bluuebunny/crossref_metadata_2025 huggingface dataset:
Construction of synthetic anti-fouling consortia: fouling control effects and polysaccharide degradation mechanisms
Authors: Qi Ji , Zhou Qicheng , Huang Danlei , Yu Zhong , Meng Fangang
Published: November 2023

The physical states and chemical components of bulk sludge determine the occurrence and development of membrane fouling in membrane bioreactors. Thus, regulation of sludge suspensions can provide new strategies for fouling control. In this study, we used “top-down” enrichment to construct a synthetic anti-fouling consortium (SAC) from bio-cake and evaluate its roles in preventing membrane fouling. The SAC was identified as Massilia-dominated and could almost wholly degrade the alginate solution (1,000 mg/L) within 72 h. Two-dimensional Fourier transformation infrared correlation spectroscopy (2D-FTIR-CoS) analysis demonstrated that the SAC induced the breakage of glycosidic bond in alginates. The co-cultivation of sludge with a low dosage of SAC (ranging from 0 to 1%) led to significant fouling mitigation, increased sludge floc size, and decreased unified membrane fouling index value (0.55 ± 0.06 and 0.11 ± 0.05). FTIR spectra and X-ray spectroscopy analyses demonstrated that the addition of SAC decreased the abundance of the O-acetylation of polysaccharides in extracellular polymeric substances. Secondary derivatives analysis of amide I spectra suggested a strong reduction in the α-helix/(β-sheet + random coil) ratio in the presence of SAC, which was expected to enhance cell aggregation. Additionally, the extracellular secretions of SAC could both inhibit biofilm formation and strongly disperse the existing biofilm strongly during the biofilm incubation tests. In summary, this study illustrates the feasibility and benefits of using SAC for fouling control and provides a new strategy for fouling control.
Rapid and non-destructive identification of Anopheles gambiae and Anopheles arabiensis mosquito species using Raman spectroscopy via machine learning classification models
Authors: Omucheni Dickson L. , Kaduki Kenneth A. , Mukabana Wolfgang R.
Published: November 2023

Background

Identification of malaria vectors is an important exercise that can result in the deployment of targeted control measures and monitoring the susceptibility of the vectors to control strategies. Although known to possess distinct biting behaviours and habitats, the African malaria vectors Anopheles gambiae and Anopheles arabiensis are morphologically indistinguishable and are known to be discriminated by molecular techniques. In this paper, Raman spectroscopy is proposed to complement the tedious and time-consuming Polymerase Chain Reaction (PCR) method for the rapid screening of mosquito identity.

Methods

A dispersive Raman microscope was used to record spectra from the legs (femurs and tibiae) of fresh anaesthetized laboratory-bred mosquitoes. The scattered Raman intensity signal peaks observed were predominantly centered at approximately 1400 cm−1, 1590 cm−1, and 2067 cm−1. These peaks, which are characteristic signatures of melanin pigment found in the insect cuticle, were important in the discrimination of the two mosquito species. Principal Component Analysis (PCA) was used for dimension reduction. Four classification models were built using the following techniques: Linear Discriminant Analysis (LDA), Logistic Regression (LR), Quadratic Discriminant Analysis (QDA), and Quadratic Support Vector Machine (QSVM).

Results

PCA extracted twenty-one features accounting for 95% of the variation in the data. Using the twenty-one principal components, LDA, LR, QDA, and QSVM discriminated and classified the two cryptic species with 86%, 85%, 89%, and 93% accuracy, respectively on cross-validation and 79%, 82%, 81% and 93% respectively on the test data set.

Conclusion

Raman spectroscopy in combination with machine learning tools is an effective, rapid and non-destructive method for discriminating and classifying two cryptic mosquito species, Anopheles gambiae and Anopheles arabiensis belonging to the Anopheles gambiae complex.
National Continuing Professional Development (CPD) training needs of pharmacists in Ethiopia
Authors: Tamiru Hamere , Huluka Solomon Assefa , Negash Bezawit , Hailu Kidu , Mekonen Zelalem Tilahun
Published: November 2023

Background

Continuing Professional Development (CPD) in pharmacy is a lifelong learning approach whereby individual pharmacists are responsible for updating and broadening their knowledge, skills, and attitudes. This is vital to ensure the delivery of high-quality patient care services. However, there is a lack of available data revealing the CPD needs of Ethiopian pharmacists. Thus, the objective of this study was to identify CPD training needs of pharmacists practicing in Ethiopia.

Methods

An institution-based cross-sectional study design with a quantitative approach was employed in this study. This assessment involved 640 pharmacists representing various sectors of the profession. Data were collected through a combination of an online platform and a face-to-face questionnaire administered in person.

Result

A total of 634 participants completed and returned the questionnaires, resulting in an impressive response rate of 99.1%. A significant majority (74.1%) of the participants possessed bachelor’s degree in pharmacy (B. Pharm). Pharmaceutical Logistics and Pharmacy administration was preferentially selected as a prior CPD course by 36% of participants, of them while Pharmacotherapy (17%), Leadership/Governance (13%), Community Pharmacy (12%), Research and Development (11%) were also the subsequent top choices by participants. Off-site face-to-face lectures (59.2%), Hybrid (face-to-face + e-learning) (54.8%), and on-site on-the-job training (45.5%) were the most convenient means of CPD course delivery. On the other hand, the participants least favored print-based or correspondence programs for CPD course delivery.

Conclusions

CPD holds great importance in the professional lives of pharmacists. It is critical for pharmacists, CPD providers, and those responsible for accrediting CPD programs to recognize the specific CPD requirements, preferred methods of delivery, and obstacles involved. This understanding is vital for establishing priorities and effectively planning CPD activities. In light of this, our study identified the most preferred CPD training courses and convenient delivery methods for pharmacists in Ethiopia. We recommend that CPD providers and accrediting bodies in Ethiopia refer to our findings when approving CPD courses.
Repurposing dimethyl fumarate as an antiepileptogenic and disease-modifying treatment for drug-resistant epilepsy
Authors: Sandouka Sereen , Singh Prince Kumar , Saadi Aseel , Taiwo Rhoda Olowe , Sheeni Yara , Zhang Taige , Deeb Larin , Guignet Michelle , White Steve H. , Shekh-Ahmad Tawfeeq
Published: November 2023

Background

Epilepsy affects over 65 million people worldwide and significantly burdens patients, caregivers, and society. Drug-resistant epilepsy occurs in approximately 30% of patients and growing evidence indicates that oxidative stress contributes to the development of such epilepsies. Activation of the Nrf2 pathway, which is involved in cellular defense, offers a potential strategy for reducing oxidative stress and epilepsy treatment. Dimethyl fumarate (DMF), an Nrf2 activator, exhibits antioxidant and anti-inflammatory effects and is used to treat multiple sclerosis.

Methods

The expression of Nrf2 and its related genes in vehicle or DMF treated rats were determined via RT-PCR and Western blot analysis. Neuronal cell death was evaluated by immunohistochemical staining. The effects of DMF in preventing the onset of epilepsy and modifying the disease were investigated in the kainic acid-induced status epilepticus model of temporal lobe epilepsy in rats.

The open field, elevated plus maze and T-Maze spontaneous alteration tests were used for behavioral assessments.

Results

We demonstrate that administration of DMF following status epilepticus increased Nrf2 activity, attenuated status epilepticus-induced neuronal cell death, and decreased seizure frequency and the total number of seizures compared to vehicle-treated animals. Moreover, DMF treatment reversed epilepsy-induced behavioral deficits in the treated rats.

Moreover, DMF treatment even when initiated well after the diagnosis of epilepsy, reduced symptomatic seizures long after the drug was eliminated from the body.

Conclusions

Taken together, these findings suggest that DMF, through the activation of Nrf2, has the potential to serve as a therapeutic target for preventing epileptogenesis and modifying epilepsy.
Characterization of intrinsic and effective fitness changes caused by temporarily fixed mutations in the SARS-CoV-2 spike E484 epitope and identification of an epistatic precondition for the evolution of E484A in variant Omicron
Authors: Schröder Simon , Richter Anja , Veith Talitha , Emanuel Jackson , Gudermann Luca , Friedmann Kirstin , Jeworowski Lara M. , Mühlemann Barbara , Jones Terry C. , Müller Marcel A. , Corman Victor M. , Drosten Christian
Published: November 2023

Background

Intrinsic fitness costs are likely to have guided the selection of lineage-determining mutations during emergence of variants of SARS-CoV-2. Whereas changes in receptor affinity and antibody neutralization have been thoroughly mapped for individual mutations in spike, their influence on intrinsic replicative fitness remains understudied.

Methods

We analyzed mutations in immunodominant spike epitope E484 that became temporarily fixed over the pandemic. We engineered the resulting immune escape mutations E484K, -A, and -Q in recombinant SARS-CoV-2. We characterized viral replication, entry, and competitive fitness with and without immune serum from humans with defined exposure/vaccination history and hamsters monospecifically infected with the E484K variant. We additionally engineered a virus containing the Omicron signature mutations N501Y and Q498R that were predicted to epistatically enhance receptor binding.

Results

Multistep growth kinetics in Vero-, Calu-3, and NCI-H1299 were identical between viruses. Synchronized entry experiments based on cold absorption and temperature shift identified only an insignificant trend toward faster entry of the E484K variant. Competitive passage experiments revealed clear replicative fitness differences. In absence of immune serum, E484A and E484Q, but not E484K, were replaced by wildtype (WT) in competition assays. In presence of immune serum, all three mutants outcompeted WT. Decreased E484A fitness levels were over-compensated for by N501Y and Q498R, identifying a putative Omicron founder background that exceeds the intrinsic and effective fitness of WT and matches that of E484K. Critically, the E484A/Q498R/N501Y mutant and E484K have equal fitness also in presence of pre-Omicron vaccinee serum, whereas the fitness gain by E484K is lost in the presence of serum raised against the E484K variant in hamsters.

Conclusions

The emergence of E484A and E484Q prior to widespread population immunity may have been limited by fitness costs. In populations already exposed to the early immune escape epitope E484K, the Omicron founder background may have provided a basis for alternative immune escape evolution via E484A. Studies of major antigenic epitope changes with and without their epistatic context help reconstruct the sequential adjustments of intrinsic fitness versus neutralization escape during the evolution of major SARS-CoV-2 variants in an increasingly immune human population.
Machine learning provides specific detection of salt and drought stresses in cucumber based on miRNA characteristics
Authors: Mohammadi Parvin , Asefpour Vakilian Keyvan
Published: November 2023

Background

Specific detection of the type and severity of plant abiotic stresses helps prevent yield loss by considering timely actions. This study introduces a novel method to detect the type and severity of stress in cucumber plants under salinity and drought conditions. Various features, i.e., morphological (image textural features), physiological/biochemical (relative water content, chlorophyll, catalase activity, anthocyanins, phenol content, and proline), as well as miRNA characteristics (the concentration of miRNA-156a, miRNA-166i, miRNA-399g, and miRNA-477b) were extracted from plant leaves, and machine learning methods were used to predict the type and severity of stress by having these features. Support vector machine (SVM) with parameters optimized by genetic algorithm (GA) and particle swarm optimization (PSO) was used for machine learning.

Results

The coefficient of determination of predicting the stress type and severity in plants under both stresses was 0.61, 0.82, and 0.99 using morphological, physiological/biochemical, and miRNA characteristics, respectively. This reveals machine learning methods optimized by metaheuristic optimization techniques can provide specific detection of salt and drought stresses in cucumber plants based on miRNA characteristics. Among the study miRNAs, miRNA-477b and miRNA-399g had the highest and lowest contribution to salt and drought stresses, respectively.

Conclusions

Comapred to conventional plant traits, miRNAs are more reliable features for providing us with valuable information about plant abiotic diseases at early stages. Using an electrochemical miRNA biosensor similar to one used in this work to measure the miRNA concentration in plant leaves and using a machine learning algorithm such as SVM enable farmers to detect the salt and drought stress at early stages in cucumber plants with very high accuracy.
Relative timing information and orthology in evolutionary scenarios
Authors: Schaller David , Hartmann Tom , Lafond Manuel , Stadler Peter F. , Wieseke Nicolas , Hellmuth Marc
Published: November 2023

Background

Evolutionary scenarios describing the evolution of a family of genes within a collection of species comprise the mapping of the vertices of a gene tree T to vertices and edges of a species tree S. The relative timing of the last common ancestors of two extant genes (leaves of T) and the last common ancestors of the two species (leaves of S) in which they reside is indicative of horizontal gene transfers (HGT) and ancient duplications. Orthologous gene pairs, on the other hand, require that their last common ancestors coincides with a corresponding speciation event. The relative timing information of gene and species divergences is captured by three colored graphs that have the extant genes as vertices and the species in which the genes are found as vertex colors: the equal-divergence-time (EDT) graph, the later-divergence-time (LDT) graph and the prior-divergence-time (PDT) graph, which together form an edge partition of the complete graph.

Results

Here we give a complete characterization in terms of informative and forbidden triples that can be read off the three graphs and provide a polynomial time algorithm for constructing an evolutionary scenario that explains the graphs, provided such a scenario exists. While both LDT and PDT graphs are cographs, this is not true for the EDT graph in general. We show that every EDT graph is perfect. While the information about LDT and PDT graphs is necessary to recognize EDT graphs in polynomial-time for general scenarios, this extra information can be dropped in the HGT-free case. However, recognition of EDT graphs without knowledge of putative LDT and PDT graphs is NP-complete for general scenarios. In contrast, PDT graphs can be recognized in polynomial-time. We finally connect the EDT graph to the alternative definitions of orthology that have been proposed for scenarios with horizontal gene transfer. With one exception, the corresponding graphs are shown to be colored cographs.
Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders
Authors: Huang Yige , Liu Bangyan , Sinha Subhash C. , Amin Sadaf , Gan Li
Published: November 2023

DNA sensing is a pivotal component of the innate immune system that is responsible for detecting mislocalized DNA and triggering downstream inflammatory pathways. Among the DNA sensors, cyclic GMP-AMP synthase (cGAS) is a primary player in detecting cytosolic DNA, including foreign DNA from pathogens and self-DNA released during cellular damage, culminating in a type I interferon (IFN-I) response through stimulator of interferon genes (STING) activation. IFN-I cytokines are essential in mediating neuroinflammation, which is widely observed in CNS injury, neurodegeneration, and aging, suggesting an upstream role for the cGAS DNA sensing pathway. In this review, we summarize the latest developments on the cGAS-STING DNA-driven immune response in various neurological diseases and conditions. Our review covers the current understanding of the molecular mechanisms of cGAS activation and highlights cGAS-STING signaling in various cell types of central and peripheral nervous systems, such as resident brain immune cells, neurons, and glial cells. We then discuss the role of cGAS-STING signaling in different neurodegenerative conditions, including tauopathies, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, as well as aging and senescence. Finally, we lay out the current advancements in research and development of cGAS inhibitors and assess the prospects of targeting cGAS and STING as therapeutic strategies for a wide spectrum of neurological diseases.
Evaluation of human papillomavirus DNA in colorectal cancer and adjacent mucosal tissue samples
Authors: Galati Luisa , Gupta Purnima , Tufaro Antonio , Marinaro Mariarosaria , Saponaro Concetta , Escobar Marcillo David Israel , Loisi Donato , Sen Rajdip , Robitaille Alexis , Brancaccio Rosario N. , Cuenin Cyrille , McKay-Chopin Sandrine , Paradiso Angelo Virgilio , Liška Václav , Souček Pavel , Zito Francesco Alfredo , Hughes David J. , Tommasino Massimo , Gheit Tarik
Published: November 2023

Background

Although the role of viral agents, such as human papillomavirus (e.g. HPV16, HPV18) in colorectal cancer (CRC) has been previously investigated, results remain inconclusive.

Methods

To further evaluate the involvement of oncogenic HPV types in CRC, 40 frozen neoplastic and 40 adjacent colonic tissues collected from Italian patients were analyzed by Luminex-based assays that detect a broad spectrum of HPV types, i.e. Alpha (n = 21), Beta (n = 46) and Gamma HPVs (n = 52). In addition, 125 frozen CRC samples and 70 surrounding mucosal tissues were collected from Czech patients and analyzed by broad spectrum PCR protocols: (i) FAP59/64, (ii) FAPM1 and (iii) CUT combined with Next Generation Sequencing (NGS).

Results

Using Luminex-basedassays, DNA from HPV16 was detected in 5% (2/40) CRC tissues from Italian patients. One HPV16 DNA-positive CRC case was subsequently confirmed positive for E6*I mRNA. Cutaneous beta HPV types were detected in 10% (4/40) adjacent tissues only, namely HPV111 (n = 3) and HPV120 (n = 1), while gamma HPV168 (n = 1) and HPV199 (n = 1) types were detected in adjacent and in tumor tissues, respectively. The NGS analysis of the CRC Czech samples identified HPV sequences from mucosal alpha-3 (HPV89), alpha-7 (HPV18, 39, 68 and 70) and alpha-10 species (HPV11), as well as cutaneous beta-1 (HPV20, 24, 93, 98, 105,124) beta-2 (HPV23), beta-3 (HPV49) and gamma-1 species (HPV205).

Conclusions

Our findings indicate that HPV types belonging to the mucosal alpha, and the ‘cutaneous’ beta and gamma genera can be detected in the colonic mucosal samples with a low prevalence rate and a low number of HPV reads by Luminex and NGS, respectively. However, additional studies are required to corroborate these findings.
Single-session intervention on growth mindset on negative emotions for university student mental health (U-SIGMA): a protocol of two-armed randomized controlled trial
Authors: Zhu Shimin , Hu Yuxi , Qi Di , Qin Nan , Chi Xinli , Luo Jiawen , Wu Jie , Huang Hua , Wu Qiaobing , Yu Lu , Ni Shiguang , Hamilton Kyra , Tse Samson
Published: November 2023

Background

The university years are a developmentally crucial phase and a peak period for the onset of mental disorders. The beliefs about the changeability of negative emotion may play an important role in help-seeking. The brief digital growth mindset intervention is potentially scalable and acceptable to enhance adaptive coping and help-seeking for mental health needs in university students. We adapted the Single-session Intervention on Growth Mindset for adolescents (SIGMA) to be applied in university students (U-SIGMA). This protocol introduces a two-armed waitlist randomized controlled trial study to examine the effectiveness and acceptability of U-SIGMA in promoting help-seeking among university students in the Greater Bay Area.

Methods

University students (N = 250, ages 18–25) from universities in the Greater Bay Area will be randomized to either the brief digital growth mindset intervention group or the waitlist control group. Participants will report on the mindsets of negative emotions, perceived control over anxiety, attitude toward help-seeking, physical activity, hopelessness, psychological well-being, depression, anxiety, and perceived stress at baseline and the 2-week and 8-week follow-ups through web-based surveys. A 30-min digital intervention will be implemented in the intervention group, with a pre- and post-intervention survey collecting intervention feedback, while the control group will receive the link for intervention after 8 weeks.

Discussion

This protocol introduces the implementation plan of U-SIMGA in multi-cities of the Greater Bay Area. The findings are expected to help provide pioneer evidence for the effectiveness and acceptability of the brief digital intervention for university students in the Chinese context and beyond and contribute to the development of accessible and effective prevention and early intervention for university students’ mental health.

Trial registration

HKU Clinical Trials Registry: HKUCTR-3012; Registered 14 April 2023. http://www.hkuctr.com/Study/Show/7a3ffbc0e03f4d1eac0525450fc5187e.
Blood biomarkers for estimating energy intake in Japanese male collegiate athletes: a pilot study
Authors: Kurosaka Yuka , Nagasawa Takaaki , Minato Kumiko , Hasegawa-Tanaka Tomomi , Naito Hisashi , Wakui Sawako , Machida Shuichi
Published: November 2023

Background

Athletes should be informed of their required energy intake in preparation for sports competitions. However, the environment in which dietary surveys can be conducted to determine the required energy intake for sports competitions is limited, and such survey will require a substantial amount of time and effort from athletes and dietitians. If certain biomarkers for estimating the energy intake can be identified, they may compensate for the shortcomings of these dietary surveys. We aimed to identify the blood biomarkers to estimate the energy intake/basal metabolic rate ratio of male athletes.

Methods

Twenty-six male athletes from a university physical education department were included and underwent measurements of height, weight, and body composition, as well as blood sampling. The dietary assessment included a 3-day dietary recall and collection of meal photographs. The basal metabolic rate was estimated using the lean body mass, while the daily energy intake/basal metabolic rate ratio was used as an index to determine the energy intake. From the 36 selected blood biomarkers, we identified the independent biomarkers for inclusion in the multiple regression analysis by assessing for pairwise correlations and multicollinearity. A formula for estimating the energy intake/basal metabolic rate was then developed using the stepwise method. A p-value of < 0.05 was considered significant.

Results

Overall, 18 of the 36 blood biomarkers were selected, and multiple regression analysis revealed that triiodothyronine, white blood cell count, and triglyceride level were significant factors that can be used to estimate the energy intake/basal metabolic rate, accounting for 60.4% of the variance. No systematic errors were observed in the estimated values, calculated using the estimation formula and dietary assessment results.

Conclusions

A combination of free triiodothyronine level, white blood cell count, and triglyceride level can be used for estimating the energy intake/basal metabolic rate of male athletes, thus compensating for the shortcomings of dietary surveys.
Pilot study: is there an influence of lower limb positioning during magnetic resonance imaging on muscle cross section shape assessment in the thigh?
Authors: Oberhofer Katja , Blum Matthias , Achermann Basil , Lorenzetti Silvio R.
Published: November 2023

Positioning in an MRI can influence quantitative measures of the muscle. The goal of this pilot study was to assess the influence of different levels of knee elevation during MRI on the predicted cross-sectional muscle shape in the thigh. Data were acquired in three healthy male participants (age: 29.3 ± 5.1y, height: 181.3 ± 6.4cm, weight: 85.1 ± 3.7kg). For each participant, three MRI scans were taken by a trained radiographer with low, moderate and high knee elevation. The shape of the anatomical cross-sectional areas of the hamstrings and quadriceps in three leg positionings were compared by fitting ellipsoidal functions to the segmented MRI data and calculating the so-called J index for every image slice using the Python scripting language. Different levels of knee elevation resulted in apparent changes in J index for all muscles except vastus medialis. Thereby, the changes were overall more pronounced in the hamstrings compared to the quadriceps. Particularly, by elevating the knee from 8 to 15 degree, the percentage changes in J index were between 7.2 and 13.6% for the hamstrings and between 0.5 and 3.3% for the quadriceps, respectively. For assessing the musculoskeletal properties by means of MRI, a standardized positioning of the leg is required and the knee joint angle should be controlled.
A comparative study of clustering methods on gene expression data for lung cancer prognosis
Authors: Zhang Jason Z. , Wang Chi
Published: November 2023

Lung cancer subtyping based on gene expression data is important for identifying patient subgroups with differing survival prognosis to facilitate customized treatment strategies for each subtype of patients. Unsupervised clustering methods are the traditional approach for clustering patients into subtypes. However, since those methods cluster patients based only on gene expression data, the resulting clusters may not always be relevant to the survival outcome of interest. In recent years, semi-supervised and supervised methods have been proposed, which leverage the survival outcome data to identify clusters more relevant to survival prognosis. This paper aims to compare the performance of different clustering methods for identifying clinically prognostic lung cancer subtypes based on two lung adenocarcinoma datasets. For each method, we clustered patients into two clusters and assessed the difference in patient survival time between clusters. Unsupervised methods were found to have large logrank p-values and no significant results in most cases. Semi-supervised and supervised methods had improved performance over unsupervised methods and very significant p-values. These results indicate that unsupervised methods are not capable of identifying clusters with significant differences in survival prognosis in most cases, while supervised and semi-supervised methods can better cluster patients into clinically useful subtypes.
Tazemetostat decreases β-catenin and CD13 protein expression in HEPG-2 and Hepatitis B virus-transfected HEPG-2 with decreased cell viability
Authors: Amin Mohamed N. , El-Far Yousra M. , El-Mowafy Mohammed , Elgaml Abdelaziz
Published: November 2023

Hepatocellular carcinoma (HCC) is one of the global health concerns. Hepatitis B virus (HBV) is one of the major causes of HCC. Poor clinical outcome of HCC patients is attributed to a small population of cancer cells known as cancer stem cells (CSCs). In this work, we studied the effect of inhibiting the enhancer of zeste homologue 2 (EZH2), a histone methyltransferase known to be overexpressed in CSCs, using tazemetostat (Taz). The effect of Taz was assessed in the HCC cell line (HEPG2) and Hepatitis B virus-transfected HEPG2 (HBV/HEPG2) cells. MTT assay showed a significant decrease in HEPG2 cells viability after 48 h treatment with either 0.5, 1, 4 or 6 μM Taz. HEPG2 and HBV/HEPG2 cells were incubated with either 0.5 or 1 μM Taz for 48 h, and then, the cells and supernatants were collected for protein expression analysis of EZH2, CD13, epithelial cell adhesion molecule (EpCAM) and β-catenin using enzyme-linked immunosorbent assay (ELISA). Taz showed a significant dose-dependent inhibition of EZH2, CD13 and β-catenin in HEPG2 and HBV/HEPG2 cells. Also, EpCAM protein levels were significantly decreased in HBV/HEPG2 but not in HEPG2 cell line alone. Our results indicate that Taz inhibition of EZH2 leads to downregulation of β-catenin signaling and eventually decreased expression of CD13 and EpCAM, which are characteristic for CSCs. The present study suggests that Taz could be a promising treatment for HCC including HBV-induced HCC that might be used in combination with radio/chemotherapy to target CSCs and prevent tumor relapse.
Musashi-2 in cancer-associated fibroblasts promotes non-small cell lung cancer metastasis through paracrine IL-6-driven epithelial-mesenchymal transition
Authors: Samart Parinya , Heenatigala Palliyage Gayathri , Issaragrisil Surapol , Luanpitpong Sudjit , Rojanasakul Yon
Published: November 2023

Background

Lung cancer, the most common cause of cancer-related mortality worldwide, is predominantly associated with advanced/metastatic disease. The interaction between tumor cells and cancer-associated fibroblasts (CAFs) in tumor microenvironment is known to be essential for regulating tumor progression and metastasis, but the underlying mechanisms, particularly the role of RNA-binding protein Musashi-2 (MSI2) in CAFs in promoting non-small cell lung cancer (NSCLC) invasiveness and metastatic spread, remain obscure.

Methods

Genomic and proteomic database analyses were performed to evaluate the potential clinical significance of MSI2 in NSCLC tumor and stromal clinical specimens. Molecular approaches were used to modify MSI2 in CAFs and determine its functional role in NSCLC cell motility in vitro using 2D and 3D models, and in metastasis in a xenograft mouse model using live-cell imaging.

Results

MSI2, both gene and protein, is upregulated in NSCLC tissues and is associated with poor prognosis and high metastatic risk in patients. Interestingly, MSI2 is also upregulated in NSCLC stroma and activated fibroblasts, including CAFs. Depletion of MSI2 in CAFs by CRISPR-Cas9 strongly inhibits NSCLC cell migration and invasion in vitro, and attenuates local and distant metastatic spread of NSCLC cells in vivo. The crosstalk between CAFs and NSCLC cells occurs via paracrine signaling, which is regulated by MSI2 in CAFs via IL-6. The secreted IL-6 promotes epithelial-mesenchymal transition in NSCLC cells, which drives metastasis.

Conclusion

Our findings reveal for the first time that MSI2 in CAFs is important in CAF-mediated NSCLC cell invasiveness and metastasis via IL-6 paracrine signaling. Therefore, targeting the MSI2/IL-6 axis in CAFs could be effective in combating NSCLC metastasis.
Mechanisms and biomarkers of immune-related adverse events in gastric cancer
Authors: Ding Ping’an , Liu Pengpeng , Meng Lingjiao , Zhao Qun
Published: November 2023

Immune-checkpoint inhibitors (ICIs), different from traditional cancer treatment models, have shown unprecedented anti-tumor effects in the past decade, greatly improving the prognosis of many malignant tumors in clinical practice. At present, the most widely used ICIs in clinical immunotherapy for a variety of solid tumors are monoclonal antibodies against cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1) and their ligand PD-L1. However, tumor patients may induce immune-related adverse events (irAEs) while performing immunotherapy, and irAE is an obstacle to the prospect of ICI treatment. IrAE is a non-specific disease caused by immune system imbalance, which can occur in many tissues and organs. For example, skin, gastrointestinal tract, endocrine system and lung. Although the exact mechanism is not completely clear, related studies have shown that irAE may develop through many ways. Such as excessive activation of autoreactive T cells, excessive release of inflammatory cytokines, elevated levels of autoantibodies, and common antigens between tumors and normal tissues. Considering that the occurrence of severe IrAE not only causes irreversible damage to the patient’s body, but also terminates immunotherapy due to immune intolerance. Therefore, accurate identification and screening of sensitive markers of irAE are the main beneficiaries of ICI treatment. Additionally, irAEs usually require specific management, the most common of which are steroids and immunomodulatory therapies. This review aims to summarize the current biomarkers for predicting irAE in gastric cancer and their possible mechanisms.
Classification and analysis of common simplifications in part-scale thermal modelling of metal additive manufacturing processes
Authors: Ranjan Rajit , Langelaar Matthijs , Van Keulen Fred , Ayas Can
Published: November 2023

Computational process modelling of metal additive manufacturing has gained significant research attention in recent past. The cornerstone of many process models is the transient thermal response during the AM process. Since deposition-scale modelling of the thermal conditions in AM is computationally expensive, spatial and temporal simplifications, such as simulating deposition of an entire layer or multiple layers, and extending the laser exposure times, are commonly employed in the literature. Although beneficial in reducing computational costs, the influence of these simplifications on the accuracy of temperature history is reported on a case-by-case basis. In this paper, the simplifications from the existing literature are first classified in a normalised simplification space based on assumptions made in spatial and temporal domains. Subsequently, all types of simplifications are investigated with numerical examples and compared with a high-fidelity reference model. The required numerical discretisation for each simplification is established, leading to a fair comparison of computational times. The holistic approach to the suitability of different modelling simplifications for capturing thermal history provides guidelines for the suitability of simplifications while setting up a thermal AM model.
Does early adversity predict aggression among Chinese male violent juvenile offenders? The mediating role of life history strategy and the moderating role of meaning in life
Authors: Gong Yuandong , Li Qingtian , Li Jiazheng , Wang Xinning , Jiang Wenning , Zhao Weiguo
Published: November 2023

Background

Adolescent aggression has long been of interest to researchers. However, few studies have examined the influencing factors and mechanisms of aggression among violent juvenile offenders. This study tests a moderated mediation model with Chinese male violent juvenile offenders as subjects. Specifically, it explores the relationship between early adversity and aggression, as well as the mechanisms of life history strategy and meaning in life in this relationship.

Methods

A total of 537 Chinese male violent juvenile offenders completed the Childhood Environment Scale, the Life History Strategy Short Form Scale, the Aggression Questionnaire, and the Meaning in Life Questionnaire. After controlling for socioeconomic status (SES), the current cross-sectional study used structural equation modeling (SEM) to examine a moderated mediation model.

Results

The results showed that life history strategy mediated the relationship between early adversity and aggression, and early adversity affected individuals’ aggression by accelerating their life history strategies. The results also showed that meaning in life moderated the relationship between early adversity and life history strategy. For individuals with high meaning in life scores, the negative predictive effect of early adversity on life history strategy was stronger than that for individuals with low meaning in life scores.

Conclusion

The results of this study can advance the understanding of how early adversity affects aggression among violent juvenile offenders and provide theoretical support for prison staff to develop educational strategies and subsequent interventions.
Intra‐articular injections in sport‐active patients with degenerative cartilage lesions or osteoarthritis of the knee: a systematic review
Authors: De Marziani Luca , Sangiorgio Alessandro , Bensa Alessandro , Boffa Angelo , Andriolo Luca , Filardo Giuseppe
Published: November 2023

Purpose

The aim of this systematic review was to analyse the available clinical evidence on intra‐articular knee injections for the treatment of degenerative cartilage lesions and osteoarthritis (OA) in sport‐active patients.

Methods

A literature search was performed in July 2023 according to the PRISMA guidelines on three electronic databases (PubMed, Cochrane, Web of Science). Studies addressing intra‐articular injections for degenerative knee cartilage lesions or knee OA in sport‐active patients were included. The Downs and Black’s “checklist for measuring quality” was used to evaluate risk of bias and quality of the included studies.

Results

Only 10 clinical studies for a total of 296 sport‐active patients were included, with a publication trend increasing over time. The studies were 9 case series and 1 RCT; 7 studies focused on hyaluronic acid (HA), 2 studies focused on platelet‐rich plasma (PRP), while 1 study compared HA and PRP. Overall, safety and positive clinical findings were for both HA and PRP, although not always with satisfactory results in terms of return to sport. The Downs and Black evaluation showed an overall poor quality of the included studies, with an average score of 21.1 points (range 19–25).

Conclusions

The available clinical evidence is still limited, with only a few studies published and an overall low‐quality of evidence, suggesting a potential role of HA and PRP injections to treat these patients. However, further high‐level trials are needed to confirm the real benefits of these treatments for the management of sport‐active patients affected by degenerative cartilage lesions or OA of the knee.
Study on active capacity and detergent application potential of low-temperature alkaline serine protease produced by new strain Exiguobacterium indicum 1.2.3
Authors: Kati Ahmet , Balci Gamze
Published: November 2023

Microorganisms have long captivated researchers for their potential to produce enzymes with diverse industrial applications. Efficient production of proteases from new strains is crucial as these enzymes play a vital role in breaking down protein bonds, enabling their use in industrial applications. Therefore, a novel Exiguobacterium indicum 1.2.3 was isolated (Istanbul, Turkiye) and characterized in this study. This strain produced alkaline serine protease, which works in lower temperatures (20–40 °C) with casein as a specific substrate. The protease was utterly stable for 3 h at 30 °C. The enzyme was also highly stable in the pH range of 8–11. The optimum activity was obtained at pH 10. The crude enzyme activity was enhanced by various metal ions and retained 147%, 125%, 124%, and 117% of its activity within 1 mM Ca2+, Mn2+, Cu2+, and Mg2+, respectively. The crude enzyme was inactive with phenylmethylsulfonyl fluoride, indicating a serine residue on the active side. The enzyme exhibited a significant proteolytic effect in the presence of surfactants and oxidizing agents. The addition of Tween 80, Triton X-100, and sodium perborate improved enzymatic activity up to 135%, 109%, and 105%, respectively. According to the washing results, the crude enzyme effectively removed the blood on different types of standard pre-stained textiles at 30 °C. In conclusion, Exiguobacterium indicum 1.2.3 is a promising candidate for protease production, with its diverse applications spanning various industrial sectors, particularly detergents.

Graphical Abstract
Insights gained from single-cell analysis of chimeric antigen receptor T-cell immunotherapy in cancer
Authors: Tang Lu , Huang Zhong-Pei , Mei Heng , Hu Yu
Published: November 2023

Advances in chimeric antigen receptor (CAR)-T cell therapy have significantly improved clinical outcomes of patients with relapsed or refractory hematologic malignancies. However, progress is still hindered as clinical benefit is only available for a fraction of patients. A lack of understanding of CAR-T cell behaviors in vivo at the single-cell level impedes their more extensive application in clinical practice. Mounting evidence suggests that single-cell sequencing techniques can help perfect the receptor design, guide gene-based T cell modification, and optimize the CAR-T manufacturing conditions, and all of them are essential for long-term immunosurveillance and more favorable clinical outcomes. The information generated by employing these methods also potentially informs our understanding of the numerous complex factors that dictate therapeutic efficacy and toxicities. In this review, we discuss the reasons why CAR-T immunotherapy fails in clinical practice and what this field has learned since the milestone of single-cell sequencing technologies. We further outline recent advances in the application of single-cell analyses in CAR-T immunotherapy. Specifically, we provide an overview of single-cell studies focusing on target antigens, CAR-transgene integration, and preclinical research and clinical applications, and then discuss how it will affect the future of CAR-T cell therapy.
Akt signaling pathway: a potential therapy for Alzheimer’s disease through glycogen synthase kinase 3 beta inhibition
Authors: Limantoro Joshua , de Liyis Bryan Gervais , Sutedja Jane Carissa
Published: November 2023

Alzheimer’s disease (AD) is a form of dementia marked by the accumulation of neuritic plaques and neurofibrillary tangles through the action of GSK-3β with both significant epidemiological and clinical impact. Current pharmacological treatment approaches are focused on symptomatic relief and aims to suppress AD’s progression rather than disease modification. This issue has triggered further investigations about tau pathology as an important component in AD’s pathophysiology, one of them being the Akt signaling pathway. Based on the problem served by AD, combined with the non-existence of conclusive therapy for this disease; hence, this study strives to further investigate the potential therapeutical benefit of Akt signaling towards AD. A total of 82 studies are included, consisting of both national and international articles creating a narrative review based on the PRISMA checklist. Variables searched on this study, include Alzheimer’s disease (AD), Akt signaling, serine-9 phosphorylation, and GSK-3β. Tau protein accumulation has been a mainstay in the physiopathology of AD, which are largely influenced by the GSK-3β expression. Akt signaling has been shown to inactivate GSK-3β through serine-9 phosphorylation. Thus, modulating and optimizing the Akt signaling pathway present encouraging prospects for the development of innovative and efficacious therapeutic strategies in addressing AD. Several studies have tried to estimate the harm and benefit as well as dose–effect relationship between Akt signaling and AD, concluding a promising beneficial effect for AD therapy. Here, we show the beneficial therapeutic effects of Akt signaling towards AD through both theoretical and empirical standpoints.
Tor network anonymity evaluation based on node anonymity
Authors: Cui Jun , Huang Changqi , Meng Huan , Wei Ran
Published: November 2023

In order to address the shortcomings of traditional anonymity network anonymity evaluation methods, which only analyze from the perspective of the overall network and ignore the attributes of individual nodes, we proposes a dynamic anonymity model based on a self-built anonymous system that combines node attributes, network behavior, and program security monitoring. The anonymity of evaluation nodes is assessed based on stable intervals and behavior baselines defined according to their normal operating status. The anonymity of the network is evaluated using an improved normalized information entropy method that refines anonymity evaluation to the anonymity of each node and expands the dimensionality of evaluation features. This paper compares the effectiveness of our proposed method with static framework information entropy and single indicator methods by evaluating the degree of anonymity provided by a self-built Tor anonymous network under multiple operating scenarios including normal and under attack. Our approach utilizes dynamically changing network anonymity based on multiple anonymous attributes and better reflects the degree of anonymity in anonymous systems.
The alleviative efficacy of sildenafil and chrysin against zinc oxide nanoparticles-provoked hepatic and blood toxicity: role of MyD88/NF-κB1/TNF-α pathway
Authors: Nageeb Mahitab M. , Amer Marwa Abdel-Moniem , Hendawy Doaa M. , Hanafy Sabah Mohamed , Elmenshawi Maha Saad , Elmakromy Gena M. , Moawed Dena Mohamed Naguib Abdel
Published: November 2023

Background

Zinc oxide nanoparticles are nanoparticles of metal oxide with semiconductor properties and proved many noxious effects on the mammalian cell. Sildenafil, a phosphodiesterase inhibitor, and chrysin, one of the flavonoids, proved to have anti-inflammatory and anti-oxidative stress effects.

Methods

48 rats were grouped into 8 groups equally. 1. (Control group) received normal diet and NaOH was added to water, 2. (chrysin group): 250 mg/kg, orally for 10 days, 3. (sildenafil group): 40 mg/kg, orally for 14 days, 4. (ZnO-NPs group): 200 mg/kg, intraperitoneal for 10 days, 5. (ZnO-NPs + chrysin as a prophylactic agent): given in the same previous doses and durations consecutively, 6. (ZnO-NPs + chrysin as a curative agent): given in the same previous doses and durations with chrysin given after ZnO-NPs administration for 10 days, 7. (ZnO-NPs + sildenafil as a curative agent): given in the same previous doses and durations with sildenafil given after ZnO-NPs administration for 10 days, and 8. (Combined treatment group chrysin + sildenafil) as combined treatment were given in the same previous doses and durations after ZnO-NPs administration for 10 days. Blood and samples from tissues were withdrawn for histopathological, biochemical studies, and comet assay at the end of the experiment.

Results

Sildenafil and chrysin proved to protect from hepatotoxicity and hematotoxicity induced by zinc oxide nanoparticles as they lessened aspartate transaminase, alanine transferase, and alkaline phosphatase levels. They also reduced the oxidative stress enzyme levels. Gene expression of myeloid differentiation factor 88, nuclear factor kappa B1, tumor necrosis factor, and DNA damage decreased with treatment. Also, there was an improvement in the histopathological picture of the liver seen with treatment. Concurrent administration of sildenafil and chrysin revealed much better improvement than either drug used alone.

Conclusion

Chrysin and sildenafil have ameliorative effects against ZnO-NPs-induced hepatotoxicity and hematotoxicity, their protective effect is either preventive with chrysin or curative with chrysin and sildenafil.