bluuebunny/crossref_metadata_2025 huggingface dataset:
Distribution of volatile organic compounds (VOCs) in the urban atmosphere of Hangzhou, East China: Temporal variation, source attribution, and impact on the secondary formations of ozone and aerosol
Authors: Wang Xin , Han Yu , Tu Xiang , Shen Jiandong , Zhang Baojun , Fu Hongbo
Published: May 2024

Volatile organic compounds (VOCs) significantly influence air quality, atmospheric chemistry, and human health. An observational study was performed at the urban site of Hangzhou, China, to analyze VOC characteristics, sources, chemical reactivities, and their impact on ozone (O3) and secondary organic aerosol (SOA) formation throughout the year 2021. During the observation period, alkanes (40.13%) emerging as the predominant VOC species. Seasonal variation in VOCs followed the order of winter (26.49 ppb) > spring (23.63 ppb) > summer (23.62 ppb) > autumn (20.47 ppb). The results of positive matrix factorization (PMF) revealed that solvent usage, combustion, and vehicle exhaust were the dominant VOC sources. Regional transport from nearby provinces also significantly contributed to VOC levels. These contributions varied seasonally, with southeastern air masses prevailing in both spring and autumn, eastern air masses impacting summer, and northwestern air masses affecting winter. The campaign-averaged value of total hydroxyl (OH) radicals was 19.08 s−1. NO2 accounted for the most significant contribution to the overall OH reactivity (39.11%), followed by VOCs (28.72%). Notable seasonal fluctuations in OH reactivity followed the order of winter (24.20 s−1) > spring (19.22 s−1) > autumn (18.07 s−1) > summer (14.86 s−1). The average ozone formation potential (OFP) for the measured VOCs was calculated as 75.54 ppb, with alkenes being the dominant contributor. The highest value was observed in spring (83.05 ppb), the lowest value was in autumn (60.43 ppb). The SOA formation potential, mainly contributed by the aromatics, was averaged as 2.92 μg m−3. Additionally, the top four SOA-contributing species across four seasons were toluene, benzene, m-xylene, and ethylbenzene. VOC–PM2.5 sensitivity analysis showed that VOCs exhibited higher sensitivity to PM2.5 on clean level (PM2.5 < 35 μg m−3) than on level with heavy pollution. Alkenes, oxygenated volatile organic compounds (OVOCs) and aromatics played significant roles in the transformations of O3 and SOA in Hangzhou. Therefore, controlling the concentrations of these species is crucial for reducing complex atmospheric pollution in the region. Overall, this study compiles scientific evidence on pollution sources in Hangzhou, providing the government with valuable information.
Seasonal variation in preference for green roof vegetation
Authors: Thorpert Petra , Ode Sang Åsa , Buffam Ishi
Published: May 2024

Green roofs are vegetation systems that are particularly well-suited to dense urban environments, and can contribute multiple ecosystem services that support biodiversity, human health, and well-being. Several health benefits are dependent on the way that people perceive the characteristics of the vegetation on the green roof, that is, their environmental appraisal. In this study we set out to explore the effects of different types of green roof vegetation, along with seasonal and successional variations, on visual aesthetical experiences, as well as perceived biodiversity. An online photo elicitation survey was conducted using standardised photographs of a selection of green roofs in Malmö, Sweden, during three different seasons. In the survey, members of the public were asked to evaluate different aesthetic qualities, and to estimate biodiversity and the stress reducing capacity for each photograph. Results showed statistical differences among roof types and by season and successional stage in terms of perceived colour, perceived biodiversity, aesthetic quality, and restorative effects, where the observed differences in perceived values were largely driven by the colour frame of the green roof. Lower scores were associated with a high percentage of red or brown-red shades (p<0.001), while higher scores were associated with a high percentages of green or white (p<0.001). The results of the study therefore have the potential to inform green roof management strategies.
Prediction of miRNAs and diseases association based on sparse autoencoder and MLP
Authors: Sun Si-Lin , Zhou Bing-Wei , Liu Sheng-Zheng , Xiu Yu-Han , Bilal Anas , Long Hai-Xia
Published: May 2024

Introduction: MicroRNAs (miRNAs) are small and non-coding RNA molecules which have multiple important regulatory roles within cells. With the deepening research on miRNAs, more and more researches show that the abnormal expression of miRNAs is closely related to various diseases. The relationship between miRNAs and diseases is crucial for discovering the pathogenesis of diseases and exploring new treatment methods.

Methods: Therefore, we propose a new sparse autoencoder and MLP method (SPALP) to predict the association between miRNAs and diseases. In this study, we adopt advanced deep learning technologies, including sparse autoencoder and multi-layer perceptron (MLP), to improve the accuracy of predicting miRNA-disease associations. Firstly, the SPALP model uses a sparse autoencoder to perform feature learning and extract the initial features of miRNAs and diseases separately, obtaining the latent features of miRNAs and diseases. Then, the latent features combine miRNAs functional similarity data with diseases semantic similarity data to construct comprehensive miRNAs-diseases datasets. Subsequently, the MLP model can predict the unknown association among miRNAs and diseases.

Result: To verify the performance of our model, we set up several comparative experiments. The experimental results show that, compared with traditional methods and other deep learning prediction methods, our method has significantly improved the accuracy of predicting miRNAs-disease associations, with 94.61% accuracy and 0.9859 AUC value. Finally, we conducted case study of SPALP model. We predicted the top 30 miRNAs that might be related to Lupus Erythematosus, Ecute Myeloid Leukemia, Cardiovascular, Stroke, Diabetes Mellitus five elderly diseases and validated that 27, 29, 29, 30, and 30 of the top 30 are indeed associated.

Discussion: The SPALP approach introduced in this study is adept at forecasting the links between miRNAs and diseases, addressing the complexities of analyzing extensive bioinformatics datasets and enriching the comprehension contribution to disease progression of miRNAs.
LTβR-RelB signaling in intestinal epithelial cells protects from chemotherapy-induced mucosal damage
Authors: Chen Qiangxing , Muñoz Amanda R. , Korchagina Anna A. , Shou Yajun , Vallecer Jensine , Todd Austin W. , Shein Sergey A. , Tumanov Alexei V. , Koroleva Ekaterina
Published: May 2024

The intricate immune mechanisms governing mucosal healing following intestinal damage induced by cytotoxic drugs remain poorly understood. The goal of this study was to investigate the role of lymphotoxin beta receptor (LTβR) signaling in chemotherapy-induced intestinal damage. LTβR deficient mice exhibited heightened body weight loss, exacerbated intestinal pathology, increased proinflammatory cytokine expression, reduced IL-22 expression, and proliferation of intestinal epithelial cells following methotrexate (MTX) treatment. Furthermore, LTβR-/-IL-22-/- mice succumbed to MTX treatment, suggesting that LTβR- and IL-22- dependent pathways jointly promote mucosal repair. Although both LTβR ligands LIGHT and LTβ were upregulated in the intestine early after MTX treatment, LIGHT-/- mice, but not LTβ-/- mice, displayed exacerbated disease. Further, we revealed the critical role of T cells in mucosal repair as T cell-deficient mice failed to upregulate intestinal LIGHT expression and exhibited increased body weight loss and intestinal pathology. Analysis of mice with conditional inactivation of LTβR revealed that LTβR signaling in intestinal epithelial cells, but not in Lgr5+ intestinal stem cells, macrophages or dendritic cells was critical for mucosal repair. Furthermore, inactivation of the non-canonical NF-kB pathway member RelB in intestinal epithelial cells promoted MTX-induced disease. Based on these results, we propose a model wherein LIGHT produced by T cells activates LTβR-RelB signaling in intestinal epithelial cells to facilitate mucosal repair following chemotherapy treatment.
Newcastle disease virus vector-based SARS-CoV-2 vaccine candidate AVX/COVID-12 activates T cells and is recognized by antibodies from COVID-19 patients and vaccinated individuals
Authors: Torres-Flores Alejandro , Ontiveros-Padilla Luis Alberto , Madera-Sandoval Ruth Lizzeth , Tepale-Segura Araceli , Gajón-Martínez Julián , Rivera-Hernández Tania , Ferat-Osorio Eduardo Antonio , Cérbulo-Vázquez Arturo , Arriaga-Pizano Lourdes Andrea , Bonifaz Laura , Paz-De la Rosa Georgina , Rojas-Martínez Oscar , Suárez-Martínez Alejandro , Peralta-Sánchez Gustavo , Sarfati-Mizrahi David , Sun Weina , Chagoya-Cortés Héctor Elías , Palese Peter , Krammer Florian , García-Sastre Adolfo , Lozano-Dubernard Bernardo , López-Macías Constantino
Published: May 2024

Introduction

Several effective vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and implemented in the population. However, the current production capacity falls short of meeting global demand. Therefore, it is crucial to further develop novel vaccine platforms that can bridge the distribution gap. AVX/COVID-12 is a vector-based vaccine that utilizes the Newcastle Disease virus (NDV) to present the SARS-CoV-2 spike protein to the immune system.

Methods

This study aims to analyze the antigenicity of the vaccine candidate by examining antibody binding and T-cell activation in individuals infected with SARS-CoV-2 or variants of concern (VOCs), as well as in healthy volunteers who received coronavirus disease 2019 (COVID-19) vaccinations.

Results

Our findings indicate that the vaccine effectively binds antibodies and activates T-cells in individuals who received 2 or 3 doses of BNT162b2 or AZ/ChAdOx-1-S vaccines. Furthermore, the stimulation of T-cells from patients and vaccine recipients with AVX/COVID-12 resulted in their proliferation and secretion of interferon-gamma (IFN-γ) in both CD4+ and CD8+ T-cells.

Discussion

The AVX/COVID-12 vectored vaccine candidate demonstrates the ability to stimulate robust cellular responses and is recognized by antibodies primed by the spike protein present in SARS-CoV-2 viruses that infected patients, as well as in the mRNA BNT162b2 and AZ/ChAdOx-1-S vaccines. These results support the inclusion of the AVX/COVID-12 vaccine as a booster in vaccination programs aimed at addressing COVID-19 caused by SARS-CoV-2 and its VOCs.
Quality of evidence supporting the role of probiotics for rheumatoid arthritis: an overview of systematic reviews
Authors: Li Weiqing , Zhang Yalan , Guo Dandan , Gong Rui , Yuan Jiaxin , Yang Huijun
Published: May 2024

Background

To evaluate the methodological quality, report quality, and evidence quality of meta-analysis (MA) and systematic review (SR) on the efficacy of probiotics in the treatment of rheumatoid arthritis (RA).

Methods

Databases were used to identify eligible SRs/MAs until February 12, 2024. The methodological quality of the studies was assessed using AMSTAR-2 tool, the quality of the literature reports was scored using PRISMA checklists, and the quality of the evidence was graded using GRADE system.

Results

Seven reviews including 21 outcomes were included. Methodological quality of the included reviews was of general low, and the entries with poor scores were 2, 4, and 7. By PRISMA checklists, there were some reporting deficiencies, and quality problems were mainly reflected in the reporting registration and protocol, comprehensive search strategy and additional analysis. GRADE results elevated the quality of evidence to be low or very low overall.

Conclusions

Probiotics may have a therapeutic effect on RA, based on the evidence provided by the SRs/MAs in this overview. Nevertheless, there is still a lack of conclusive evidence due to methodological limitations in the included research. To make trustworthy judgments regarding the efficacy of probiotics in the treatment of RA, more large-scale, high-quality randomized controlled trials are still required.
The causal effect of adipose tissue on Hodgkin’s lymphoma: two-sample Mendelian randomization study and validation
Authors: Wu Lihua , Liao Fei , Guo Xiangli , Li Nainong
Published: May 2024

Background

Extensive research has been conducted on the correlation between adipose tissue and the risk of malignant lymphoma. Despite numerous observational studies exploring this connection, uncertainty remains regarding a causal relationship between adipose tissue and malignant lymphoma.

Methods

The increase or decrease in adipose tissue was represented by the height of BMI. The BMI and malignant lymphoma genome-wide association studies (GWAS) used a summary dataset from the OPEN GWAS website. Single-nucleotide polymorphisms (SNPs) that met the criteria of P <5e–8 and LD of r2 = 0.001 in the BMI GWAS were chosen as genetic instrumental variants (IVs). Proxy SNPs with LD of r2 > 0.8 were identified, while palindromic and outlier SNPs were excluded. Mendelian randomization (MR) analysis used five methods, including inverse-variance weighted (IVW) model, weighted median (WM), MR-Egger, simple mode, and weighted mode. Sensitivity assessments included Cochran’s Q test, MR-Egger intercept test, and leave-one-out analysis. Participants randomly selected by the National Center for Health Statistics (NHANSE) and newly diagnosed HL patients at Fujian Medical University Union Hospital were used for external validation.

Results

The results of the MR analysis strongly supported the causal link between BMI and Hodgkin’s lymphoma (HL). The research demonstrated that individuals with lower BMI face a significantly increased risk of developing HL, with a 91.65% higher risk (ORIVW = 0.0835, 95% CI 0.0147 – 0.4733, P = 0.005). No signs of horizontal or directional pleiotropy were observed in the MR studies. The validation results aligned with the results from the MR analysis (OR = 0.871, 95% CI 0.826 – 0.918, P< 0.001). And there was no causal relationship between BMI and non-Hodgkin’s lymphoma (NHL).

Conclusions

The MR analysis study demonstrated a direct correlation between lower BMI and HL. This suggested that a decrease in adipose tissue increases the risk of developing HL. Nevertheless, further research is essential to grasp the underlying mechanism of this causal association comprehensively.
Integrated mRNA–miRNA transcriptome profiling of blood immune responses potentially related to pulmonary fibrosis in forest musk deer
Authors: Qi Wen-Hua , Hu Li-Fan , Gu Yu-Jiawei , Zhang Xiao-Yan , Jiang Xue-Mei , Li Wu-Jiao , Qi Jun-Sheng , Xiao Guo-Sheng , Jie Hang
Published: May 2024

Background

Forest musk deer (FMD, Moschus Berezovskii) is a critically endangered species world-widely, the death of which can be caused by pulmonary disease in the farm. Pulmonary fibrosis (PF) was a huge threat to the health and survival of captive FMD. MicroRNAs (miRNAs) and messenger RNAs (mRNAs) have been involved in the regulation of immune genes and disease development. However, the regulatory profiles of mRNAs and miRNAs involved in immune regulation of FMD are unclear.

Methods

In this study, mRNA-seq and miRNA-seq in blood were performed to constructed coexpression regulatory networks between PF and healthy groups of FMD. The hub immune- and apoptosis-related genes in the PF blood of FMD were explored through Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Further, protein–protein interaction (PPI) network of immune-associated and apoptosis-associated key signaling pathways were constructed based on mRNA-miRNA in the PF blood of the FMD. Immune hub DEGs and immune hub DEmiRNAs were selected for experimental verification using RT-qPCR.

Results

A total of 2744 differentially expressed genes (DEGs) and 356 differentially expressed miRNAs (DEmiRNAs) were identified in the PF blood group compared to the healthy blood group. Among them, 42 DEmiRNAs were negatively correlated with 20 immune DEGs from a total of 57 correlations. The DEGs were significantly associated with pathways related to CD molecules, immune disease, immune system, cytokine receptors, T cell receptor signaling pathway, Th1 and Th2 cell differentiation, cytokine-cytokine receptor interaction, intestinal immune network for IgA production, and NOD-like receptor signaling pathway. There were 240 immune-related DEGs, in which 186 immune-related DEGs were up-regulated and 54 immune-related DEGs were down-regulated. In the protein-protein interaction (PPI) analysis of immune-related signaling pathway, TYK2, TLR2, TLR4, IL18, CSF1, CXCL13, LCK, ITGB2, PIK3CB, HCK, CD40, CD86, CCL3, CCR7, IL2RA, TLR3, and IL4R were identified as the hub immune genes. The mRNA-miRNA coregulation analysis showed that let-7d, miR-324-3p, miR-760, miR-185, miR-149, miR-149-5p, and miR-1842-5p are key miRNAs that target DEGs involved in immune disease, immune system and immunoregulation.

Conclusion

The development and occurrence of PF were significantly influenced by the immune-related and apoptosis-related genes present in PF blood. mRNAs and miRNAs associated with the development and occurrence of PF in the FMD.
Current situation and issues regarding termination of risk management plans in Japan
Authors: Kameyama Natsuko , Hosaka Aoi , Maeda Hideki
Published: May 2024

Introduction

In Japan, drugs approved after the 2013 implementation of the risk management plan (RMP) have the opportunity to be evaluated for RMP termination. However, the guidelines for risk management following the termination of an RMP remain unclear. Drugs are evaluated for RMP termination at the timing of reexamination. Reexamination system is unique to Japan and initiated in 1979, verifies the approved efficacy and safety of a newly marketed drug based on the data from its actual use over a certain period. This study investigated drugs in Japan for which the RMP requirement was lifted upon reexamination and those for which it was not. We organized their characteristics and considered future issues.

Methods

We identified drugs with RMPs and obtained information on RMP termination from the public website of the Pharmaceuticals and Medical Devices Agency (PMDA). The survey period spanned 10 years, from April 2013, when the RMP was implemented, to March 2023.

Results

During the survey period, 72 drugs with RMPs completed reexamination in Japan. The RMP requirement was lifted for 69 drugs (95.8%) and remained for three drugs (4.2%). Upon RMP termination, 16 out of 69 drugs (23.2%) had important potential risks not listed in the package insert, with malignant neoplasm being the most common. Eleven drugs (15.9%) had important missing information not listed in the package insert, with the most common being the impact on cardiovascular risk. Two drugs (2.9%) had ongoing additional pharmacovigilance activities, and 43 drugs (62.3%) had additional risk minimization activities.

Conclusion

Upon reexamination completion, the RMP requirement was lifted for many drugs and remained for a few. Should safety concerns require continued attention following reexamination, we advocate for the continuation of the RMP, guided by more explicit rules. In light of the harmonization of RMP rules with those of other countries, there is a desire for enhanced drug safety management.
Are all fibrinogen concentrates the same? The effects of two fibrinogen therapies in an afibrinogenemic patient and in a fibrinogen deficient plasma model. A clinical and laboratory case report
Authors: Goodarzi Soutiam , Abu-Hanna Jeries , Harper Sarah , Khan Dalia , Morrow Gael , Curry Nicola
Published: May 2024

The choice of treatments for inherited, or acquired, fibrinogen deficient states is expanding and there are now several fibrinogen concentrate therapies commercially available. Patients with the rare inherited bleeding disorder, afibrinogenemia, commonly require life-long replacement therapy with fibrinogen concentrate to prevent hemorrhagic complications. Recent reports in the setting of acquired bleeding, namely trauma hemorrhage, have highlighted the potential importance of the different compositions of fibrinogen supplements, including cryoprecipitate and the various plasma- derived concentrates. Clot strength and the subsequent susceptibility of a clot to lysis is highly dependent on the amount of fibrinogen as well as its structural composition, the concentration of pro- and anti-coagulant factors, as well as fibrinolytic regulators, such as factor XIII (FXIII). This report details the effects of two commercially available fibrinogen concentrates (Riastap®, CSL Behring and Fibryga®, Octapharma) on important functional measures of clot formation and lysis in a patient with afibrinogenemia. Our report offers insights into the differential effects of these concentrates, at the clot level, according to the variable constituents of each product, thereby emphasizing that the choice of fibrinogen concentrate can influence the stability of a clot in vivo. Whether this alters clinical efficacy is yet to be understood.
Case report: A case of bradycardia triggered by diarrhea
Authors: Lei Meixian , Cao Yuan , Yuan Mingqing , Xiong Jie , He Huabin
Published: May 2024

BRASH syndrome is a vicious cycle of hyperkalemia and bradycardia and is an under-recognized life-threatening clinical diagnosis. It is usually initiated by hypovolemia or hyperkalemia. We report here on the case of a 92-year-old man with hypertension and heart failure who presented to the emergency department with weakness following diarrhea. He was on amlodipine, benazepril, metoprolol, furosemide and spironolactone. The patient’s blood pressure was 88/53 mmHg and the serum creatinine was 241 μmol/L. Within 2 h, the patient’s heart rate decreased from 58 beats per minute to 26 beats per minute, and serum potassium levels gradually increased from 6.07 mmol/L to 7.3 mmol/L. The electrocardiogram showed a junctional escape rhythm with accidental sinus capture. The diagnosis of BRASH syndrome was made based on clinical symptoms, a biochemical profile and the results of an electrocardiogram. The patient was rapidly stabilized with the administration of intravenous calcium gluconate, dextrose and insulin, 5% sodium bicarbonate, 0.9% sodium chloride, furosemide, and oral zirconium cyclosilicate. Sinus rhythm at a heart rate of 75 bpm was detected 5 h later, along with normal serum potassium levels. After 2 weeks, kidney function returned to normal. Clinicians should be alert to patients with hyperkalemia and maintain a high index of suspicion for BRASH syndrome. Timely diagnosis and comprehensive intervention are critical for better outcomes in managing patients with BRASH.
Prognostic value of the systemic immune-inflammation index in critically ill elderly patients with hip fracture: evidence from MIMIC (2008–2019)
Authors: Liu Zhen-Jiang , Li Gen-He , Wang Jing-Xuan , Mo Zhi-Hong , Yang Kang-Yong , Shen Chu-Long , Shen Zhao-Xiong
Published: May 2024

Background

The systemic immune-inflammation index (SII) showed an extensive link between immunological dysfunction and the activation of systemic inflammation. Several studies have confirmed the application of SII to orthopedic diseases. However, the significance of SII in critically ill elderly individuals with hip fracture who require intensive care unit (ICU) admission is not yet known. This study centered on exploring the relationship between SII and clinical outcomes among critically ill elderly hip fracture individuals.

Methods

The study centered around elderly patients experiencing severe illness following hip fractures and requiring admission to the ICU. These patients from the MIMIC-IV database formed the basis of this study’s cohort. We stratified them into quartiles according to their SII levels. The results involved the mortality at 30 days and 1 year post-admission. Then we employ Cox proportional hazards regression analysis as well as restricted cubic splines to explore the association between the SII and clinical results in critically ill elderly patients with hip fracture.

Results

The study encompassed 991 participants, among whom 63.98% identified as females. Notably, the mortality rates attributed to any cause within 30 days and 1 year after hospitalization stood at 19.68 and 33.40%, respectively. The multivariate Cox proportional hazards model disclosed a significant correlation between an elevated SII and all-cause mortality. Following adjustments for confounding variables, individuals with a high SII showed a notable correlation with 30-day mortality [adjusted hazard ratio (HR), 1.065; 95% confidence interval (CI), 1.044–1.087; p < 0.001] and 1-year mortality (adjusted HR, 1.051; 95% CI, 1.029–1.074; p < 0.001). Furthermore, the analysis of restricted cubic splines demonstrated a progressive increase in the risk of all-cause death as the SII value rose.

Conclusion

Among critically ill elderly patients with hip fracture, the SII exhibits a non-linear association that positively correlates with both 30-day and 1-year all-cause mortality rates. The revelation indicates that the SII may play a vital role in identifying patients with hip fractures who face an escalated risk of mortality due to any cause.
Metagenomic, organoleptic profiling, and nutritional properties of fermented kombucha tea substituted with recycled substrates
Authors: Selvaraj Suriyapriya , Gurumurthy Kalaichelvan
Published: May 2024

Kombucha fermentation yields a diverse range of beneficial macro and micronutrients. In our study, we examined the metabolites, antioxidant activity, organoleptic characteristics, and nutritional attributes of traditionally prepared kombucha tea, using black tea and sugar (control) as substrates, and compared them with tea made from tea dust and blackstrap molasses (test). Kombucha tea crafted from functional raw materials exhibited enhanced sensory qualities and improved health-promoting properties. The levels of tannins, flavonoids, and phenols play a crucial role in determining the antioxidant activity of kombucha tea. Using the DPPH and FRAP methods, we investigated the antioxidant activity throughout the fermentation period, ranging from day 0 to day 12, under optimized conditions. The results consistently demonstrated an initial increase in antioxidant activity from day 0 to 6, followed by a decline from day 6 to 12. Notably, statistical analysis revealed that the antioxidant activity of the test sample was significantly better (p > 0.001) compared to the control sample. The nutritional content of the kombucha from day 6 of the test sample is higher than the control sample provided sugars (fructose 0.4 ± 0.1, glucose 0.7 ± 0.1, sucrose 1.4 ± 0.1) g/100 mL, minerals (calcium, 19.4 ± 0.15, iron 23.1 ± 0.25, and potassium 28.3 ± 0.25) mg/100 mL, vitamins (B1 0.58 ± 0.01, B2 0.30 ± 0.02, B3 0.33 ± 0.02, B6 0.75 ± 0.02, B9 0.19 ± 0.03, B12 0.9 ± 0.03, and C 1.38 ± 0.06) mg/100 mL, sodium 4.35 ± 0.25 mg/100 mL, calories 14.85 ± 0.25 mg/100 mL, carbohydrates 3.135 ± 0.12, and acids (acetic acid 4.20 ± 0.02, glucuronic acid 1.78 ± 0.02) mg/100 mL on day 12. The predominant microbial species identified in both control and test samples included Komagataeibacter rhaeticus, Gluconobacter oxydans, Brettanomyces bruxellensis, and Zygosaccharomyces bailli, each with varying dominance levels. These microorganisms play essential roles in metabolizing sugars, generating acids, and contributing to the distinctive flavor profile of kombucha. Sensory evaluations of the control and test samples were analyzed, and the overall preference was 88% for the test sample with tea dust and molasses. The sensory characteristics of the test sample included a fruity smell (41%), fizzy texture (66%), bright color (47%), and a fruity taste (67%), with overall acceptability (56%) rating it as excellent. Our research contributes to a deeper understanding of the interplay between raw materials, microbial composition, and the resulting composition of bioactive compounds.
Developing a new host-vector system for Deinococcus grandis
Authors: Sakai Miyabi , Shimosaka Taichi , Katsumata Kosuke , Yohda Masafumi , Narumi Issay
Published: May 2024

Deinococcus spp. are known for their radiation resistance, toxic compound removal, and production of valuable substances. Therefore, developing gene expression systems for Deinococcus spp. is crucial in advancing genetic engineering applications. To date, plasmid vectors that express foreign genes in D. radiodurans and D. geothermalis have been limited to plasmid pI3 and its derivatives. In contrast, plasmid vectors that express foreign genes in D. grandis include plasmid pZT23 and its derivatives. In this study, we developed a new system for the stable introduction and retention of expression plasmids for D. grandis. Two cryptic plasmids were removed from the wild-type strain to generate the TY3 strain. We then constructed a shuttle vector plasmid, pGRC5, containing the replication initiation region of the smallest cryptic plasmid, pDEGR-3, replication initiation region of the E. coli vector, pACYC184, and an antibiotic resistance gene. We introduced pGRC5, pZT23-derived plasmid pZT29H, and pI3-derived plasmid pRADN8 into strain TY3, and found their coexistence in D. grandis cells. The quantitative PCR assay results found that pGRC5, pZT29H, and pRADN8 had relative copy numbers of 11, 26, and 5 per genome, respectively. Furthermore, we developed a new plasmid in which the luciferase gene was controlled by the promoter region, which contained radiation-desiccation response operator sequences for D. grandis DdrO, a stress response regulon repressor in D. grandis, hence inducing gene expression via ultraviolet-C light irradiation. These plasmids are expected to facilitate the removal and production of toxic and valuable substances, in D. grandis, respectively, particularly of those involving multiple genes.
Fingolimod synergizes and reverses K. pneumoniae resistance to colistin
Authors: Geng Xiang , Zhang Zhen-Dong , Li Yu-Xi , Hao Ruo-Chen , Yang Ya-Jun , Liu Xi-Wang , Li Jian-Yong
Published: May 2024

Klebsiella pneumoniae (K. pneumoniae) infection and the rapid spread of multi-drug resistant (MDR) bacteria pose a serious threat to global healthcare. Polymyxin E (colistin), a group of cationic antimicrobial polypeptides, is currently one of the last resort treatment options against carbapenem-resistant Gram-negative pathogens. The effectiveness of colistin has been compromised due to its intensive use. This study found that fingolimod (FLD), a natural product derivative, exhibited a significant synergistic bactericidal effect on K. pneumoniae when combined with colistin, both in vitro and in vivo. The checkerboard method was employed to assess the in vitro synergistic effect of FLD with colistin. FLD enhanced the susceptibility of bacteria to colistin and lowered effectively minimum inhibitory concentrations (MIC) when compared to colistin MIC, and the fractional inhibitory concentrations (FIC) value was less than 0.3. The time-kill curve demonstrated that the combination treatment of FLD and colistin had significant bactericidal efficacy. The in vitro concurrent administration of colistin and FLD resulted in heightening membrane permeability, compromising cell integrity, diminishing membrane fluidity, and perturbing membrane homeostasis. They also induced alterations in membrane potential, levels of reactive oxygen species, and adenosine triphosphate synthesis, ultimately culminating in bacterial death. Moreover, the combination of FLD with colistin significantly influenced fatty acid metabolism. In the mouse infection model, the survival rate of mice injected with K. pneumoniae was significantly improved to 67% and pathological damage was significantly relieved with combination treatment of FLD and colistin when compared with colistin treatment. This study highlights the potential of FLD in combining with colistin for treating infections caused by MDR isolates of K. pneumoniae.
New cytotoxic indole derivatives with anti-FADU potential produced by the endophytic fungus Penicillium oxalicum 2021CDF-3 through the OSMAC strategy
Authors: Song Wei , Ji Lianlian , Zhang Yanxia , Cao Longhe
Published: May 2024

Fungi possess well-developed secondary metabolism pathways that are worthy of in-depth exploration. The One Strain Many Compounds (OSMAC) strategy is a useful method for exploring chemically diverse secondary metabolites. In this study, continued chemical investigations of the marine red algae-derived endophytic fungus Penicillium oxalicum 2021CDF-3 cultured in PDB media yielded six structurally diverse indole derivatives, including two new prenylated indole alkaloids asperinamide B (1) and peniochroloid B (5), as well as four related derivatives (compounds 2–4 and 6). The chemical structures of these compounds, including the absolute configurations of 1 and 5, were determined by extensive analyses of HRESIMS, 1D and 2D NMR spectroscopic data, and TDDFT-ECD calculations. Compound 1 was found to possess an unusual 3-pyrrolidone dimethylbenzopyran fused to the bicyclo[2.2.2]diazaoctane moiety, which was rare in previously reported prenylated indole alkaloids. In vitro cytotoxic experiments against four human tumor cell lines (HeLa, HepG2, FADU, and A549) indicated that 1 strongly inhibited the FADU cell line, with an IC50 value of 0.43 ± 0.03 μM. This study suggested that the new prenylated indole alkaloid 1 is a potential lead compound for anti-FADU drugs.
A systematic analysis of affinity tags in the haloarchaeal expression system, Haloferax volcanii for protein purification
Authors: Karan Ram , Renn Dominik , Allers Thorsten , Rueping Magnus
Published: May 2024

Extremophilic proteins are valuable in various fields, but their expression can be challenging in traditional hosts like Escherichia coli due to misfolding and aggregation. Haloferax volcanii (H. volcanii), a halophilic expression system, offers a solution. This study examined cleavable and non-cleavable purification tags at both the N- and C-termini when fused with the superfolder green fluorescent protein (sfGFP) in H. volcanii. Our findings reveal that an N-terminal 8xHis-tag or Strep-tag®II significantly enhances protein production, purity, and yield in H. volcanii. Further experiments with mCherry and halophilic alcohol dehydrogenase (ADH) showed improved expression and purification yields when the 8xHis-tag or Strep-tag®II was positioned at the C-terminus for mCherry and at the N-terminus for ADH. Co-positioning 8xHis-tag and Twin-Strep-tag® at the N-terminus of sfGFP, mCherry, and ADH yielded significantly enhanced results. These findings highlight the importance of thoughtful purification tag design and selection in H. volcanii, providing valuable insights for improving protein production and purification with the potential to advance biotechnological applications.
4,4′-methylenediphenol reduces Aβ-induced toxicity in a Caenorhabditis elegans model of Alzheimer’s disease
Authors: Yu Xingzhi , Tao Jie , Xiao Tian , Duan Xiaohua
Published: May 2024

Introduction

Gastrodia elata Blume is a widely used medicinal and edible herb with a rich chemical composition. Moreover, prescriptions containing Gastrodia elata are commonly used for the prevention and treatment of cardiovascular, cerebrovascular, and aging-related diseases. Recent pharmacological studies have confirmed the antioxidant and neuroprotective effects of Gastrodia elata, and, in recent years, this herb has also been used in the treatment of Alzheimer’s disease (AD) and other neurodegenerative disorders. We have previously shown that 4,4′-methylenediphenol, a key active ingredient of Gastrodia elata, can mitigate amyloid-β (Aβ)-induced paralysis in AD model worms as well as prolong the lifespan of the animals, thus displaying potential as a treatment of AD.

Methods

We investigated the effects of 4,4′-methylenediphenol on AD and aging through paralysis, lifespan, and behavioral assays. In addition, we determined the anti-AD effects of 4,4′-methylenediphenol by reactive oxygen species (ROS) assay, lipofuscin analysis, thioflavin S staining, metabolomics analysis, GFP reporter gene worm assay, and RNA interference assay and conducted in-depth studies on its mechanism of action.

Results

4,4′-Methylenediphenol not only delayed paralysis onset and senescence in the AD model worms but also enhanced their motility and stress tolerance. Meanwhile, 4,4′-methylenediphenol treatment also reduced the contents of reactive oxygen species (ROS) and lipofuscin, and decreased Aβ protein deposition in the worms. Broad-spectrum targeted metabolomic analysis showed that 4,4′-methylenediphenol administration had a positive effect on the metabolite profile of the worms. In addition, 4,4′-methylenediphenol promoted the nuclear translocation of DAF-16 and upregulated the expression of SKN-1, SOD-3, and GST-4 in the respective GFP reporter lines, accompanied by an enhancement of antioxidant activity and a reduction in Aβ toxicity; importantly, our results suggested that these effects of 4,4′-methylenediphenol were mediated, at least partly, via the activation of DAF-16.

Conclusion

We have demonstrated that 4,4′-methylenediphenol can reduce Aβ-induced toxicity in AD model worms, suggesting that it has potential for development as an anti-AD drug. Our findings provide ideas and references for further research into the anti-AD effects of Gastrodia elata and its active ingredients.
Cathepsin-mediated regulation of alpha-synuclein in Parkinson’s disease: a Mendelian randomization study
Authors: Lin Liyu , Wu Zilun , Luo Haocheng , Huang Yunxuan
Published: May 2024

Objective

The observational association between cathepsin and Parkinson’s disease (PD) has been partially explored in previous research. However, the causal relationship remains unclear. In this study, our objective is to investigate the causal link between cathepsin and PD using Mendelian randomization (MR) analysis and elucidate the underlying mechanisms governing their interaction.

Methods

Utilizing bidirectional two-sample MR and multivariable MR, we systematically investigates the causal relationship between nine cathepsins and PD. The data pertaining to cathepsins were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS Project, while data related to PD were sourced from versions R9 and R10 of the FinnGen database. The primary analytical method utilized was the inverse variance weighted (IVW), with MR analysis initially conducted using PD data from R9, complemented by a series of sensitivity analyses. Subsequently, replication analysis was performed on the R10 dataset, and meta-analysis were employed to merge the findings from both datasets. To explore potential mechanisms by which Cathepsins may impact PD, MR analyses were performed on significant Cathepsins with alpha-synuclein. MR analysis and colocalization analysis were conducted on expression quantitative trait loci (eQTL) data of gene related to alpha-synuclein with PD data.

Result

Forward MR analyses revealed more cathepsin B (CTSB) associated with less PD risk (OR = 0.898, 95%CI: 0.834–0.966, p = 0.004), while more cathepsin H (CTSH) (OR = 1.076, 95%CI: 1.007–1.149, p = 0.029) and more cathepsin S (CTSS) (OR = 1.076, 95%CI: 1.007–1.150, p = 0.030) associated with increasing PD risk. Meta-analyses validated these associations. Multivariate MR Results were consistent with those before adjustment. No significant results were observed in bidirectional MR analysis. In the investigation of the underlying mechanism, our findings demonstrate that CTSB significantly reduces the levels of alpha-synuclein (OR = 0.909, 95%CI: 0.841–0.983, p = 0.017). Concurrently, a genetically determined positive correlation between alpha-synuclein and PD is illuminated by both eQTL MR and colocalization analysis.

Conclusion

In conclusion, this MR study yields robust evidence suggesting an association between elevated levels of CTSB and reduced PD risk, mediated by the downregulation of alpha-synuclein levels. Conversely, higher levels of CTSH and CTSS are associated with an increased risk of PD. These findings offer novel insights into the pathophysiological mechanisms of PD and identify potential drug targets for disease prevention and treatment warranting further clinical investigations.
Awakenings in triplicate: in ontogeny, after immobility, and to the presence of a congener. Comments on Ilan Golani’s concept of the mobility gradient
Authors: Kortmulder Koenraad
Published: May 2024

Golani’s concept of the “mobility gradient” describes the unfolding of motor behavior after immobility and in ontogeny. The two processes run parallel and are similar across vertebrates. In both time scales, the trend is for the behavior to progressively become enriched, cover more dimensions (motor expansion) and become less dependent on external stimuli (stimulus-bound). This paper addresses the question whether the gradient extends into social, interactive behavior. Observation of natural groups larger than dyads may help answering that question. As an example, the natural social behavior of a fish, Pethia nigrofasciata is described in some detail. It is concluded that their motor behavior expands in the course of their daily spawning period.
On designing a configurable UAV autopilot for unmanned quadrotors
Authors: Bhar Ali , Sayadi Mounir
Published: May 2024

Unmanned Aerial Vehicles (UAVs) and quadrotors are being used in an increasing number of applications. The detection and management of forest fires is continually improved by the incorporation of new economical technologies in order to prevent ecological degradation and disasters. Using an inner-outer loop design, this paper discusses an attitude and altitude controller for a quadrotor. As a highly nonlinear system, quadrotor dynamics can be simplified by assuming several assumptions. Quadrotor autopilot is developed using nonlinear feedback linearization technique, LQR, SMC, PD, and PID controllers. Often, these approaches are used to improve control and to reject disturbances. PD-PID controllers are also deployed in the tracking and surveillance of smoke or fire by intelligent algorithms. In this paper, the efficiency using a combined PD-PID controllers with adjustable parameters have been studied. The performance was assessed by simulation using matlab Simulink. The computational study conducted to assess the proposed approach showed that the PD-PID combination presented in this paper yields promising outcomes.
Synergy quality assessment of muscle modules for determining learning performance using a realistic musculoskeletal model
Authors: Fukunishi Akito , Kutsuzawa Kyo , Owaki Dai , Hayashibe Mitsuhiro
Published: May 2024

How our central nervous system efficiently controls our complex musculoskeletal system is still debated. The muscle synergy hypothesis is proposed to simplify this complex system by assuming the existence of functional neural modules that coordinate several muscles. Modularity based on muscle synergies can facilitate motor learning without compromising task performance. However, the effectiveness of modularity in motor control remains debated. This ambiguity can, in part, stem from overlooking that the performance of modularity depends on the mechanical aspects of modules of interest, such as the torque the modules exert. To address this issue, this study introduces two criteria to evaluate the quality of module sets based on commonly used performance metrics in motor learning studies: the accuracy of torque production and learning speed. One evaluates the regularity in the direction of mechanical torque the modules exert, while the other evaluates the evenness of its magnitude. For verification of our criteria, we simulated motor learning of torque production tasks in a realistic musculoskeletal system of the upper arm using feed-forward neural networks while changing the control conditions. We found that the proposed criteria successfully explain the tendency of learning performance in various control conditions. These result suggest that regularity in the direction of and evenness in magnitude of mechanical torque of utilized modules are significant factor for determining learning performance. Although the criteria were originally conceived for an error-based learning scheme, the approach to pursue which set of modules is better for motor control can have significant implications in other studies of modularity in general.
Coordinated reset stimulation of plastic neural networks with spatially dependent synaptic connections
Authors: Kromer Justus A. , Tass Peter A.
Published: May 2024

Background

Abnormal neuronal synchrony is associated with several neurological disorders, including Parkinson’s disease (PD), essential tremor, dystonia, and epilepsy. Coordinated reset (CR) stimulation was developed computationally to counteract abnormal neuronal synchrony. During CR stimulation, phase-shifted stimuli are delivered to multiple stimulation sites. Computational studies in plastic neural networks reported that CR stimulation drove the networks into an attractor of a stable desynchronized state by down-regulating synaptic connections, which led to long-lasting desynchronization effects that outlasted stimulation. Later, corresponding long-lasting desynchronization and therapeutic effects were found in animal models of PD and PD patients. To date, it is unclear how spatially dependent synaptic connections, as typically observed in the brain, shape CR-induced synaptic downregulation and long-lasting effects.

Methods

We performed numerical simulations of networks of leaky integrate-and-fire neurons with spike-timing-dependent plasticity and spatially dependent synaptic connections to study and further improve acute and long-term responses to CR stimulation.

Results

The characteristic length scale of synaptic connections relative to the distance between stimulation sites plays a key role in CR parameter adjustment. In networks with short synaptic length scales, a substantial synaptic downregulation can be achieved by selecting appropriate stimulus-related parameters, such as the stimulus amplitude and shape, regardless of the employed spatiotemporal pattern of stimulus deliveries. Complex stimulus shapes can induce local connectivity patterns in the vicinity of the stimulation sites. In contrast, in networks with longer synaptic length scales, the spatiotemporal sequence of stimulus deliveries is of major importance for synaptic downregulation. In particular, rapid shuffling of the stimulus sequence is advantageous for synaptic downregulation.

Conclusion

Our results suggest that CR stimulation parameters can be adjusted to synaptic connectivity to further improve the long-lasting effects. Furthermore, shuffling of CR sequences is advantageous for long-lasting desynchronization effects. Our work provides important hypotheses on CR parameter selection for future preclinical and clinical studies.
Case report: Heterozygous variation in the IGHMBP2 gene leading to spinal muscular atrophy with respiratory distress type 1
Authors: Zhou Chaoai , Chen Zefu , Chen Qiqing , Feng Xiaowei
Published: May 2024

A rare autosomal recessive genetic disease is spinal muscular atrophy with respiratory distress type 1 (SMARD 1; OMIM #604320), which is characterized by progressive distal limb muscle weakness, muscular atrophy, and early onset of respiratory failure. Herein, we report the case of a 4-month-old female infant with SMARD type 1 who was admitted to our hospital owing to unexplained distal limb muscle weakness and early respiratory failure. This report summarizes the characteristics of SMARD type 1 caused by heterozygous variation in the immunoglobulin mu DNA binding protein 2 (IGHMBP2) gene by analyzing its clinical manifestations, genetic variation characteristics, and related examinations, aiming to deepen clinicians’ understanding of the disease, assisting pediatricians in providing medical information to parents and improving the decision-making process involved in establishing life support.