested. The designed compounds exhibited potent inhibitory activity at sub-micromolar IC50 concentrations against MCF-7, MDA-MB-231, and A549 cell lines. Notably, U2 and U3 demonstrated the highest activity, particularly against MCF-7 cells. Respectively, both U2 and U3 showed potential BCL-2 inhibition activity with IC50 values of 1.2 ± 0.02 and 11.10 ± 0.07 µM using an ELISA binding assay compared with 0.62 ± 0.01 µM for gossypol, employed as a positive control. Molecular docking analysis suggested stable interactions of compound U2 at the Bcl-2 binding site through hydrogen bonding, pi-pi stacking, and hydrophobic interactions. Furthermore, U2 demonstrated significant induction of apoptosis and cell cycle arrest at the G1/S phase. Importantly, U2 displayed a favourable safety profile on HDF human dermal normal fibroblast cells at 10-fold greater IC50 values compared with MDA-MB-231 cells. These findings underscore the therapeutic potential of compound U2 as a Bcl-2 inhibitor and provide insights into its molecular mechanisms of action.
Immunosuppressive Activity of Exosomes from Granulocytic Myeloid-Derived Suppressor Cells in a Murine Model of Immune Bone Marrow Failure
Authors: Manley Ash Lee , Chen Jichun , Fitzgerald Wendy , Feng Xingmin , Young Neal S.
Published: September 2023

We previously reported that granulocytic myeloid-derived suppressor cells (G-MDSCs) suppressed T-cell activation and attenuated bone marrow failure (BMF) in a minor histocompatibility (minor-H) antigen mismatched murine aplastic anemia (AA) model. In the current study, we tested the hypothesis that exosomes, a subset of extracellular vesicles, are responsible at least partially for G-MDSCs’ therapeutic efficacy. Indeed, exosomes isolated from GMDSCs (G-MDSC-exos) suppressed CD4+ and CD8+ T-cell proliferation in vitro and mildly attenuated immune BMF in the minor-H mismatched AA model. G-MDSC-exos treatment significantly increased red blood cells, hemoglobin, and total bone marrow (BM) cells, and moderately reduced BM CD8+ T cells. G-MDSC-exos’ effects were associated with upregulations in an array of lymphocyte-suppression-related miRNAs such as hsa-miR-142-5p, miR-19a-3p, and miR-19b-3p in both BM CD4+ and CD8+ T cells. We concluded that G-MDSC-exos attenuate immune BMF via modulating the delivery of immunosuppressive miRNAs into activated T lymphocytes.
Rhizosphere Microbe Affects Soil Available Nitrogen and Its Implication for the Ecological Adaptability and Rapid Growth of Dendrocalamus sinicus, the Strongest Bamboo in the World
Authors: Dou Peitong , Cheng Qian , Liang Ning , Bao Changyan , Zhang Zhiming , Chen Lingna , Yang Hanqi
Published: September 2023

The interaction between soil microbes and plants has a significant effect on soil microbial structure and function, as well as plant adaptability. However, the effect of soil micro-organisms on ecological adaption and rapid growth of woody bamboos remains unclear. Here, 16S rRNA and ITS rRNA genes of rhizosphere micro-organisms were sequenced, and the soil properties of three different types of Dendrocalamus sinicus were determined at the dormancy and germination stages of rhizome buds. The result showed that each type of D. sinicus preferred to absorb ammonia nitrogen (NH4+-N) rather than nitrate nitrogen (NO3−-N) and required more NH4+-N at germination or rapid growth period than during the dormancy period. In total, nitrogen fixation capacity of soil bacteria in the straight type was significantly higher than that in the introduced straight type, while the ureolysis capacity had an opposite trend. Saprophytic fungi were the dominant fungal functional taxa in habitat soils of both straight and introduced straight type. Our findings are of great significance in understanding how soil microbes affect growth and adaptation of woody bamboos, but also for soil management of bamboo forests in red soil.
Exploring PCSK9 Genetic Impact on Lipoprotein(a) via Dual Approaches: Association and Mendelian Randomization
Authors: Chang Ya-Ching , Hsu Lung-An , Ko Yu-Lin
Published: September 2023

Previous investigations have suggested an association between the PCSK9 common polymorphism E670G and Lipoprotein(a) (Lp(a)) levels, as well as a link between plasma PCSK9 levels and Lp(a) concentrations. However, the causal relationship between plasma PCSK9 and Lp(a) levels remains uncertain. In this study, we explored the association between PCSK9 E670G polymorphism and Lp(a) levels in 614 healthy Taiwanese individuals. Employing a two-sample Mendelian randomization (MR) analysis using openly accessible PCSK9 and Lp(a) summary statistics from the genome-wide association studies (GWAS) and UK Biobank, we aimed to determine if a causal link exists between plasma PCSK9 levels and Lp(a) concentrations. Our findings reveal that the E670G G allele is independently associated with a decreased likelihood of developing elevated Lp(a) levels. This association persists even after adjusting for common cardiovascular risk factors and irrespective of lipid profile variations. The MR analysis, utilizing six PCSK9 GWAS-associated variants as instrumental variables to predict plasma PCSK9 levels, provides compelling evidence of a causal relationship between plasma PCSK9 levels and Lp(a) concentration. In conclusion, our study not only replicates the association between the PCSK9 E670G polymorphism and Lp(a) levels but also confirms a causative relationship between PCSK9 levels and Lp(a) concentrations through MR analysis.
Discovery of Bacteroides uniformis F18-22 as a Safe and Novel Probiotic Bacterium for the Treatment of Ulcerative Colitis from the Healthy Human Colon
Authors: Dai Wei , Zhang Jiaxue , Chen Lu , Yu Junhong , Zhang Junyi , Yin Hua , Shang Qingsen , Yu Guangli
Published: September 2023

Previous studies have demonstrated that the intestinal abundance of Bacteroides uniformis is significantly higher in healthy controls than that in patients with ulcerative colitis (UC). However, what effect B. uniformis has on the development of UC has not been characterized. Here, we show for the first time that B. uniformis F18-22, an alginate-fermenting bacterium isolated from the healthy human colon, protects against dextran-sulfate-sodium (DSS)-induced UC in mice. Specifically, oral intake of B. uniformis F18-22 alleviated colon contraction, improved intestinal bleeding and attenuated mucosal damage in diseased mice. Additionally, B. uniformis F18-22 improved gut dysbiosis in UC mice by increasing the abundance of anti-inflammatory acetate-producing bacterium Eubacterium siraeum and decreasing the amount of pro-inflammatory pathogenetic bacteria Escherichia-Shigella spp. Moreover, B. uniformis F18-22 was well-tolerated in mice and showed no oral toxicity after repeated daily administration for 28 consecutive days. Taken together, our study illustrates that B. uniformis F18-22 is a safe and novel probiotic bacterium for the treatment of UC from the healthy human colon.
Hyperinsulinemia Impairs Clathrin-Mediated Endocytosis of the Insulin Receptor and Activation of Endothelial Nitric Oxide Synthase in Brain Endothelial Cells
Authors: DiLucia Stephanie G. , Kendrick B. Jacob , Sims-Robinson Catrina
Published: September 2023

Adequate perfusion of cerebral tissues, which is necessary for the preservation of optimal brain health, depends on insulin signaling within brain endothelial cells. Proper insulin signaling relies on the regulated internalization of insulin bound to the insulin receptor, a process which is disrupted by hyperinsulinemia via an unknown mechanism. Thus, the goal of this study was to characterize the impact of hyperinsulinemia on the regulation of molecular targets involved in cerebral blood flow and insulin receptor internalization into brain endothelial cells. The phosphorylation of molecular targets associated with cerebral blood flow and insulin receptor internalization was assessed in hyperinsulinemic brain endothelial cells. Insulin receptor uptake into cells was also examined in the setting of endocytosis blockade. Our data demonstrate that hyperinsulinemia impairs the activation of endothelial nitric oxide synthase. These data correspond with an impairment in clathrin-mediated endocytosis of the insulin receptor and dysregulated phosphorylation of key internalization effectors. We conclude that hyperinsulinemia alters the phosphorylation of molecular targets involved in clathrin-mediated endocytosis, disrupts signaling through the insulin receptor, and hinders the capacity for blood flow regulation by brain endothelial cells.
Estrogens, Estrogen Receptors and Tumor Microenvironment in Ovarian Cancer
Authors: Kozieł Marta Justyna , Piastowska-Ciesielska Agnieszka Wanda
Published: September 2023

Ovarian cancer is one of the most common cancers in women and the most concerning issues in gynecological oncology in recent years. It is postulated that many factors may contribute to the development of ovarian cancer, including hormonal imbalance. Estrogens are a group of hormones that have an important role both in physiological and pathological processes. In ovarian cancer, they may regulate proliferation, invasiveness and epithelial to mesenchymal transition. Estrogen signaling also takes part in the regulation of the biology of the tumor microenvironment. This review summarizes the information connected with estrogen receptors, estrogens and their association with a tumor microenvironment. Moreover, this review also includes information about the changes in estrogen receptor expression upon exposition to various environmental chemicals.
Adipokines and Inflammatory Markers in Acute Myocardial Infarction Patients with and without Obstructive Sleep Apnea: A Comparative Analysis
Authors: Vega-Jasso Ana L. , Amezcua-Guerra Luis M. , González-Pacheco Héctor , Sandoval-Zárate Julio , González-Díaz César A. , Escobar-Alvarado Jennifer , Manzano-Luna Jennifer D. , Brianza-Padilla Malinalli
Published: September 2023

An association has been suggested between acute myocardial infarction (AMI) and obstructive sleep apnea (OSA). Considering the role of adipose-tissue-derived inflammatory mediators (adipokines) and the shared risk factor of obesity in OSA and AMI, this study aimed to investigate the involvement of adipokines in AMI patients with and without OSA. Serum levels of adipokines and inflammatory mediators were quantified, and home respiratory polygraphy was conducted. A total of 30 AMI patients and 25 controls were included. Patients with AMI exhibited elevated levels of resistin (7.4 vs. 3.7 ng/mL), interleukin-6 (8.8 vs. 1.3 pg/mL), and endothelin-1 (3.31 vs. 1.8 pg/mL). Remarkably, AMI patients with concomitant OSA exhibited higher levels of resistin (7.1 vs. 3.7 ng/mL), interleukin-6 (8.9 vs. 1.3 pg/mL), endothelin-1 (3.2 vs. 1.8 pg/mL), creatin kinase (1430 vs. 377 U/L), creatine kinase-MB (64.6 vs. 9.7 ng/mL), and troponin T (2298 vs. 356 pg/mL) than their non-OSA counterparts. Leptin showed a correlation with OSA severity markers. OSA was associated with greater cardiac damage in AMI patients. Our findings underscore that adipokines alone are not sufficient to discriminate the risk of AMI in the presence of OSA. Further research is necessary to determine the potential mechanisms contributing to exacerbated cardiac damage in patients with both conditions.
Cancer/Testis Antigens as Targets for RNA-Based Anticancer Therapy
Authors: Shim Kyeonghee , Jo Hyein , Jeoung Dooil
Published: September 2023

In the last few decades, RNA-based drugs have emerged as a promising candidate in the treatment of various diseases. The introduction of messenger RNA (mRNA) as a vaccine or therapeutic agent enables the production of almost any functional protein/peptide. The key to applying RNA therapy in clinical trials is developing safe and effective delivery systems. Exosomes and lipid nanoparticles (LNPs) have been exploited as promising vehicles for drug delivery. This review discusses the feasibility of exosomes and LNPs as vehicles for mRNA delivery. Cancer/testis antigens (CTAs) show restricted expression in normal tissues and widespread expression in cancer tissues. Many of these CTAs show expression in the sera of patients with cancers. These characteristics of CTAs make them excellent targets for cancer immunotherapy. This review summarizes the roles of CTAs in various life processes and current studies on mRNAs encoding CTAs. Clinical studies present the beneficial effects of mRNAs encoding CTAs in patients with cancers. This review highlight clinical studies employing mRNA-LNPs encoding CTAs.
The Genomic Signatures of Linitis Plastica Signal the Entrance into a New Era: Novel Approaches for Diagnosis and Treatment
Authors: Christodoulidis Grigorios , Koumarelas Konstantinos Eleftherios , Kouliou Marina Nektaria , Samara Maria , Thodou Eleni , Zacharoulis Dimitris
Published: September 2023

Linitis Plastica (LP) is a rare and aggressive tumor with a distinctive development pattern, leading to the infiltration of the gastric wall, the thickening of the gastric folds and a “leather bottle appearance”. LP is an extremely heterogeneous tumor caused by mutations in oncogenic and tumor suppressive genes, as well as molecular pathways, along with mutations in stromal cells and proteins related to tight junctions. Elucidating the molecular background of tumorigenesis and clarifying the correlation between cancerous cells and stromal cells are crucial steps toward discovering novel diagnostic methods, biomarkers and therapeutic targets/agents. Surgery plays a pivotal role in LP management, serving both as a palliative and curative procedure. In this comprehensive review, we aim to present all recent data on the molecular background of LP and the novel approaches to its management.
The Role of Adipokines in the Pathologies of the Central Nervous System
Authors: Huber Korbinian , Szerenos Emilia , Lewandowski Dawid , Toczylowski Kacper , Sulik Artur
Published: September 2023

Adipokines are protein hormones secreted by adipose tissue in response to disruptions in physiological homeostasis within the body’s systems. The regulatory functions of adipokines within the central nervous system (CNS) are multifaceted and intricate, and they have been identified in a number of pathologies. Therefore, specific adipokines have the potential to be used as biomarkers for screening purposes in neurological dysfunctions. The systematic review presented herein focuses on the analysis of the functions of various adipokines in the pathogenesis of CNS diseases. Thirteen proteins were selected for analysis through scientific databases. It was found that these proteins can be identified within the cerebrospinal fluid either by their ability to modify their molecular complex and cross the blood–brain barrier or by being endogenously produced within the CNS itself. As a result, this can correlate with their measurability during pathological processes, including Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, depression, or brain tumors.
Mucoadhesive Mesoporous Silica Particles as Versatile Carriers for Doxorubicin Delivery in Cancer Therapy
Authors: Zaltariov Mirela-Fernanda , Ciubotaru Bianca-Iulia , Ghilan Alina , Peptanariu Dragos , Ignat Maria , Iacob Mihail , Vornicu Nicoleta , Cazacu Maria
Published: September 2023

Due to their structural, morphological, and behavioral characteristics (e.g., large volume and adjustable pore size, wide functionalization possibilities, excellent biocompatibility, stability, and controlled biodegradation, the ability to protect cargoes against premature release and unwanted degradation), mesoporous silica particles (MSPs) are emerging as a promising diagnostic and delivery platform with a key role in the development of next-generation theranostics, nanovaccines, and formulations. In this study, MSPs with customized characteristics in-lab prepared were fully characterized and used as carriers for doxorubicin (DOX). The drug loading capacity and the release profile were evaluated in media with different pH values, mimicking the body conditions. The release data were fitted to Higuchi, Korsmeyer–Peppas, and Peppas–Sahlin kinetic models to evaluate the release constant and the mechanism. The in vitro behavior of functionalized silica particles showed an enhanced cytotoxicity on human breast cancer (MCF-7) cells. Bio- and mucoadhesion on different substrates (synthetic cellulose membrane and porcine tissue mucosa)) and antimicrobial activity were successfully assessed, proving the ability of the OH- or the organically modified MSPs to act as antimicrobial and mucoadhesive platforms for drug delivery systems with synergistic effects.
Influence of Surface Contaminants and Hydrocarbon Pellicle on the Results of Wettability Measurements of Titanium
Authors: Kido Daisuke , Komatsu Keiji , Suzumura Toshikatsu , Matsuura Takanori , Cheng James , Kim Jeong , Park Wonhee , Ogawa Takahiro
Published: September 2023

Hydrophilicity/hydrophobicity—or wettability—is a key surface characterization metric for titanium used in dental and orthopedic implants. However, the effects of hydrophilicity/hydrophobicity on biological capability remain uncertain, and the relationships between surface wettability and other surface parameters, such as topography and chemistry, are poorly understood. The objective of this study was to identify determinants of surface wettability of titanium and establish the reliability and validity of the assessment. Wettability was evaluated as the contact angle of ddH2O. The age of titanium specimens significantly affected the contact angle, with acid-etched, microrough titanium surfaces becoming superhydrophilic immediately after surface processing, hydrophobic after 7 days, and hydrorepellent after 90 days. Similar age-related loss of hydrophilicity was also confirmed on sandblasted supra-micron rough surfaces so, regardless of surface topography, titanium surfaces eventually become hydrophobic or hydrorepellent with time. On age-standardized titanium, surface roughness increased the contact angle and hydrophobicity. UV treatment of titanium regenerated the superhydrophilicity regardless of age or surface roughness, with rougher surfaces becoming more superhydrophilic than machined surfaces after UV treatment. Conditioning titanium surfaces by autoclaving increased the hydrophobicity of already-hydrophobic surfaces, whereas conditioning with 70% alcohol and hydrating with water or saline attenuated pre-existing hydrophobicity. Conversely, when titanium surfaces were superhydrophilic like UV-treated ones, autoclaving and alcohol cleaning turned the surfaces hydrorepellent and hydrophobic, respectively. UV treatment recovered hydrophilicity without exception. In conclusion, surface roughness accentuates existing wettability and can either increase or decrease the contact angle. Titanium must be age-standardized when evaluating surface wettability. Surface conditioning techniques significantly but unpredictably affect existing wettability. These implied that titanium wettability is significantly influenced by the hydrocarbon pellicle and other contaminants inevitably accumulated. UV treatment may be an effective strategy to standardize wettability by making all titanium surfaces superhydrophilic, thereby allowing the characterization of individual surface topography and chemistry parameters in future studies.
Recent Advances in High-Content Imaging and Analysis in iPSC-Based Modelling of Neurodegenerative Diseases
Authors: Menduti Giovanna , Boido Marina
Published: September 2023

In the field of neurodegenerative pathologies, the platforms for disease modelling based on patient-derived induced pluripotent stem cells (iPSCs) represent a valuable molecular diagnostic/prognostic tool. Indeed, they paved the way for the in vitro recapitulation of the pathological mechanisms underlying neurodegeneration and for characterizing the molecular heterogeneity of disease manifestations, also enabling drug screening approaches for new therapeutic candidates. A major challenge is related to the choice and optimization of the morpho-functional study designs in human iPSC-derived neurons to deeply detail the cell phenotypes as markers of neurodegeneration. In recent years, the specific combination of high-throughput screening with subcellular resolution microscopy for cell-based high-content imaging (HCI) screening allowed in-depth analyses of cell morphology and neurite trafficking in iPSC-derived neuronal cells by using specific cutting-edge microscopes and automated computational assays. The present work aims to describe the main recent protocols and advances achieved with the HCI analysis in iPSC-based modelling of neurodegenerative diseases, highlighting technical and bioinformatics tips and tricks for further uses and research. To this end, microscopy requirements and the latest computational pipelines to analyze imaging data will be explored, while also providing an overview of the available open-source high-throughput automated platforms.
Genome-Wide Identification and Evolution of the GRF Gene Family and Functional Characterization of PbGRF18 in Pear
Authors: Zhu Rongxiang , Cao Beibei , Sun Manyi , Wu Jun , Li Jiaming
Published: September 2023

Proteins encoded by the G-box regulating factor (GRF, also called 14-3-3) gene family are involved in protein–protein interactions and mediate signaling transduction, which play important roles in plant growth, development, and stress responses. However, there were no detailed investigations of the GRF gene family in pear at present. In this study, we identified 25 GRF family members in the pear genome. Based on a phylogenetic analysis, the 25 GRF genes were clustered into two groups; the ε group and the non-ε group. Analyses of the exon–intron structures and motifs showed that the gene structures were conserved within each of the ε and non-ε groups. Gene duplication analysis indicated that most of the PbGRF gene expansion that occurred in both groups was due to WGD/segmental duplication. Phosphorylation sites analysis showed that the main phosphorylation sites of PbGRF proteins were serine residues. For gene expression, five PbGRF genes (PbGRF7, PbGRF11, PbGRF16, PbGRF21, and PbGRF23) were highly expressed in fruits, and PbGRF18 was highly expressed in all tissues. Further analysis revealed that eight PbGRF genes were significantly differentially expressed after treatment with different sugars; the expression of PbGRF7, PbGRF8, and PbGRF11 significantly increased, implying the involvement of these genes in sugar signaling. In addition, subcellular localization studies showed that the tested GRF proteins localize to the plasma membrane, and transgenic analysis showed that PbGRF18 can increase the sugar content in tomato leaves and fruit. The results of our research establish a foundation for functional determination of PbGRF proteins, and will help to promote a further understanding of the regulatory network in pear fruit development.
Heat Stress Alleviation by Exogenous Calcium in the Orchid Dendrobium nobile Lindl: A Biochemical and Transcriptomic Analysis
Authors: Fan Yijun , Ma Jie , Liu Yuanyuan , Tan Xueyan , Li Xuebing , Xu Erya , Xu Linlong , Luo Aoxue
Published: September 2023

The growth of Dendrobium nobile is sensitive to heat stress. To find an effective method for enhancing heat tolerance, this study investigated the relieving effect of exogenous calcium at different concentrations (0 mmol/L, 5 mmol/L, 10 mmol/L, 15 mmol/L, 20 mmol/L CaCl2) on heat stress in D. nobile. Principal component analysis was used to screen the optimal exogenous calcium concentration, and transcriptome analysis was used to reveal its possible heat tolerance mechanism. The results showed that compared with the T0, a 10 mmol/L calcium treatment: increased the average leaf length, leaf width, plant height, and fresh matter accumulation of D. nobile by 76%, 103.39%, 12.97%, and 12.24%, respectively (p < 0.05); significantly increased chlorophyll a (Chla), chlorophyll b (Chlb), carotenoids(Car), ascorbic acid (ASA), glutathione (GSH), and flavonoids by 15.72%, 8.54%, 11.88%, 52.17%, 31.54%, and 36.12%, respectively; and effectively enhanced the enzyme activity of the antioxidant system, increasing superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) by 1.38, 1.61, and 2.16 times, respectively (p < 0.05); At the same time, the treatment can effectively reduce the yellow leaf rate and defoliation rate of D. nobile under heat stress. The principal component analysis method and membership function were used to calculate the D value to rank the relief effects of each calcium treatment group, and the results also showed that 10 mmol/L CaCl2 had the best relief effect. Transcriptomics testing identified 7013 differentially expressed genes, of which 2719 were upregulated, and 294 were downregulated. Among them, genes such as HSPA1s, HSP90A, HSPBP1, ATG8, COMT, REF1, E1.11.1.7, along with transcription factors such as MYB, bHLH, WRKY, and NAC, formed the network of tolerance to heat stress in D. nobile. This study provides new insights for improving the cultivation techniques of D. nobile.
Involvement of IL-1β-Mediated Necroptosis in Neurodevelopment Impairment after Neonatal Sepsis in Rats
Authors: Liao Zhimin , Zhu Qing , Huang Han
Published: September 2023

The mechanism of long-term cognitive impairment after neonatal sepsis remains poorly understood, although long-lasting neuroinflammation has been considered the primary contributor. Necroptosis is actively involved in the inflammatory process, and in this study, we aimed to determine whether neonatal sepsis-induced long-term cognitive impairment was associated with activation of necroptosis. Rat pups on postnatal day 3 (P3) received intraperitoneal injections of lipopolysaccharide (LPS, 1 mg/kg) to induce neonatal sepsis. Intracerebroventricular injection of IL-1β-siRNA and necrostatin-1 (NEC1) were performed to block the production of IL-1β and activation of necroptosis in the brain, respectively. The Morris water maze task and fear conditioning test were performed on P28–P32 and P34–P35, respectively. Enzyme-linked immunosorbent assay (ELISA), quantitative real-time PCR (RT-PCR), and Western blotting were used to examine the expression levels of proinflammatory cytokines and necroptosis-associated proteins, such as receptor-interacting protein 1 (RIP1) and receptor-interacting protein 3 (RIP3). Sustained elevation of IL-1β level was observed in the brain after initial neonatal sepsis, which would last for at least 32 days. Sustained necroptosis activation was also observed in the brain. Knockdown of IL-1β expression in the brain alleviated necroptosis and improved long-term cognitive function. Direct inhibition of necroptosis also improved neurodevelopment and cognitive performance. This research indicated that sustained activation of necroptosis via IL-1β contributed to long-term cognitive dysfunction after neonatal sepsis.
Chemokine Binding to Tenascin-C Influences Chemokine-Induced Immune Cell Migration
Authors: Domaingo Alissa , Jokesch Philipp , Schweiger Alexandra , Gschwandtner Martha , Gerlza Tanja , Koch Manuel , Midwood Kim S. , Kungl Andreas J.
Published: September 2023

Tenascin-C (TNC) is a complex glycoprotein of the extracellular matrix (ECM) involved in a plethora of (patho-)physiological processes, such as oncogenesis and inflammation. Since chemokines play an essential role in both disease processes, we have investigated here the binding of TNC to some of the key chemokines, namely CCL2, CCL26, CXCL8, CXCL10, and CXCL12. Thereby, a differential chemokine-TNC binding pattern was observed, with CCL26 exhibiting the highest and CCL2 the lowest affinity for TNC. Heparan sulfate (HS), another member of the ECM, proved to be a similarly high-affinity ligand of TNC, with a Kd value of 730 nM. Chemokines use glycosa-minoglycans such as HS as co-receptors to induce immune cell migration. Therefore, we assumed an influence of TNC on immune cell chemotaxis due to co-localization within the ECM. CCL26- and CCL2-induced mobilization experiments of eosinophils and monocytes, respectively, were thus performed in the presence and the absence of TNC. Pre-incubation of the immune cells with TNC resulted in a 3.5-fold increase of CCL26-induced eosinophil chemotaxis, whereas a 1.3-fold de-crease in chemotaxis was observed when monocytes were pre-incubated with CCL2. As both chemokines have similar HS binding but different TNC binding affinities, we speculate that TNC acts as an attenuator in monocyte and as an amplifier in eosinophil mobilization by impeding CCL2 from binding to HS on the one hand, and by reinforcing CCL26 to bind to HS on the other hand.
Effect of Fermentation Scale on Microbiota Dynamics and Metabolic Functions for Indigo Reduction
Authors: Farjana Nowshin , Furukawa Hiromitsu , Sumi Hisako , Yumoto Isao
Published: September 2023

During indigo dyeing fermentation, indigo reduction for the solubilization of indigo particles occurs through the action of microbiota under anaerobic alkaline conditions. The original microbiota in the raw material (sukumo: composted indigo plant) should be appropriately converged toward the extracellular electron transfer (EET)-occurring microbiota by adjusting environmental factors for indigo reduction. The convergence mechanisms of microbiota, microbial physiological basis for indigo reduction, and microbiota led by different velocities in the decrease in redox potential (ORP) at different fermentation scales were analyzed. A rapid ORP decrease was realized in the big batch, excluding Actinomycetota effectively and dominating Alkalibacterium, which largely contributed to the effective indigo reduction. Functional analyses of the microbiota related to strong indigo reduction on approximately day 30 indicated that the carbohydrate metabolism, prokaryotic defense system, and gene regulatory functions are important. Because the major constituent in the big batch was Alkalibacterium pelagium, we attempted to identify genes related to EET in its genome. Each set of genes for flavin adenine dinucleotide (FAD) transportation to modify the flavin mononucleotide (FMN)-associated family, electron transfer from NADH to the FMN-associated family, and demethylmenaquinone (DMK) synthesis were identified in the genome sequence. The correlation between indigo intensity reduction and metabolic functions suggests that V/A-type H+/Na+-transporting ATPase and NAD(P)H-producing enzymes drive membrane transportations and energization in the EET system, respectively.
The Generation of a Nanobody-Based ELISA for Human Microsomal Epoxide Hydrolase
Authors: He Qiyi , McCoy Mark R. , Qi Meng , Morisseau Christophe , Yang Huiyi , Xu Chengpeng , Shey Rachel , Goodman Michael C. , Zhao Suqing , Hammock Bruce D.
Published: September 2023

A microsomal epoxide hydrolase (mEH) metabolizes in vivo in both xenobiotic and endogenous epoxides associated with signaling function. Findings in patients suggest that mEH might be a biomarker for several diseases, including metastatic cancer and viral hepatitis. To easily quantify mEH, nanobodies specific to the human mEH were isolated from a phage library of llama VHHs. Four unique clones were obtained and used for developing ELISAs. Three formats of double antibody sandwich assays were investigated using different detection strategies. Using PolyHRP, the signal was strongly amplified, yielding a 22-fold lower LOD (12 pg mL−1) than the ‘conventional’. To further validate the performance of the immunoassays, human tissue samples were analyzed by nanobody-based ELISAs and compared to the enzyme activities (R2 > 0.95). The results demonstrate that these nanobodies are powerful tools for the quantification of human mEH and could eventually result in a bedside assay.