bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of DLL3-related genes affecting the prognosis of patients with colon adenocarcinoma
Authors: Xiang Jinyu , Gong Wenjing , Liu Jiannan , Zhang Huijuan , Li Ming , Wang Rujian , Lv Yaodong , Sun Ping
Published: May 2023

Background: Delta-like ligand 3 (DLL3) is one of the NOTCH family of ligands, which plays a pro- or anti-carcinogenic role in some cancers. But the role of DLL3 in colon adenocarcinoma (COAD) has not been studied in depth.

Materials and methods: First, we used Kaplan-Meier (K-M) curve to evaluate the effect of DLL3 on the prognosis of COAD in The Cancer Genome Atlas (TCGA), which was further validated in clinical samples for immunohistochemistry. Then we screened for differentially expressed genes (DEGs) of DLL3 by analyzing datasets of COAD samples from Gene Expression Omnibus (GEO) and TCGA. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and Gene Set Enrichment Analysis (GSEA) were conducted to explore the underlying mechanisms of DLL3-related in the development and prognosis of COAD. On the basis of DLL3-related signature genes, a prognostic model and a nomogram were constructed. Finally, CIBERSORT was applied to assess the proportion of immune cell types in COAD sample.

Results: Survival analysis showed a significant difference in overall survival between high- and low-expression group (p = 0.0092), with COAD patients in the high-group having poorer 5-year survival rate. Gene functional enrichment analysis revealed that DLL3-related DEGs were mainly enriched in tumor- and immunity-related signaling pathways, containing AMPK pathway and mitophagy-animal. The comparison of COAD tumor and normal, DLL3 high- and low-expression groups by GSEA found that AMPK signaling pathway and mitophagy-animal were inhibited. Nomogram constructed from DLL3-related signature genes had a good predictive effect on the prognosis of COAD. We found the highest correlation between DLL3 and interstitial dendritic cell (iDC), natural killer (NK) cell and Interstitial dendritic cell (Tem). DLL3 was also revealed to be diagnostic for COAD. In clinical sample, we identified higher DLL3 expression in colon cancer tissue than in adjacent control (p < 0.0001) and in metastasis than in primary lesion (p = 0.0056). DLL3 expression was associated with stage and high DLL3 expression was observed to predict poorer overall survival (p = 0.004).

Conclusion: It suggested that DLL3 may offer prognostic value and therapeutic potential for individualized treatment of COAD, and that it may has a diagnostic role in COAD.
SPARTIN: a Bayesian method for the quantification and characterization of cell type interactions in spatial pathology data
Authors: Osher Nathaniel , Kang Jian , Krishnan Santhoshi , Rao Arvind , Baladandayuthapani Veerabhadran
Published: May 2023

Introduction: The acquisition of high-resolution digital pathology imaging data has sparked the development of methods to extract context-specific features from such complex data. In the context of cancer, this has led to increased exploration of the tumor microenvironment with respect to the presence and spatial composition of immune cells. Spatial statistical modeling of the immune microenvironment may yield insights into the role played by the immune system in the natural development of cancer as well as downstream therapeutic interventions.

Methods: In this paper, we present SPatial Analysis of paRtitioned Tumor-Immune imagiNg (SPARTIN), a Bayesian method for the spatial quantification of immune cell infiltration from pathology images. SPARTIN uses Bayesian point processes to characterize a novel measure of local tumor-immune cell interaction, Cell Type Interaction Probability (CTIP). CTIP allows rigorous incorporation of uncertainty and is highly interpretable, both within and across biopsies, and can be used to assess associations with genomic and clinical features.

Results: Through simulations, we show SPARTIN can accurately distinguish various patterns of cellular interactions as compared to existing methods. Using SPARTIN, we characterized the local spatial immune cell infiltration within and across 335 melanoma biopsies and evaluated their association with genomic, phenotypic, and clinical outcomes. We found that CTIP was significantly (negatively) associated with deconvolved immune cell prevalence scores including CD8+ T-Cells and Natural Killer cells. Furthermore, average CTIP scores differed significantly across previously established transcriptomic classes and significantly associated with survival outcomes.

Discussion: SPARTIN provides a general framework for investigating spatial cellular interactions in high-resolution digital histopathology imaging data and its associations with patient level characteristics. The results of our analysis have potential implications relevant to both treatment and prognosis in the context of Skin Cutaneous Melanoma. The R-package for SPARTIN is available at https://github.com/bayesrx/SPARTIN along with a visualization tool for the images and results at: https://nateosher.github.io/SPARTIN.
Clinical value of anoikis-related genes and molecular subtypes identification in bladder urothelial carcinoma and in vitro validation
Authors: Dong Ying , Xu Chaojie , Su Ganglin , Li Yanfeng , Yan Bing , Liu Yuhan , Yin Tao , Mou Shuanzhu , Mei Hongbing
Published: May 2023

Background

Anoikis is a programmed cell death process that was proven to be associated with cancer. Uroepithelial carcinoma of the bladder (BLCA) is a malignant disease of the urinary tract and has a strong metastatic potential. To determine whether anoikis-associated genes can predict the prognosis of BLCA accurately, we evaluated the prognostic value of anoikis-associated genes in BLCA and constructed the best model to predict prognosis.

Method

The BLCA transcriptome data were downloaded from TCGA and GEO databases, and genes with differential expression were selected and then clustered using non-negative matrix factorization (NMF). The genes with the most correlation with anoikis were screened and identified using univariate Cox regression, lasso regression, and multivariate Cox regression. The GEO dataset was used for external validation. Nomograms were created based on risk characteristics in combination with clinical variants and the performance of the model was validated with receiver operating characteristic (ROC) curves. The immunotherapeutic significance of this risk score was assessed using the immune phenomenon score (IPS). IC50 values of predictive chemotherapeutic agents were calculated. Finally, we used RT-qPCR to determine the mRNA expression of four genes, CALR, FASN, CASP6, and RAD9A.

Result

We screened 406 tumor samples and 19 normal tissue samples from the TCGA database. Based on anoikis-associated genes, we classified patients into two subtypes (C1 and C2) using NMF method. Subsequently, nine core genes were screened by multiple methods after analysis, which were used to construct risk profiles. The design of nomograms based on risk profiles and clinical variables, ROC, and calibration curves confirmed that the model could well have the ability to predict the survival of BLCA patients at 1, 3, and 5 years. By predicting the IC50 values of chemotherapeutic drugs, it was learned that the high-risk group (HRG) was more susceptible to paclitaxel, gemcitabine, and cisplatin, and the low-risk group (LRG) was more susceptible to veriparib and afatinib.

Conclusion

In summary, the risk score of anoikis-associated genes can be applied as a predictor to predict the prognosis of BLCA in clinical practice.
The genetically predicted causal relationship of inflammatory bowel disease with bone mineral density and osteoporosis: evidence from two-sample Mendelian randomization
Authors: Xu Dengyong , Chen Yao , Gao Xing , Xie Weidong , Wang Ya , Shen Jiaying , Yang Guang , Xie Binbin
Published: May 2023

Background

Many existing studies indicated that patients with inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), tend to have the risk of low total body bone mineral density (BMD), and are more likely to have osteoporosis (OS). To determine the causal relationship between IBD and bone metabolic disorders, we herein performed a two-sample Mendelian randomization analysis (TSMR) using publicly available summary statistics.

Methods

Summary statistics of total body BMD, OS and IBD were downloaded from the Open Genome-Wide Association Study (GWAS), FinnGen consortium and International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). The European and East Asian populations have consisted in this Mendelian Randomization (MR) work. A range of quality control procedures were taken to select eligible instrument SNPs closely associated with total body BMD, OS and IBD. To make the conclusions more reliable, we applied five robust analytical methods, among which the inverse variance weighting (IVW) method acted as the major method. Besides, heterogeneity, pleiotropy and sensitivity were evaluated.

Results

In the European population, the genetic association of UC on total body BMD (OR=0.97, 95%CI=0.96,0.99, P<0.001) and overall IBD on total body BMD (OR=0.98, 95%CI=0.97,1.00, P=0.013) were significant, while the effect of CD on total body BMD was not significant enough (OR=0.99, 95%CI=0.98,1.00, P=0.085). All of UC, CD and overall IBD can be the genetic risk factor of having OS with pathological fracture (UC: OR=1.13, 95%CI=1.02,1.26, P=0.024, CD: OR=1.14, 95%CI=1.05,1.25, P=0.003, overall IBD: OR=1.13, 95%CI=1.02,1.24, P=0.015). In East Asian groups, only CD had a causal relationship with OS (OR=1.04, 95% CI=1.01,1.07, P=0.019).

Conclusion

Our study revealed genetically predicted associations between IBD on total body BMD and OS in European and East Asian populations. This work supplemented the results of previous retrospective studies and demonstrated the necessity of BMD monitoring in patients with IBD.
Impact of peptide:HLA complex stability for the identification of SARS-CoV-2-specific CD8+T cells
Authors: Lie-Andersen Olivia , Hübbe Mie Linder , Subramaniam Krishanthi , Steen-Jensen Daniel , Bergmann Ann Christina , Justesen Daniel , Holmström Morten Orebo , Turtle Lance , Justesen Sune , Lança Telma , Hansen Morten
Published: May 2023

Induction of a lasting protective immune response is dependent on presentation of epitopes to patrolling T cells through the HLA complex. While peptide:HLA (pHLA) complex affinity alone is widely exploited for epitope selection, we demonstrate that including the pHLA complex stability as a selection parameter can significantly reduce the high false discovery rate observed with predicted affinity. In this study, pHLA complex stability was measured on three common class I alleles and 1286 overlapping 9-mer peptides derived from the SARS-CoV-2 Spike protein. Peptides were pooled based on measured stability and predicted affinity. Strikingly, stability of the pHLA complex was shown to strongly select for immunogenic epitopes able to activate functional CD8+T cells. This result was observed across the three studied alleles and in both vaccinated and convalescent COVID-19 donors. Deconvolution of peptide pools showed that specific CD8+T cells recognized one or two dominant epitopes. Moreover, SARS-CoV-2 specific CD8+T cells were detected by tetramer-staining across multiple donors. In conclusion, we show that stability analysis of pHLA is a key factor for identifying immunogenic epitopes.
Therapeutic strategies to enhance immune response induced by multiple myeloma cells
Authors: Liu Zhaoyun , Yang Chun , Liu Xiaohan , Xu Xintong , Zhao Xianghong , Fu Rong
Published: May 2023

Multiple myeloma (MM)as a haematological malignancy is still incurable. In addition to the presence of somatic genetic mutations in myeloma patients, the presence of immunosuppressive microenvironment greatly affects the outcome of treatment. Although the discovery of immunotherapy makes it possible to break the risk of high toxicity and side effects of traditional chemotherapeutic drugs, there are still obstacles of ineffective treatment or disease recurrence. In this review, we discuss therapeutic strategies to further enhance the specific anti-tumor immune response by activating the immunogenicity of MM cells themselves. New ideas for future myeloma therapeutic approaches are provided.
Mechanism of mesenchymal stem cells and exosomes in the treatment of age-related diseases
Authors: Li Jia , Huang Yuling , Sun Haiyan , Yang Lina
Published: May 2023

Mesenchymal stem cells (MSCs) from multiple tissues have the capability of multidirectional differentiation and self-renewal. Many reports indicated that MSCs exert curative effects on a variety of age-related diseases through regeneration and repair of aging cells and organs. However, as research has progressed, it has become clear that it is the MSCs derived exosomes (MSC-Exos) that may have a real role to play, and that they can be modified to achieve better therapeutic results, making them even more advantageous than MSCs for treating disease. This review generalizes the biological characteristics of MSCs and exosomes and their mechanisms in treating age-related diseases, for example, MSCs and their exosomes can treat age-related diseases through mechanisms such as oxidative stress (OS), Wnt/β-catenin signaling pathway, mitogen-activated protein kinases (MAPK) signaling pathway, and so on. In addition, current in vivo and in vitro trials are described, and ongoing clinical trials are discussed, as well as the prospects and challenges for the future use of exosomes in disease treatment. This review will provide references for using exosomes to treat age-related diseases.
Sjögren’s syndrome: novel insights from proteomics and miRNA expression analysis
Authors: Kamounah Sarah , Sembler-Møller Maria Lynn , Nielsen Claus Henrik , Pedersen Anne Marie Lynge
Published: May 2023

Introduction

Sjögren’s syndrome (SS) is a systemic autoimmune disease, which affects the exocrine glands leading to glandular dysfunction and, particularly, symptoms of oral and ocular dryness. The aetiology of SS remains unclear, and the disease lacks distinctive clinical features. The current diagnostic work-up is complex, invasive and often time-consuming. Thus, there is an emerging need for identifying disease-specific and, ideally, non-invasive immunological and molecular biomarkers that can simplify the diagnostic process, allow stratification of patients, and assist in monitoring the disease course and outcome of therapeutic intervention in SS.

Methods

This systematic review addresses the use of proteomics and miRNA-expression profile analyses in this regard.

Results and discussion

Out of 272 papers that were identified and 108 reviewed, a total of 42 papers on proteomics and 23 papers on miRNA analyses in saliva, blood and salivary gland tissue were included in this review. Overall, the proteomic and miRNA studies revealed considerable variations with regard to candidate biomarker proteins and miRNAs, most likely due to variation in sample size, processing and analytical methods, but also reflecting the complexity of SS and patient heterogeneity. However, interesting novel knowledge has emerged and further validation is needed to confirm their potential role as biomarkers in SS.
How to communicate with patients in written asynchronous online conversations: an intervention study with undergraduate medical students in a cross-over design
Authors: Festl-Wietek Teresa , Erschens Rebecca , Griewatz Jan , Zipfel Stephan , Herrmann-Werner Anne
Published: May 2023

Introduction

The patient-physician encounter is the core element in the treatment of patients and the diagnosis of disease. In these times of digitalization, patient-physician communication is increasingly taking place online: patients embrace new possibilities offered digitally, and physicians are encouraged to adapt accordingly. Since a huge part of online communication is written, this study aims to investigate how medical students communicate with patients online by focusing on their written competencies and whether an intervention might improve their competencies.

Methods

This study was performed in an explanatory cross-sectional manner with a cross-over design. Second-year medical students participated. An intervention was developed on how to formulate an appropriate written response to a patient’s request and integrated a longitudinal communication class. The intervention consists of education on general set-up (e.g., greetings), syntax, spelling, content and kind of communication (e.g., appreciative attitude). After meeting a patient in a simulated role play medical students received the patient’s request via a digital platform. The control group had the same simulated role play and the same task but they received the intervention on communication afterwards. Intervention and control group were statistically compared based on a checklist.

Results

Twenty-nine medical students took part in the study. The results showed that the medical students had basic competencies in dealing with written communication independent if they received the intervention (CG: M = 3.86 ± 1.23 vs. IG: M = 4.07 ± 1.03; p = 0.625). Similar results were also for the emotional competency ratings (MCG = 3.36 ± 1.08; MIG = 3.67 ± 0.98; p = 0.425).The intervention was able to lead to a more appreciative response toward patient.

Discussion

Intervention on basic competencies such as simple language and clear presentation might not be needed as an integral part in medical education. However, medical students should learn how to present empathic and authentic behavior in written online communication.
Study protocol: BRInging the Diabetes prevention program to GEriatric Populations
Authors: Beasley Jeannette M. , Johnston Emily A. , Sevick Mary Ann , Jay Melanie , Rogers Erin S. , Zhong Hua , Zabar Sondra , Goldberg Eric , Chodosh Joshua
Published: May 2023

In the Diabetes Prevention Program (DPP) randomized, controlled clinical trial, participants who were  ≥ 60 years of age in the intensive lifestyle (diet and physical activity) intervention had a 71% reduction in incident diabetes over the 3-year trial. However, few of the 26.4 million American adults age ≥65 years with prediabetes are participating in the National DPP. The BRInging the Diabetes prevention program to GEriatric Populations (BRIDGE) randomized trial compares an in-person DPP program Tailored for Older AdulTs (DPP-TOAT) to a DPP-TOAT delivered via group virtual sessions (V-DPP-TOAT) in a randomized, controlled trial design (N = 230). Eligible patients are recruited through electronic health records (EHRs) and randomized to the DPP-TOAT or V-DPP-TOAT arm. The primary effectiveness outcome is 6-month weight loss and the primary implementation outcome is intervention session attendance with a non-inferiority design. Findings will inform best practices in the delivery of an evidence-based intervention.
Long-term fertilization coupled with rhizobium inoculation promotes soybean yield and alters soil bacterial community composition
Authors: Wei Wanling , Guan Dawei , Ma Mingchao , Jiang Xin , Fan Fenliang , Meng Fangang , Li Li , Zhao Baisuo , Zhao Yubin , Cao Fengming , Chen Huijun , Li Jun
Published: May 2023

Microbial diversity is an important indicator of soil fertility and plays an indispensable role in farmland ecosystem sustainability. The short-term effects of fertilization and rhizobium inoculation on soil microbial diversity and community structure have been explored extensively; however, few studies have evaluated their long-term effects. Here, we applied quantitative polymerase chain reaction (qPCR) and amplicon sequencing to characterize the effect of 10-year fertilizer and rhizobium inoculation on bacterial communities in soybean bulk and rhizosphere soils at the flowering–podding and maturity stages. Four treatments were examined: non-fertilization control (CK), phosphorus and potassium fertilization (PK), nitrogen and PK fertilization (PK + N), and PK fertilization and Bradyrhizobium japonicum 5821 (PK + R). Long-term co-application of rhizobium and PK promoted soybean nodule dry weight by 33.94% compared with PK + N, and increased soybean yield by average of 32.25%, 5.90%, and 5.00% compared with CK, PK, and PK + N, respectively. The pH of PK + R was significantly higher than that of PK and PK + N at the flowering–podding stage. The bacterial abundance at the flowering–podding stage was positively correlated with soybean yield, but not at the maturity stage. The significant different class Gemmatimonadetes, and the genera Gemmatimonas, and Ellin6067 in soil at the flowering–podding stage were negatively correlated with soybean yield. However, the bacterial community at class and genus levels at maturity had no significant effect on soybean yield. The key bacterial communities that determine soybean yield were concentrated in the flowering–podding stage, not at maturity stage. Rhizosphere effect, growth period, and treatment synergies resulted in significant differences in soil bacterial community composition. Soil organic matter (OM), total nitrogen (TN), pH, and available phosphorus (AP) were the main variables affecting bacterial community structure. Overall, long-term co-application of rhizobium and fertilizer not only increased soybean yield, but also altered soil bacterial community structure through niche reconstruction and microbial interaction. Rhizobium inoculation plays key role in reducing nitrogen fertilizer application and promoting sustainable agriculture practices.
Causal relationship in gut microbiota and upper urinary urolithiasis using Mendelian randomization
Authors: Zhang Ruiqiao , Zhao Weijie , Zhao Ruijie , Zhao Yunhai , Zhang Yanlong , Liang Xuezhi
Published: May 2023

Background

Several reports in recent years have found an association between gut microbiota and upper urinary urolithiasis. However, the causal relationship between them remains to be clarified.

Methods

Genetic variation is used as a tool in Mendelian randomization for inference of whether exposure factors have a causal effect on disease outcomes. We selected summary statistics from a large genome-wide association study of the gut microbiome published by the MiBioGen consortium with a sample size of 18,340 as an exposure factor and upper urinary urolithiasis data from FinnGen GWAS with 4,969 calculi cases and 213,445 controls as a disease outcome. Then, a two-sample Mendelian randomization analysis was performed by applying inverse variance-weighted, MR-Egger, maximum likelihood, and weighted median. In addition, heterogeneity and horizontal pleiotropy were excluded by sensitivity analysis.

Results

IVW results confirmed that class Deltaproteobacteria (OR = 0.814, 95% CI: 0.666–0.995, P = 0.045), order NB1n (OR = 0.833, 95% CI: 0.737–0.940, P = 3.15 × 10−3), family Clostridiaceae1 (OR = 0.729, 95% CI: 0.581–0.916, P = 6.61 × 10−3), genus Barnesiella (OR = 0.695, 95% CI: 0.551–0.877, P = 2.20 × 10−3), genus Clostridium sensu_stricto_1 (OR = 0.777, 95% CI: 0.612–0.986, P = 0.0380), genus Flavonifractor (OR = 0.711, 95% CI: 0.536–0.944, P = 0.0181), genus Hungatella (OR = 0.829, 95% CI: 0.690–0.995, P = 0.0444), and genus Oscillospira (OR = 0.758, 95% CI: 0.577–0.996, P = 0.0464) had a protective effect on upper urinary urolithiasis, while Eubacterium xylanophilum (OR =1.26, 95% CI: 1.010–1.566, P = 0.0423) had the opposite effect. Sensitivity analysis did not find outlier SNPs.

Conclusion

In summary, a causal relationship was found between several genera and upper urinary urolithiasis. However, we still need further randomized controlled trials to validate.
Landscapes of gut microbiome and bile acid signatures and their interaction in HBV-associated acute-on-chronic liver failure
Authors: Bao Zhiwei , Wei Runan , Zheng Xiaoping , Zhang Ting , Bi Yunjiao , Shen Sijia , Zou Pengfei , Zhang Junjie , Yan Huadong , Li Ming D. , Yang Zhongli , Gao Hainv
Published: May 2023

Introduction

Submassive hepatic necrosis (SMHN, defined as necrosis of 15–90% of the entire liver on explant) is a likely characteristic pathological feature of ACLF in patients with hepatitis B cirrhosis. We aimed to comprehensively explore microbiome and bile acids patterns across enterhepatic circulation and build well-performing machine learning models to predict SMHN status.

Methods

Based on the presence or absence of SMHN, 17 patients with HBV-related end-stage liver disease who received liver transplantation were eligible for inclusion. Serum, portal venous blood, and stool samples were collected for comparing differences of BA spectra and gut microbiome and their interactions. We adopted the random forest algorithm with recursive feature elimination (RF-RFE) to predict SMHN status.

Results

By comparing total BA spectrum between SMHN (−) and SMHN (+) patients, significant changes were detected only in fecal (P = 0.015). Compared with the SMHN (+) group, the SMHN (−) group showed that UDCA, 7-KLCA, 3-DHCA, 7-KDCA, ISOLCA and α-MCA in feces, r-MCA, 7-KLCA and 7-KDCA in serum, γ-MCA and 7-KLCA in portal vein were enriched, and TUDCA in feces was depleted. PCoA analysis showed significantly distinct overall microbial composition in two groups (P = 0.026). Co-abundance analysis showed that bacterial species formed strong and broad relationships with BAs. Among them, Parabacteroides distasonis had the highest node degree. We further identified a combinatorial marker panel with a high AUC of 0.92.

Discussion

Our study demonstrated the changes and interactions of intestinal microbiome and BAs during enterohepatic circulation in ACLF patients with SMHN. In addition, we identified a combinatorial marker panel as non-invasive biomarkers to distinguish the SMHN status with high AUC.
Metabolomics of infectious diseases in the era of personalized medicine
Authors: Rahman Mahbuba , Schellhorn Herb E.
Published: May 2023

Infectious diseases continue to be a major cause of morbidity and mortality worldwide. Diseases cause perturbation of the host’s immune system provoking a response that involves genes, proteins and metabolites. While genes are regulated by epigenetic or other host factors, proteins can undergo post-translational modification to enable/modify function. As a result, it is difficult to correlate the disease phenotype based solely on genetic and proteomic information only. Metabolites, however, can provide direct information on the biochemical activity during diseased state. Therefore, metabolites may, potentially, represent a phenotypic signature of a diseased state. Measuring and assessing metabolites in large scale falls under the omics technology known as “metabolomics”. Comprehensive and/or specific metabolic profiling in biological fluids can be used as biomarkers of disease diagnosis. In addition, metabolomics together with genomics can be used to differentiate patients with differential treatment response and development of host targeted therapy instead of pathogen targeted therapy where pathogens are more prone to mutation and lead to antimicrobial resistance. Thus, metabolomics can be used for patient stratification, personalized drug formulation and disease control and management. Currently, several therapeutics and in vitro diagnostics kits have been approved by US Food and Drug Administration (FDA) for personalized treatment and diagnosis of infectious diseases. However, the actual number of therapeutics or diagnostics kits required for tailored treatment is limited as metabolomics and personalized medicine require the involvement of personnel from multidisciplinary fields ranging from technological development, bioscience, bioinformatics, biostatistics, clinicians, and biotechnology companies. Given the significance of metabolomics, in this review, we discussed different aspects of metabolomics particularly potentials of metabolomics as diagnostic biomarkers and use of small molecules for host targeted treatment for infectious diseases, and their scopes and challenges in personalized medicine.
The association between cognitive impairment, gait speed, and Walk ratio
Authors: Knapstad Mari Kalland , Naterstad Ingvill , Bogen Bård
Published: May 2023

Background

Gait speed has been found to be associated with cognitive function. However, gait speed is an unspecific measure that may not be informative about gait patterns. The Walk ratio (step length divided by step frequency) can be measured without specialized equipment, and has been suggested as an indicator of central gait control. However, the association with cognitive function is unknown.

Research question

Is there a relationship between Walk ratio and cognitive function, and gait speed and cognitive function?

Methods

This was a systematic literature review of studies where spatiotemporal gait parameters was reported in populations with cognitive impairment. The search was performed through PubMed, PEDro, AMED, Cochrane, Embase, MEDLINE, and PsycINFO. The studies had to contain either the Walk ratio, or report average step length and average step frequency. In the latter case, the average step length was divided by the average step frequency. The studies also had to report gait speed and the minimal mental state examination (MMSE). Studies testing patients on treadmills or that did not state the exclusion of patients with neurologic or orthopedic diseases, possible affecting gait ability, were excluded.

Results

A total of 24 studies were included, consisting of 909 patients with cognitive impairment and 4,108 healthy controls. The patient group had a lower Walk ratio (mean difference 0.07, p ≤ 0.001) and gait speed (mean difference 0.26, p ≤ 0.001) than the healthy controls. Using linear regression models, we found an association between the MMSE and the Walk ratio (R2 = 0.29, p < 0.001) and gait speed (R2 = 0.41, p < 0.001) in separate, unadjusted models. In a final model with Walk ratio, gait speed and age, Walk ratio was not significantly associated with MMSE, while gait speed was.

Significance

Our results suggest that preferred gait speed may be preferable to the Walk ratio when assessing older adults with cognitive impairment.
Intermittent theta burst stimulation attenuates oxidative stress and reactive astrogliosis in the streptozotocin-induced model of Alzheimer’s disease-like pathology
Authors: Stanojevic Jelena B. , Zeljkovic Milica , Dragic Milorad , Stojanovic Ivana R. , Ilic Tihomir V. , Stevanovic Ivana D. , Ninkovic Milica B.
Published: May 2023

Introduction

Intracerebroventricularly (icv) injected streptozotocin (STZ) is a widely used model for sporadic Alzheimer’s disease (sAD)-like pathology, marked by oxidative stress-mediated pathological progression. Intermittent theta burst stimulation (iTBS) is a noninvasive technique for brain activity stimulation with the ability to induce long-term potentiation-like plasticity and represents a promising treatment for several neurological diseases, including AD. The present study aims to investigate the effect of the iTBS protocol on the animal model of STZ-induced sAD-like pathology in the context of antioxidant, anti-inflammatory, and anti-amyloidogenic effects in the cortex, striatum, hippocampus, and cerebellum.

Methods

Male Wistar rats were divided into four experimental groups: control (icv normal saline solution), STZ (icv STZ—3 mg/kg), STZ + iTBS (STZ rats subjected to iTBS protocol), and STZ + Placebo (STZ animals subjected to placebo iTBS noise artifact). Biochemical assays and immunofluorescence microscopy were used to evaluate functional and structural changes.

Results

The icv STZ administration induces oxidative stress and attenuates antioxidative capacity in all examined brain regions. iTBS treatment significantly reduced oxidative and nitrosative stress parameters. Also, iTBS decreased Aβ-1-42and APP levels. The iTBS enhances antioxidative capacity reported as elevated activity of its enzymatic and non-enzymatic components. In addition, iTBS elevated BDNF expression and attenuated STZ-induced astrogliosis confirmed by decreased GFAP+/VIM+/C3+cell reactivity in the hippocampus.

Discussion

Our results provide experimental evidence for the beneficial effects of the applied iTBS protocol in attenuating oxidative stress, increasing antioxidant capacity and decreasing reactive astrogliosis in STZ-administrated rats.
Behavioral domains in compulsive rats: implications for understanding compulsive spectrum disorders
Authors: Martín-González Elena , Olmedo-Córdoba Manuela , Prados-Pardo Ángeles , Cruz-Garzón Daniel J. , Flores Pilar , Mora Santiago , Moreno-Montoya Margarita
Published: May 2023

Introduction

Compulsive behavior has been proposed as a transdiagnostic trait observed in different neuropsychiatric disorders, such as obsessive-compulsive disorder, autism, and schizophrenia. Research Domain Criteria (RDoC) strategy could help to disentangle the neuropsychological basis of compulsivity for developing new therapeutic and preventive approaches. In preclinical research, the selection of high-drinker (HD) vs. low-drinker (LD) animals by schedule-induced polydipsia (SIP) is considered a putative model of compulsivity, which includes a well-differentiated behavioral pattern.

Methods

The purpose of this research was to assess the cognitive control and the negative valence system domains in a phenotype of compulsive HD rats. After the selection of animals as HD or LD, we assessed behavioral inflexibility by probabilistic spatial reversal learning (PSRL), motor and cognitive impulsivity by variable delay-to-signal (VDS), and risky decision-making by rodent gambling task (rGT).

Results

HD rats performed fewer reversals and showed less probability of pressing the same lever that was previously reinforced on PSRL, more premature responses after the exposure to longer delays on VDS, and more disadvantageous risky choices on rGT. Moreover, HD animals performed more perseverative responses under the punishment period on rGT.

Discussion

These results highlight that HD compulsive phenotype exhibits behavioral inflexibility, insensitivity to positive feedback, waiting impulsivity, risky decision-making, and frustrative non-reward responsiveness. Moreover, these findings demonstrate the importance of mapping different behavioral domains to prevent, treat, and diagnose compulsive spectrum disorders correctly.
Development and characterization of novel jGCaMP8f calcium sensor variants with improved kinetics and fluorescence response range
Authors: Tran Oanh , Hughes Holly J. , Carter Tom , Török Katalin
Published: May 2023

Introduction

Genetically encoded biosensors for monitoring intracellular calcium changes have advanced our understanding of cell signaling and neuronal activity patterns in health and disease. Successful application of GCaMP biosensors to a wide range of biological questions requires that sensor properties such as brightness and dynamic range, ligand affinity and response kinetics be tuned to the specific conditions or phenomena to be investigated. Random as well as rational targeted mutations of such sensor molecules have led to a number of important breakthroughs in this field, including the calcium sensors GCaMP6f and GCaMP6fu. jGCaMP8f of the most recently developed generation is promising a step-change in in vivo imaging with further increased fluorescence dynamic range. Here, we critically examine the biophysical properties of jGCaMP8f and report development by rational design of two novel variants of jGCaMP8f.

Methods

We determined the in vitro biophysical properties of jGCaMP8f and selected variants by fluorescence spectroscopies and compared their performance monitoring intracellular Ca2+ transients with previously developed fast and bright GCaMP sensors by live cell imaging.

Results

We demonstrate that the physiologically highly relevant Mg2+ not only majorly affects the kinetic responses of GCaMPs but also their brightness and fluorescence dynamic range. We developed novel variants jGCaMP8f L27A which has threefold faster off-kinetics and jGCaMP8f F366H which shows a ∼3-fold greater dynamic range than jGCaMP8f, in vitro as well as in HEK293T cells and endothelial cell line HUVEC in response to ATP stimulation.

Discussion

We discuss the importance of optimization of biosensors for studying neurobiology in the context of the novel variants of jGCaMP8f. The jGCaMP8f F366H variant with a large dynamic range has the potential to improve in vivo imaging outcomes with increased signal-to-noise ratio. The L27A variant with faster kinetics than jGCaMP8f has larger cellular responses than previous fast GCaMP variants. The jGCaMP8f generation and novel improved variants presented here will further increase the application potential of GECIs in health and disease.
Causal relationship between ischemic stroke and its subtypes and frozen shoulder: a two-sample Mendelian randomization analysis
Authors: Lv Xiaofeng , Hu Zeng , Liang Fangqi , Liu Shanshan , Gong Haiping , Du Jihang , Deng Xinmin , Qian Jun-Hui , Nie Qian , Luo Jian
Published: May 2023

Background

Previous epidemiological and other studies have shown an association between ischemic stroke (IS) and frozen shoulder (FS). However, the causal relationship between them remains unclear. Therefore, the present study aimed to investigate the causal relationship between IS and FS using a two-sample Mendelian randomization method.

Methods

Our research was divided into two stages: discovery and replication. The data were extracted from publicly available genome-wide association studies (GWAS). We selected a large sample of IS (n = 440, 328) and its subtypes (large-artery atherosclerotic stroke (LAS), cardioembolic stroke (CES), and stroke caused by small-vessel disease (SVS) and lacunar stroke (n = 254, 959) as exposure data. Additionally, we selected a large sample of FS as outcome data (n = 451, 099). Inverse variance weighting (IVW) was applied as the primary analysis method. The weighted median, MR-Egger, simple model, and weighted model were used as complementary analysis methods to assess causal effects. Moreover, heterogeneity was analyzed using Cochran's Q-test with IVW and MR-Egger. The MR-Egger intercept and MR-PRESSO analysis methods were used for pleiotropy testing. The stability of the results was also assessed using a leave-one-out analysis.

Results

In the discovery stage, the IVW approach revealed an odds ratio (OR) of 1.207 with a 95% confidence interval (CI) of 1.027–1.417 and a P-value of 0.022. This suggests a causal association between IS levels and an increased risk of FS. In the subtype studies of IS, the findings were negative. However, during the replication stage, a significant causal link was found between selected lacunar strokes and FS with an OR of 1.252, a 95% CI of 1.105–1.419, and a P-value of 0.0004. All studies had no pleiotropy or heterogeneity, and the findings were robust.

Conclusions

Our study confirmed the causal relationship between any IS level and increased risk of FS. Furthermore, the same results were obtained in the replication stage with lacunar stroke as an exposure factor. However, there was no direct causal relationship between the subtypes of IS and FS. Our study provides theoretical support for shoulder care for patients with IS.
Auditory P300 in individuals with high schizotypy: associations of schizotypal traits with amplitude and latency under different oddball conditions
Authors: Deng Jue , Chen Siwei , Ou Yuanhua , Zhang Yuanjun , Lin Ziyue , Shen Yane , Ye Yiduo
Published: May 2023

Background

The aim of this study was to compare the characteristics of auditory P300 between non-clinical individuals with high and low schizotypal traits, and investigate the relationship between schizotypy and P300 under various oddball conditions.

Methods

An extreme-group design was adopted. After screening 1,519 young adults using the Schizotypal Personality Questionnaire (SPQ), sixty-three participants were chosen and divided into two groups (schizotypy group: 31 participants; control group: 32 participants). Basic demographic information was assessed and matched between groups. Depression and anxiety indexes were evaluated and controlled. The P300 component was evoked by an auditory oddball paradigm with different frequencies and durations.

Results

(1) The duration P300 amplitude at PZ site was significantly weaker in the schizotypy group than in the control group [F(1,54) = 7.455, p = 0.009, ηp2 = 0.121]. (2) In the schizotypy group, the latency of frequency P300 at PZ site under large-variant oddball condition was significantly correlated with total SPQ scores (rp = 0.451, p = 0.018) and disorganized dimension scores (rp = 0.381, p = 0.050). (3) In the control group, significantly negative correlations was found between the negative dimension score of SPQ and the frequency P300 amplitudes under small variant condition (PZ: rp = −0.393, p = 0.043; CPZ: rp = −0.406, p = 0.035). In addition, a significant negative relationship was found between disorganized dimension scores and the duration P300 latency at CPZ site under large-variant oddball condition (rp = −0.518, p = 0.006). Moreover, a significant negative association was found between the duration P300 amplitude at CPZ site under small-variant oddball condition and negative factor scores (rp = −0.410, p = 0.034).

Conclusion

Individuals with high schizotypal traits were likely to have deficient attention and hypoactive working memory for processing auditory information, especially the duration of sounds. P300 effects were correlated with negative and disorganized schizotypy, rather than positive schizotypy. There were diverse patterns of relationship between schizotypal traits and P300 under different oddball conditions, suggesting that characteristics and parameters of target stimuli should be considered cautiously when implementing an auditory oddball paradigm for individuals with schizophrenia spectrum.
Association between DRD2/ANKK1 rs1800497 C > T polymorphism and post-traumatic stress disorder susceptibility: a multivariate meta-analysis
Authors: Niu Yu-Ming , Zhang Jie , Tang Hong , Cao Lu-Hua , Jiang Ting-Yun , Hu Yuan-Yuan
Published: May 2023

Background

Previous studies have suggested that the DRD2/ANKK1 rs1800497 C > T polymorphism plays a critical role in the risk of post-traumatic stress disorder (PTSD). However, published data are inconsistent or even contradictory. Therefore, we conducted a meta-analysis to explore the underlying correlation between the rs1800497 C > T polymorphism and PTSD risk.

Materials and methods

A total of five online databases were searched, and all related studies were reviewed up to 1 October 2022. Critical information was extracted, and quality assessment was conducted for all included studies. Multivariate meta-analyses were performed for the genetic model choice, and the odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to examine the statistical power of the genetic models. In addition, heterogeneity, sensitivity, cumulative analysis, and publication bias were analyzed to guarantee statistical power.

Result

Overall, 12 observational studies involving 5,515 subjects were included and analyzed in this meta-analysis. Multivariate analysis indicated that a co-dominant genetic model was most likely the best choice. Pooled results revealed an elevated PTSD risk in mutated homozygote TT carriers in the general population (TT vs. CC: OR = 1.73, 95% CI = 1.14–2.62, P = 0.01, I2 = 58.9%) and other specific subgroups. Moreover, similar results were observed in other genetic models using univariate analysis.

Conclusion

Current evidence suggests that the DRD2/ANKK1 rs1800497 C > T polymorphism may contribute to PTSD susceptibility.
Pharmaceutical prospects of Silymarin for the treatment of neurological patients: an updated insight
Authors: Ranjan Shovit , Gautam Akash
Published: May 2023

Background

Silymarin is a polyphenolic flavonoid complex extricated from dried fruits and seeds of the plant Silybum marianum L. Chemically, it is a mixture of flavonolignan complexes consisting of silybin, isosilybin, silychristin, silydianin, a minor quantity of taxifolin, and other polyphenolic compounds, which possess different bio medicinal values.

Purpose

This review critically looks into the current status, pharmaceutical prospects and limitations of the clinical application of Silymarin for treating neurological disorders. In particular, Silymarin’s medicinal properties and molecular mechanisms are focused on providing a better-compiled understanding helpful in its neuro-pharmacological or therapeutic aspects.

Methods

This review was compiled by the literature search done using three databases, i.e., PubMed (Medline), EMBASE and Science Direct, up to January 2023, using the keywords-Silymarin, neurological disorders, cognitive disorders, Type 2 Diabetes, pharmaceutical prospects and treatment. Then, potentially relevant publications and studies (matching the eligible criteria) were retrieved and selected to explain in this review using PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) study flow chart.

Result

Since its discovery, it has been widely studied as a hepatoprotective drug for various liver disorders. However, in the last 10–15 years, several research studies have shown its putative neuroprotective nature against various brain disorders, including psychiatric, neurodegenerative, cognitive, metabolic and other neurological disorders. The main underlying neuroprotective mechanisms in preventing and curing such disorders are the antioxidant, anti-inflammatory, anti-apoptotic, pro-neurotrophic and pro-estrogenic nature of the bioactive molecules.

Conclusion

This review provides a lucid summary of the well-studied neuroprotective effects of Silymarin, its underlying molecular mechanisms and current limitations for its usage during neurological disorders. Finally, we have suggested a future course of action for developing it as a novel herbal drug for the treatment of brain diseases.