bluuebunny/crossref_metadata_2025 huggingface dataset:
Plant-Based Vaccines Against COVID-19 for Massive Vaccination in Africa
Authors: El Jaddaoui Islam , Al Idrissi Najib , Hamdi Salsabil , Wakrim Lahcen , Nejjari Chakib , Amzazi Saaïd , Elouahabi Abdelatif , Bakri Youssef , Ghazal Hassan
Published: August 2022

During the unprecedented COVID-19 pandemic, the primary goal of many countries has been to achieve herd immunity through the organization of massive vaccination campaigns. Nevertheless, developing countries, including Africans, have been facing limited vaccine supply. Conventional inactivated or subunit vaccines are widely used across the world; however, their production is costly and could be limited by the supply chain during a pandemic such as COVID-19. Genetic vaccines, such as mRNA- or adenovirus-based vaccines, have been developed as alternatives but are still costly and require low-temperature storage. The plant-based vaccine concept has attracted increasing attention in recent years due to its potential advantages, such as low cost, high production volume, and thermostability. In this review, we propose plant-based vaccines as an attractive alternative for massive and rapid vaccination protocols against COVID-19 in African countries by exploiting local crops. In addition, we discuss the mechanisms of action, required standards, benefits, challenges, and prospects for the application of this novel biotechnological tool in the African continent.
Effectiveness of a hybrid digital substance abuse prevention approach combining e-Learning and in-person class sessions
Authors: Griffin Kenneth W. , Williams Christopher , Botvin Caroline M. , Sousa Sandra , Botvin Gilbert J.
Published: August 2022

Background

Effective school-based programs for preventing substance abuse offer considerable public health potential. Yet limited class time and uneven implementation fidelity can be barriers to widespread adoption and high-quality implementation. A hybrid digital approach may be effective and help address these barriers.

Objective

To evaluate the effectiveness of a hybrid substance abuse prevention program for middle school students consisting of e-learning modules and in-person class sessions.

Design

Twenty-three United States (U.S.) middle schools were randomly assigned either to an intervention condition (13 schools) or a treatment-as-usual control condition (10 schools) where standard health education material was delivered. There were 1,447 participants who completed the pre-test and post-test assessments, of which 48.3% were male and 51.7% female.

Intervention

The hybrid digital intervention consisted of 14 brief e-learning modules and six classroom sessions adapted from an evidence-based program designed for classroom implementation to increase knowledge of adverse consequences of substance use and improve social skills, personal coping skills, and skills for resisting social influences to smoke, drink, or use drugs.

Measures

Participating students completed online pre-test and post-test surveys to assess substance use, knowledge, and life skills.

Results

There were significant reductions in substance use for the hybrid digital condition compared to the control condition as well as significant increases in health knowledge, skills knowledge, and life skills.

Conclusions

A hybrid digital approach to substance abuse prevention is effective and offers potential for overcoming common barriers to widespread adoption and high-quality implementation.
Validation of the modified radiographic union score for tibia fractures (mRUST) in murine femoral fractures
Authors: Alentado Vincent J. , Knox Adam M. , Staut Caio A. , McGuire Anthony C. , Chitwood Joseph R. , Mostardo Sarah L. , Shaikh Mustufa Z. , Blosser Rachel J. , Dadwal Usashi C. , Chu Tien-Min Gabriel , Collier Christopher D. , Li Jiliang , Liu Ziyue , Kacena Melissa A. , Natoli Roman M.
Published: August 2022

Bony union is a primary predictor of outcome after surgical fixation of long bone fractures. Murine models offer many advantages in assessing bony healing due to their low costs and small size. However, current fracture recovery investigations in mice frequently rely on animal sacrifice and costly analyses. The modified Radiographic Union Score for Tibia fractures (mRUST) scoring system is a validated metric for evaluating bony healing in humans utilizing plain radiographs, which are relatively inexpensive and do not require animal sacrifice. However, its use has not been well established in murine models. The aim of this study was to characterize the longitudinal course of mRUST and compare mRUST to other conventional murine fracture analyses. 158 mice underwent surgically created midshaft femur fractures. Mice were evaluated after fracture creation and at 7, 10, 14, 17, 21, 24, 28, 35, and 42 days post-injury. mRUST scoring of plain radiographs was performed by three orthopaedic surgeons in a randomized, blinded fashion. Interrater correlations were calculated. Micro-computed tomography (μCT) was analyzed for tissue mineral density (TMD), total callus volume (TV), bone volume (BV), trabecular thickness, trabecular number, and trabecular separation. Histomorphometry measures of total callus area, cartilage area, fibrous tissue area, and bone area were performed in a blinded fashion. Ultimate torque, stiffness, toughness, and twist to failure were calculated from torque-twist curves. A sigmoidal log-logistic curve fit was generated for mRUST scores over time which shows mRUST scores of 4 to 6 at 7 days post-injury that improve to plateaus of 14 to 16 by 24 days post-injury. mRUST interrater correlations at each timepoint ranged from 0.51 to 0.86, indicating substantial agreement. mRUST scores correlated well with biomechanical, histomorphometry, and μCT parameters, such as ultimate torque (r=0.46, p<0.0001), manual stiffness (r=0.51, p<0.0001), bone percentage based on histomorphometry (r=0.86, p<0.0001), cartilage percentage (r=-0.87, p<0.0001), tissue mineral density (r=0.83, p<0.0001), BV/TV based on μCT (r=0.65, p<0.0001), and trabecular thickness (r=0.78, p<0.0001), among others. These data demonstrate that mRUST is reliable, trends temporally, and correlates to standard measures of murine fracture healing. Compared to other measures, mRUST is more cost-effective and non-terminal. The mRUST log-logistic curve could be used to characterize differences in fracture healing trajectory between experimental groups, enabling high-throughput analysis.
Energy-efficient tram speed trajectory optimization considering the influence of the traffic light
Authors: He Jing , Li YanHuan , Long SiHui , Xu YuTing , Chen JiaQi
Published: August 2022

The tram typically adopts the form of semi-independent right of way, which is affected by the traffic light at junctions. The parking and wait time of the tram due to red lights will increase the energy consumption and reduce the passenger comfort. This paper proposes a speed trajectory optimization approach for the tram without parking when encountering a red light. This approach is realized by reasonably adjusting the running time and speed of the tram between two adjacent sections bounded by the traffic light at the junction, on the premise that the total travel time of the whole section remains unchanged. In the model, the constraints of tram movement, speed limits, and line conditions are considered. Moreover, considering the influence of the traffic light, the comfort and traffic light constraints are added to establish the energy-efficient tram speed trajectory optimization model. The nonlinear constraints in the optimization model are converted to linear constraints using the segmental approximation method and adding constraints. As a result, the optimization model is reformulated into a mixed-integer linear programming model, which could be solved by a commercial solver like CPLEX. Numerical experiments are conducted with a 3,660 m long section of the tram line with the traffic light at the junction. The experimental results show that the speed trajectory optimization approach considering the influence of the traffic light proposed in this paper can reduce the total energy consumption by 23.46% and improve passenger comfort.
Identification of key controlling factors of ozone pollution in Jinan, northern China over 2013–2020
Authors: Liang Di , Yan Huaizhong , Tian Yong , Liu Yalin , Hao Saimei , Bai Haoqiang , Zhang Guiqin , Deng Wei
Published: August 2022

Urban ozone (O3) pollution has become a prominent environmental threat to public health while the relationship between O3 formation and driving factors remains elusive, particularly for megacities in the Shandong Peninsula of China. In this study, we use intensive ambient measurements of trace gases to comprehensively investigate the magnitude of O3 pollution in Jinan city from 2013 to 2020. Further, emission inventory and OMI NO2 columns are used for probing changes in precursor emissions. Ground-level measurements indicate degraded O3 air quality afterward in 2015 and depict city-wide elevated O3 levels (higher than 140 μg/m3 in the warm season). For precursor emissions, it is found that NOx emissions have decreased more than 30% due to successful regulation efforts, which is in excellent agreement with NO2 columns from OMI. The method of objective synoptic weather pattern classification [T-Mode principal component analysis (PCT)] is adopted to distinguish the associated meteorological parameters under various synoptic patterns which govern the variability in regional O3 levels. Among identified synoptic patterns, Type 2 and Type 8 featured by low sea level pressure (SLP), high temperature, and strong ultraviolet radiation are the most prevalent synoptic patterns in spring and summer, respectively, which are prone to the occurrence of O3 exceedances. This work provides a detailed view of long-term O3 levels and the relationship between precursors and meteorological conditions in a typical densely populated city in northern China, showing implications for developing O3 mitigation strategies.
Examining SNP-SNP interactions and risk of clinical outcomes in colorectal cancer using multifactor dimensionality reduction based methods
Authors: Curtis Aaron , Yu Yajun , Carey Megan , Parfrey Patrick , Yilmaz Yildiz E. , Savas Sevtap
Published: August 2022

Background: SNP interactions may explain the variable outcome risk among colorectal cancer patients. Examining SNP interactions is challenging, especially with large datasets. Multifactor Dimensionality Reduction (MDR)-based programs may address this problem.

Objectives: 1) To compare two MDR-based programs for their utility; and 2) to apply these programs to sets of MMP and VEGF-family gene SNPs in order to examine their interactions in relation to colorectal cancer survival outcomes.

Methods: This study applied two data reduction methods, Cox-MDR and GMDR 0.9, to study one to three way SNP interactions. Both programs were run using a 5-fold cross validation step and the top models were verified by permutation testing. Prognostic associations of the SNP interactions were verified using multivariable regression methods. Eight datasets, including SNPs from MMP family genes (n = 201) and seven sets of VEGF-family interaction networks (n = 1,517 SNPs) were examined.

Results: ∼90 million potential interactions were examined. Analyses in the MMP and VEGF gene family datasets found several novel 1- to 3-way SNP interactions. These interactions were able to distinguish between the patients with different outcome risks (regression p-values 0.03–2.2E-09). The strongest association was detected for a 3-way interaction including CHRM3.rs665159_EPN1.rs6509955_PTGER3.rs1327460 variants.

Conclusion: Our work demonstrates the utility of data reduction methods while identifying potential prognostic markers in colorectal cancer.
Structural-Guided Identification of Small Molecule Inhibitor of UHRF1 Methyltransferase Activity
Authors: Awal Md Abdul , Nur Suza Mohammad , Al Khalaf Ali Khalaf , Rehan Mohd , Ahmad Aamir , Hosawi Salman Bakr I. , Choudhry Hani , Khan Mohammad Imran
Published: August 2022

Ubiquitin-like containing plant homeodomain Ring Finger 1 (UHRF1) protein is recognized as a cell-cycle-regulated multidomain protein. UHRF1 importantly manifests the maintenance of DNA methylation mediated by the interaction between its SRA (SET and RING associated) domain and DNA methyltransferase-1 (DNMT1)-like epigenetic modulators. However, overexpression of UHRF1 epigenetically responds to the aberrant global methylation and promotes tumorigenesis. To date, no potential molecular inhibitor has been studied against the SRA domain. Therefore, this study focused on identifying the active natural drug-like candidates against the SRA domain. A comprehensive set of in silico approaches including molecular docking, molecular dynamics (MD) simulation, and toxicity analysis was performed to identify potential candidates. A dataset of 709 natural compounds was screened through molecular docking where chicoric acid and nystose have been found showing higher binding affinities to the SRA domain. The MD simulations also showed the protein ligand interaction stability of and in silico toxicity analysis has also showed chicoric acid as a safe and nontoxic drug. In addition, chicoric acid possessed a longer interaction time and higher LD50 of 5000 mg/kg. Moreover, the global methylation level (%5 mC) has been assessed after chicoric acid treatment was in the colorectal cancer cell line (HCT116) at different doses. The result showed that 7.5 µM chicoric acid treatment reduced methylation levels significantly. Thus, the study found chicoric acid can become a possible epidrug-like inhibitor against the SRA domain of UHRF1 protein.
Comprehensive analysis of karyopherin alpha family expression in lung adenocarcinoma: Association with prognostic value and immune homeostasis
Authors: Lan Xiuwen , Zhao Lin , Zhang Jian , Shao Yingchun , Qv Yunmeng , Huang Jian , Cai Li
Published: August 2022

Background: Karyopherin alpha (KPNA), a nuclear transporter, has been implicated in the development as well as the progression of many types of malignancies. Immune homeostasis is a multilevel system which regulated by multiple factors. However, the functional significance of the KPNA family in the pathogenesis of lung adenocarcinoma (LUAD) and the impact of immune homeostasis are not well characterized.

Methods: In this study, by integrating the TCGA-LUAD database and Masked Somatic Mutation, we first conducted an investigation on the expression levels and mutation status of the KPNA family in patients with LUAD. Then, we constructed a prognostic model based on clinical features and the expression of the KPNA family. We performed functional enrichment analysis and constructed a regulatory network utilizing the differential genes in high-and low-risk groups. Lastly, we performed immune infiltration analysis using CIBERSORT.

Results: Analysis of TCGA datasets revealed differential expression of the KPNA family in LUAD. Kaplan-Meier survival analyses indicated that the high expression of KPNA2 and KPNA4 were predictive of inferior overall survival (OS). In addition, we constructed a prognostic model incorporating clinical factors and the expression level of KPNA4 and KPNA5, which accurately predicted 1-year, 3-years, and 5-years survival outcomes. Patients in the high-risk group showed a poor prognosis. Functional enrichment analysis exhibited remarkable enrichment of transcriptional dysregulation in the high-risk group. On the other hand, gene set enrichment analysis (GSEA) displayed enrichment of cell cycle checkpoints as well as cell cycle mitotic in the high-risk group. Finally, analysis of immune infiltration revealed significant differences between the high-and low-risk groups. Further, the high-risk group was more prone to immune evasion while the inflammatory response was strongly associated with the low-risk group.

Conclusions: the KPNA family-based prognostic model reflects many biological aspects of LUAD and provides potential targets for precision therapy in LUAD.
Colorectal cancer vaccines: The current scenario and future prospects
Authors: Jia Wenqing , Zhang Tao , Huang Haiyan , Feng Haoran , Wang Shaodong , Guo Zichao , Luo Zhiping , Ji Xiaopin , Cheng Xi , Zhao Ren
Published: August 2022

Colorectal cancer (CRC) is one of the most common cancers worldwide. Current therapies such as surgery, chemotherapy, and radiotherapy encounter obstacles in preventing metastasis of CRC even when applied in combination. Immune checkpoint inhibitors depict limited effects due to the limited cases of CRC patients with high microsatellite instability (MSI-H). Cancer vaccines are designed to trigger the elevation of tumor-infiltrated lymphocytes, resulting in the intense response of the immune system to tumor antigens. This review briefly summarizes different categories of CRC vaccines, demonstrates the current outcomes of relevant clinical trials, and provides particular focus on recent advances on nanovaccines and neoantigen vaccines, representing the trend and emphasis of CRC vaccine development.
Exploring whole proteome to contrive multi-epitope-based vaccine for NeoCoV: An immunoinformtics and in-silico approach
Authors: Aziz Shahkaar , Waqas Muhammad , Halim Sobia Ahsan , Ali Amjad , Iqbal Aqib , Iqbal Maaz , Khan Ajmal , Al-Harrasi Ahmed
Published: August 2022

Neo-Coronavirus (NeoCoV) is a novel Betacoronavirus (β-CoVs or Beta-CoVs) discovered in bat specimens in South Africa during 2011. The viral sequence is highly similar to Middle East Respiratory Syndrome, particularly that of structural proteins. Thus, scientists have emphasized the threat posed by NeoCoV associated with human angiotensin-converting enzyme 2 (ACE2) usage, which could lead to a high death rate and faster transmission rate in humans. The development of a NeoCoV vaccine could provide a promising option for the future control of the virus in case of human infection. In silico predictions can decrease the number of experiments required, making the immunoinformatics approaches cost-effective and convenient. Herein, with the aid of immunoinformatics and reverse vaccinology, we aimed to formulate a multi-epitope vaccine that may be used to prevent and treat NeoCoV infection. Based on the NeoCoV proteins, B-cell, cytotoxic T lymphocyte (CTL), and helper T lymphocyte (HTL) epitopes were shortlisted. Four vaccines (Neo-1–4) were devised by fusing shortlisted epitopes with appropriate adjuvants and linkers. The secondary and three-dimensional structures of final vaccines were then predicted. The binding interactions of these potential vaccines with toll-like immune receptors (TLR-2, TLR-3, and TLR-4) and major histocompatibility complex molecules (MHC-I and II) reveal that they properly fit into the receptors’ binding domains. Besides, Neo-1 and Neo-4 vaccines exhibited better docking energies of -101.08 kcal/mol and -114.47 kcal/mol, respectively, with TLR-3 as compared to other vaccine constructs. The constructed vaccines are highly antigenic, non-allergenic, soluble, non-toxic, and topologically assessable with good physiochemical characteristics. Codon optimization and in-silico cloning confirmed efficient expression of the designed vaccines in Escherichia coli strain K12. In-silico immune simulation indicated that Neo-1 and Neo-4 vaccines could induce a strong immune response against NeoCoV. Lastly, the binding stability and strong binding affinity of Neo-1 and Neo-4 with TLR-3 receptor were validated using molecular dynamics simulations and free energy calculations (Molecular Mechanics/Generalized Born Surface Area method). The final vaccines require experimental validation to establish their safety and effectiveness in preventing NeoCoV infections.
Recent malaria does not substantially impact COVID-19 antibody response or rates of symptomatic illness in communities with high malaria and COVID-19 transmission in Mali, West Africa
Authors: Woodford John , Sagara Issaka , Diawara Halimatou , Assadou Mahamadoun Hamady , Katile Abdoulaye , Attaher Oumar , Issiaka Djibrilla , Santara Gaoussou , Soumbounou Ibrahim H. , Traore Seydou , Traore Moussa , Dicko Oumar M. , Niambele Sidi Mohamed , Mahamar Almahamoudou , Kamate Bourama , Haidara Bayaya , Sissoko Kourane , Sankare Seydou , Diarra Sadio dite Koni , Zeguime Amatigue , Doritchamou Justin Y. A. , Zaidi Irfan , Dicko Alassane , Duffy Patrick E.
Published: August 2022

Malaria has been hypothesized as a factor that may have reduced the severity of the COVID-19 pandemic in sub-Saharan Africa. To evaluate the effect of recent malaria on COVID-19 we assessed a subgroup of individuals participating in a longitudinal cohort COVID-19 serosurvey that were also undergoing intensive malaria monitoring as part of antimalarial vaccine trials during the 2020 transmission season in Mali. These communities experienced a high incidence of primarily asymptomatic or mild COVID-19 during 2020 and 2021. In 1314 individuals, 711 were parasitemic during the 2020 malaria transmission season; 442 were symptomatic with clinical malaria and 269 had asymptomatic infection. Presence of parasitemia was not associated with new COVID-19 seroconversion (29.7% (211/711) vs. 30.0% (181/603), p=0.9038) or with rates of reported symptomatic seroconversion during the malaria transmission season. In the subsequent dry season, prior parasitemia was not associated with new COVID-19 seroconversion (30.2% (133/441) vs. 31.2% (108/346), p=0.7499), with symptomatic seroconversion, or with reversion from seropositive to seronegative (prior parasitemia: 36.2% (64/177) vs. no parasitemia: 30.1% (37/119), p=0.3842). After excluding participants with asymptomatic infection, clinical malaria was also not associated with COVID-19 serostatus or symptomatic seroconversion when compared to participants with no parasitemia during the monitoring period. In communities with intense seasonal malaria and a high incidence of asymptomatic or mild COVID-19, we did not demonstrate a relationship between recent malaria and subsequent response to COVID-19. Lifetime exposure, rather than recent infection, may be responsible for any effect of malaria on COVID-19 severity.
A novel multi-dimensional reliability approach for floating wind turbines under power production conditions
Authors: Xu Xiaosen , Xing Yihan , Gaidai Oleg , Wang Kelin , Patel Karan Sandipkumar , Dou Peng , Zhang Zhongyu
Published: August 2022

Floating offshore wind turbines (FOWT) generate green renewable energy and are a vital part of the modern offshore wind energy industry. Robust predicting extreme offshore loads during FOWT operations is an important safety concern. Excessive structural bending moments may occur during certain sea conditions, posing an operational risk of structural damage. This paper uses the FAST code to analyze offshore wind turbine structural loads due to environmental loads acting on a specific FOWT under actual local environmental conditions. The work proposes a unique Gaidai-Fu-Xing structural reliability approach that is probably best suited for multi-dimensional structural responses that have been simulated or measured over a long period to produce relatively large ergodic time series. In the context of numerical simulation, unlike existing reliability approaches, the novel methodology does not need to re-start simulation again each time the system fails. As shown in this work, an accurate forecast of the probability of system failure can be made using measured structural response. Furthermore, traditional reliability techniques cannot effectively deal with large dimensionality systems and cross-correction across multiple dimensions. The paper aims to establish a state-of-the-art method for extracting essential information concerning extreme responses of the FOWT through simulated time-history data. Three key components of structural loads are analyzed, including the blade-root out-of-plane bending moment, tower fore-aft bending moment, and mooring line tension. The approach suggested in this study allows predicting failure probability efficiently for a non-linear multi-dimensional dynamic system as a whole.
Changes of serofast status in HIV negative asymptomatic neurosyphilis patients after treatment
Authors: Liu Jing , Zhao Tian-Wei , Zhou Chun , Yan Hui-Wen , Lun Wen-Hui
Published: August 2022

Serofast status after therapy in syphilis patients is a common phenomenon. A proportion of patients who have serofast status exhibit abnormal cerebrospinal fluid test results, which can be defined as asymptomatic neurosyphilis (ANS); however, it remains unclear whether ANS patients can achieve serological cure after anti-neurosyphilis treatment as quickly as other serofast patients. In this study, non-treponemal pallidum antibody serological responses were studied in ANS and serofast control patients, and the cumulative rates of serological cure in the ANS group were 9.6, 22.1, 25.9, and 30.2% in 3, 6, 9, and 12 month after treatment, which were statistically higher than those of the serofast control group. The change gap in serological cure rates was even more pronounced within 6 months after treatment, but the majority of ANS patients had no change in serofast status at 12 months after treatment. Our study indicates that anti-neurosyphilis therapy can partially change the serofast status. As serofast status cannot easily be changed even under neurosyphilis treatment in the majority of patients, the pathogenesis of this condition needs further research.
Cross-Border Transmissions of the Delta Substrain AY.29 During Tokyo Olympic and Paralympic Games
Authors: Koyama Takahiko , Tokumasu Reitaro , Katayama Kotoe , Saito Ayumu , Kudo Michiharu , Imoto Seiya
Published: August 2022

Tokyo Olympic and Paralympic Games, postponed for the COVID-19 pandemic, were finally held in the summer of 2021. Just before the games, the Alpha variant was being replaced with the more contagious Delta variant. AY.4 substrain AY.29, which harbors two additional characteristic mutations of 5239C > T (NSP3 Y840Y) and 5514T > C (NSP3 V932A), emerged in Japan and became dominant in Tokyo by the time of the Olympic Games. Variants of SARS-CoV-2 genomes were performed to extract AY.29 Delta substrain samples with 5239C > T and 5514T > C. Phylogenetic analysis was performed to illustrate how AY.29 strains evolved and were introduced into countries abroad. Simultaneously, ancestral searches were performed for the overseas AY.29 samples to identify their origins in Japan using the maximum variant approach. As of January 10, 2022, 118 samples were identified in 20 countries. Phylogenetic analysis and ancestral searches identified 55 distinct introductions into those countries. The United States had 50 samples with 10 distinct introductions, and the United Kingdom had 13 distinct strains introduced in 18 samples. Other countries or regions with multiple introductions were Canada, Germany, South Korea, Hong Kong, Thailand, and the Philippines. Among the 20 countries, most European and North American countries have vaccination rates over 50% and sufficient genomic surveillances are conducted; transmissions seem contained. However, propagation to unvaccinated regions might have caused unfathomable damages. Since samples in those unvaccinated countries are also undersampled with a longer lead time for data sharing, it will take longer to grasp the whole picture. More rigorous departure screenings for the participants from the unvaccinated countries might have been necessary.
Impact of microcin J25 on the porcine microbiome in a continuous culture model
Authors: Naimi Sabrine , Zirah Séverine , Greppi Anna , Lacroix Christophe , Rebuffat Sylvie , Fliss Ismail
Published: August 2022

The increased prevalence of Salmonella spp. resistance in swine spurs the search for alternatives to antibiotics. Microcin J25 (MccJ25), a bacteriocin produced by Escherichia coli, is a potent inhibitor of several pathogenic bacteria including Salmonella enterica. In this study, we aimed to evaluate in vitro the impact of MccJ25 on the composition and the metabolic activity of the swine colonic microbiota. The PolyFermS in vitro continuous fermentation model was used here with modified Macfarlane medium to simulate the porcine proximal colon. During 35 days of fermentation, a first-stage reactor containing immobilized swine fecal microbiota fed two second-stage control and test reactors operated in parallel and used to test the effects of MccJ25 on the composition and the metabolic activity of the microbiota. Reuterin, a broad-spectrum antimicrobial compound produced by Limosilactobacillus reuteri, a lactic acid bacterium naturally present in the gastro-intestinal tract of human and animals, and the antibiotic rifampicin were tested for comparison. Sequencing of 16S rRNA was performed using the Illumina MiSeq technology to evaluate microbial diversity, and liquid chromatography coupled to mass spectrometry (LC-MS) followed by multivariate analysis was used to assess the bacteriocin/antibiotic degradation products and to monitor changes in the swine colonic microbiota metabolome. The results show that MccJ25 or reuterin treatments only induce subtle changes of both the microbial diversity and the metabolome of the swine colon microbiota, while rifampicin induces significant modification in amino acid levels. Although these findings need being validated in vivo, this study affords a first proof of concept for considering MccJ25 as a possible alternative to antibiotics for veterinary and farming applications, taking into account its pathogen-selective and potent inhibitory activity.
E3 ligase RNF5 inhibits type I interferon response in herpes simplex virus keratitis through the STING/IRF3 signaling pathway
Authors: Liu Zhi , Xia Likun
Published: August 2022

Herpes simplex keratitis (HSK), caused by the herpes simplex virus 1 (HSV-1), is a major blinding disease in developed countries. HSV-1 can remain latent in the host for life and cannot be eradicated. The infection causes the secretion of various cytokines and aggregation of inflammatory cells. In the early stage of inflammation, mainly neutrophils infiltrate the cornea, and CD4+T cells mediate the immunopathological changes in herpetic stromal keratitis in the subsequent progression. The STING/IRF3-mediated type I interferon (IFN) response can effectively inhibit viral replication and control infection, but the activity of STING is affected by various ubiquitination modifications. In this study, we found that the expression of RNF5 was elevated in corneal tissues and corneal epithelial cells after infection with HSV-1. Immunofluorescence staining confirmed that RNF5 was mainly expressed in the corneal epithelial layer. We silenced and overexpressed RNF5 expression in corneal epithelial cells and then inoculated them with HSV-1. We found that the expressions of STING, p-IRF3, p-TBK1, and IFN-β mRNA increased after RNF5 silencing. The opposite results were obtained after RNF5 overexpression. We also used siRNA to silence RNF5 in the mouse cornea and then established the HSK model. Compared with the siRNA-control group, the siRNA-RNF5 group showed significantly improved corneal inflammation, reduced clinical scores and tear virus titers, and significantly increased corneal IFN-β expression. In addition, the expressions of the proinflammatory cytokines IL-6 and TNF-α in the corneal tissue were significantly decreased, indicating that RNF5 silencing could effectively promote IFN-I expression, inhibit virus replication, alleviate inflammation, and reduce corneal inflammatory damage. In summary, our results suggest that RNF5 limits the type I IFN antiviral response in HSV corneal epithelitis by inhibiting STING/IRF3 signaling.
Molecular Mechanism of Xingnao Kaiqiao Pill for Perioperative Neurocognitive Disorder and Its Correlation With Immune and Inflammatory Signaling Pathways Based on Network Pharmacology and Molecular Docking
Authors: Zhang Weiwei , Shi Gaoxiang , Wang Hui , Feng Miaomiao , Gao Xiang , Xie Qipeng , Zhang Ning , Lv Zhigan
Published: August 2022

To investigate the molecular mechanism of Xingnao Kaiqiao Pill in the treatment of perioperative neurocognitive disorder (PND) from the perspective of network pharmacology and molecular docking technology. Active ingredients of Xingnao Kaiqiao Pill were screened from the traditional Chinese medicine database and analysis platform, and the putative targets were predicted. The GeneCards database was searched to obtain PND-related targets. The genes corresponding to the targets were searched and annotated on the UniProt database. The VennDiagram package in R was employed to obtain common target genes. The overlap genes were introduced into STRING to obtain a protein-protein interaction (PPI) network; thus, key targets were screened. The target relationship network of “Xingnao Kaiqiao Pill–traditional Chinese medicine–compound–common target” was constructed by Cytoscape software. Using R language package Bioconductor, Gene Ontology (GO) and pathway enrichment analysis (Kyoto Encyclopedia of Genes and Genomes Pathway, KEGG Pathway) were performed on the common target genes. A total of 45 active ingredients of Xingnao Kaiqiao Pill were screened, with 182 potential targets, and 1,579 PND-related targets were retrieved from the GeneCards databases (Score ≥ 1). Using VennDiagram, 132 overlap genes were gotten. Xingnao Kaiqiao Pill mainly acted on targets, such as MAPK and JUN. GO enrichment analysis displayed G protein-coupled amine receptor activity, nuclear receptor activity, ligand-activated transcription factor activity, G protein-coupled neurotransmitter receptor activity, steroid hormone receptor activity, and cytokine receptor activity. KEGG enrichment analysis exhibited 157 signaling pathways. The regulation of interleukin 17, tumor necrosis factor, hypoxia-inducible factor-1, and MAPK signaling pathways affected central nervous system (CNS) inflammatory response, cellular immunity, tumor-related signaling pathways, protected neurons, and inhibited PND. The active ingredients of Xingnao Kaiqiao Pill adjust interleukin 17, tumor necrosis factor, hypoxia-inducible factor-1, and MAPK signaling pathways by acting on cell targets, such as JUN, MAPK, AKT1, etc., and finally exert a therapeutic effect on PND.
Detecting apathy in patients with cerebral small vessel disease
Authors: Cai Xiaoping , Zhào Hóngyi , Li Zhiyi , Ding Yu , Huang Yonghua
Published: August 2022

Background

Apathy is attracting more and more attention in clinical practice. As one of the most common features of cerebral small vessel disease (CSVD), the assessment of apathy still mainly relies on observers. With the development of Information and Communication Technologies (ICTs), new objective tools take part in the early detection of apathy.

Objectives

To detect apathy in patients with CSVD and find out the relationship between apathy and actigraphic data sampled from the diurnal and nocturnal periods.

Methods

A total of 56 patients with CSVD were recruited for a cross-sectional observational study. Apathy was diagnosed by the diagnostic criteria for apathy in neurocognitive disorders. The presence of lacunes, white matter hyperintensities, cerebral microbleeds (CMBs), and perivascular spaces (PVS) in magnetic resonance imaging (MRI) images were rated independently. Actigraph devices were worn in the non-dominant hands of each subject for 7 consecutive days to collect samples of raw data, and diurnal vector magnitude (VM) and a series of sleep quality variables were obtained.

Results

We found that the frequency of apathy in Chinese patients with CSVD reached 37.50%. Patients in the Apathy+ group showed more lacunes and CMBs, and higher Fazekas scores in comparison to apathy-group individuals. Diurnal VM, instead of other sleep quality variables, was lower in CSVD patients with apathy relative to those without apathy. Lastly, we discovered that diurnal VM and total time in bed (TTB) correlated negatively with apathy severity in patients with CSVD.

Conclusion

Actigraphy is a promising choice to evaluate apathy in patients with CSVD.
Machine-learning analysis of intrinsically disordered proteins identifies key factors that contribute to neurodegeneration-related aggregation
Authors: Ganne Akshatha , Balasubramaniam Meenakshisundaram , Ayyadevara Srinivas , Shmookler Reis Robert J.
Published: August 2022

Protein structure is determined by the amino acid sequence and a variety of post-translational modifications, and provides the basis for physiological properties. Not all proteins in the proteome attain a stable conformation; roughly one third of human proteins are unstructured or contain intrinsically disordered regions exceeding 40% of their length. Proteins comprising or containing extensive unstructured regions are termed intrinsically disordered proteins (IDPs). IDPs are known to be overrepresented in protein aggregates of diverse neurodegenerative diseases. We evaluated the importance of disordered proteins in the nematode Caenorhabditis elegans, by RNAi-mediated knockdown of IDPs in disease-model strains that mimic aggregation associated with neurodegenerative pathologies. Not all disordered proteins are sequestered into aggregates, and most of the tested aggregate-protein IDPs contribute to important physiological functions such as stress resistance or reproduction. Despite decades of research, we still do not understand what properties of a disordered protein determine its entry into aggregates. We have employed machine-learning models to identify factors that predict whether a disordered protein is found in sarkosyl-insoluble aggregates isolated from neurodegenerative-disease brains (both AD and PD). Machine-learning predictions, coupled with principal component analysis (PCA), enabled us to identify the physiochemical properties that determine whether a disordered protein will be enriched in neuropathic aggregates.
Risk factors for postoperative delirium in geriatric patients with hip fracture: A systematic review and meta-analysis
Authors: Qi Yi-ming , Li Ying-juan , Zou Ji-hong , Qiu Xiao-dong , Sun Jie , Rui Yun-feng
Published: August 2022

Objectives

This systematic review and meta-analysis was conducted to identify the potential risk factors for postoperative delirium in geriatric patients with hip fracture.

Methods

PubMed, EMBASE, and Cochrane Library were searched from inception until December 31st, 2021. A combined searching strategy of subject words and free words was adopted. Studies involving risk factors for postoperative delirium in elderly patients undergoing hip fracture surgeries were reviewed. Qualities of included studies were assessed using the Newcastle–Ottawa Scale. Data were pooled and a meta-analysis was performed using Review Manager 5.3.

Results

A total of 37 studies were included. The following risk factors were significant: advanced age (per year increase) (OR: 1.05, 95% CI 1.04–1.07), age>80 years (OR: 2.26, 95% CI 1.47–3.47), male (OR: 1.53, 95% CI 1.37–1.70), preoperative cognitive impairment (OR:3.20, 95% CI 2.12–4.83), preoperative dementia (OR: 2.74, 95% CI 2.18–3.45), preoperative delirium (OR: 9.23, 95% CI 8.26–10.32), diabetes (OR: 1.18, 95% CI 1.05–1.33), preoperative functional dependence (OR: 1.31, 95% CI 1.11–1.56), ASA level (per level increase) (OR: 1.63, 95% CI 1.04–2.57), ASA level≥3(OR: 1.76, 95% CI 1.39–2.24), low albumin (OR: 3.30, 95% CI 1.44–7.55), medical comorbidities (OR: 1.15, 95% CI 1.06–1.25), Parkinson's disease (OR: 4.17, 95% CI 1.68–10.31) and surgery delay>48 h (OR: 1.90, 95% CI 1.36–2.65).

Conclusions

Clinicians should be alert to patients with those risk factors. To identify the risk factors more precisely, more research studies with larger sample size and better design should be conducted.
Phosphatidylserine, inflammation, and central nervous system diseases
Authors: Ma Xiaohua , Li Xiaojing , Wang Wenjuan , Zhang Meng , Yang Bo , Miao Zhigang
Published: August 2022

Phosphatidylserine (PS) is an anionic phospholipid in the eukaryotic membrane and is abundant in the brain. Accumulated studies have revealed that PS is involved in the multiple functions of the brain, such as activation of membrane signaling pathways, neuroinflammation, neurotransmission, and synaptic refinement. Those functions of PS are related to central nervous system (CNS) diseases. In this review, we discuss the metabolism of PS, the anti-inflammation function of PS in the brain; the alterations of PS in different CNS diseases, and the possibility of PS to serve as a therapeutic agent for diseases. Clinical studies have showed that PS has no side effects and is well tolerated. Therefore, PS and PS liposome could be a promising supplementation for these neurodegenerative and neurodevelopmental diseases.
Endotoxin removal therapy with Polymyxin B immobilized fiber column as a COVID-19-bedside strategy protocol for endotoxic shock
Authors: De Rosa Silvia , Zanella Monica , Samoni Sara , Ronco Claudio
Published: August 2022

Endotoxin-induced sepsis is a leading cause of ICU mortality. From 1994 to the present, PMX-HP has been available as an adjuvant therapy for endotoxin removal and immunomodulation. The efficacy and usefulness of this therapy have been demonstrated for more than a quarter of a century and are partially supported by clinical studies. However, it appears that selected subgroups of patients with endotoxic shock and with appropriate timing could benefit. Endotoxemia may be involved in the pathophysiology of COVID-19, based on enterocyte dysfunction and malabsorptive syndrome. Due to the characteristics of the microbiota, Gram-negative bacteria or their fragments (i.e., endotoxin) may translocate into the systemic circulation leading to inflammatory activation, immune dysfunction, and sepsis. In addition, patients with severe forms of COVID-19 are at risk of superimposed infections. Endotoxemia can arise due to the translocation of Gram-negative bacteria or their fragments from the gut barrier. According to the most updated evidence available from large randomized trials, septic shock patients with MODS > 9 and EA levels ranging from 0.6 to 0.9 are those who may benefit the most from PMX‐HP treatment in terms of improvement of survival. As shown in a previous publication, we believe that similarly to the source control, microbiological cultures, and antibiotics administration, EA evaluation at regular intervals, and the targeted use of PMX‐HP could be lifesaving and adequate within the golden hour for the diagnosis and treatment of endotoxic shock. In our center, we applied a diagnostic-clinical flowchart also for endotoxic shock related to COVID-19.
The repeat length of C9orf72 is associated with the survival of amyotrophic lateral sclerosis patients without C9orf72 pathological expansions
Authors: Tang Lu , Chen Lu , Liu Xiaolu , He Ji , Ma Yan , Zhang Nan , Fan Dongsheng
Published: August 2022

Objective

To explore whether the repeat lengths of the chromosome 9 open reading frame 72 (C9orf72) gene and the ataxin-2 (ATXN2) gene in amyotrophic lateral sclerosis (ALS) patients without C9orf72 repeat expansions confer a risk of ALS or survival disadvantages in ALS.

Methods

We screened a hospital-based cohort of Chinese patients with sporadic ALS without C9orf72 repeat expansions and neurologically healthy controls for C9orf72 GGGGCC and AXTN2 CAG repeat length to compare the frequency of possible detrimental length alleles using several thresholds. Furthermore, the clinical features of ALS were compared between patients with ALS subgroups using different length thresholds of maximum C9orf72 and ATXN2 repeat alleles, such as sex, age of onset, diagnostic delay, and survival.

Results

Overall, 879 sporadic patients with ALS and 535 controls were included and the repeat lengths of the C9orf72 and ATXN2 were both detected. We found significant survival differences in patients using a series of C9orf72 repeat length thresholds from 2 to 5, among which the most significant difference was at the cutoff value of 2 (repeats 2 vs. >2: median survival 67 vs. 55 months, log-rank p = 0.032). Furthermore, Cox regression analysis revealed the role of age of onset [hazard ratio (HR) 1.04, 95% CI 1.03–1.05, p < 0.001], diagnostic delay (0.95, 0.94–0.96, p < 0.001), and carrying C9orf72 repeat length of 2 (0.72, 0.59–0.89, p = 0.002) in the survival of patients without C9orf72 repeat expansions. In addition, bulbar onset was associated with poorer survival when the patients carried the maximum C9orf72 repeat allele over 2 (1.81, 1.32–2.48, p < 0.001). However, no survival difference was found when applying a series of continuous cutoff values of ATXN2 or stratified by C9orf72 repeats of 2.

Conclusion

The length of 2 in the maximum C9orf72 repeat allele was identified to be associated with favorable survival in ALS patients without C9orf72 repeat expansions. Our findings from the clinical setting implicated the possible cutoff definition of detrimental C9orf72 repeats, which should be helpful in the understanding of genetics in ALS and in clinical genetic counseling.
Functional recovery priorities and community rehabilitation service preferences of spinal cord injury individuals and caregivers of Chinese ethnicity and cultural background
Authors: Lam Chor Yin , Koljonen Paul Aarne , Yip Christopher Chun Hei , Su Ivan Yuen Wang , Hu Yong , Wong Yat Wa , Cheung Kenneth Man Chee
Published: August 2022

Introduction

Spinal cord injury (SCI) causes significant and permanent disability affecting motor, sensory and autonomic functions. We conducted a survey on the priorities of functional recovery and preferences for community rehabilitation services in a cohort of Chinese individuals with SCI as well as the primary caregivers. The study also investigated their views on advanced technology and research.

Methods

An online platform with a self-administered questionnaire was used to collect the opinions of clients that received services from an SCI follow-up clinic, a self-help association, or a non-government organization from 1 September−31 December 2021.

Results

Eighty-seven subjects (74 individuals with SCI−48 tetraplegic, 26 paraplegic, and 13 caregivers) responded to the survey. Recovery of arm/hand function was given the highest priority among tetraplegics, followed by upper trunk/body strength and balance, and bladder/bowel function. Sexual function had a significant lower ranking than all priority areas except normal sensation (p < 0.05). Paraplegics viewed bladder/bowel function as the most important area of functional recovery, followed by walking movement, upper trunk/body strength and balance, elimination of chronic pain, and regaining normal sensation. There was no statistically significant difference among the top priority areas (p > 0.05). In contrast to previous studies done in Western populations, the study revealed that sexual function was ranked as the lowest by all 3 groups of respondents (tetraplegics, paraplegics, and caregivers). The majority of participants thought community rehabilitation services were inadequate. Most of the respondents were interested to try advanced technology which would facilitate their daily life and rehabilitation. About half of the individuals with SCI thought advance in technology and research could bring significant improvement in their quality of life in the coming 10 years.

Conclusion

This survey is the first study specifically looking into the recovery and rehabilitation priorities of a Chinese population of individuals with SCI. This is also the first study to investigate the priorities of the primary caregivers of SCI individuals. The findings are useful as a reference for planning of future research and provision of rehabilitation services for the SCI community locally and in other parts of China.