bluuebunny/crossref_metadata_2025 huggingface dataset:
Analyses of thymocyte commitment to regulatory T cell lineage in thymus of healthy subjects and patients with 22q11.2 deletion syndrome
Authors: Borna Simon , Dejene Beruh , Lakshmanan Uma , Schulze Janika , Weinberg Kenneth , Bacchetta Rosa
Published: March 2023

The Chromosome 22q11.2 deletion syndrome (22q11.2DS) results in an inborn error of immunity due to defective thymic organogenesis. Immunological abnormalities in 22q11.2DS patients are thymic hypoplasia, reduced output of T lymphocytes by the thymus, immunodeficiency and increased incidence of autoimmunity. While the precise mechanism responsible for increased incidence of autoimmunity is not completely understood, a previous study suggested a defect in regulatory T cells (Treg) cell lineage commitment during T cell development in thymus. Here, we aimed to analyze this defect in more detail. Since Treg development in human is still ill-defined, we first analyzed where Treg lineage commitment occurs. We performed systematic epigenetic analyses of the Treg specific demethylation region (TSDR) of the FOXP3 gene in sorted thymocytes at different developmental stages. We defined CD3+CD4+CD8+ FOXP3+CD25+ as the T cell developmental stage in human where TSDR demethylation first occurs. Using this knowledge, we analyzed the intrathymic defect in Treg development in 22q11.2DS patients by combination of TSDR, CD3, CD4, CD8 locus epigenetics and multicolor flow cytometry. Our data showed no significant differences in Treg cell frequencies nor in their basic phenotype. Collectively, these data suggest that although 22q11.2DS patients present with reduced thymic size and T cell output, the frequencies and the phenotype of Treg cell at each developmental stage are surprisingly well preserved.
Identification of a novel immune landscape signature as effective diagnostic markers related to immune cell infiltration in diabetic nephropathy
Authors: Zhou Huandi , Mu Lin , Yang Zhifen , Shi Yonghong
Published: March 2023

Background

The study aimed to identify core biomarkers related to diagnosis and immune microenvironment regulation and explore the immune molecular mechanism of diabetic nephropathy (DN) through bioinformatics analysis.

Methods

GSE30529, GSE99325, and GSE104954 were merged with removing batch effects, and different expression genes (DEGs) were screened at a criterion |log2FC| >0.5 and adjusted P <0.05. KEGG, GO, and GSEA analyses were performed. Hub genes were screened by conducting PPI networks and calculating node genes using five algorithms with CytoHubba, followed by LASSO and ROC analysis to accurately identify diagnostic biomarkers. In addition, two different GEO datasets, GSE175759 and GSE47184, and an experiment cohort with 30 controls and 40 DN patients detected by IHC, were used to validate the biomarkers. Moreover, ssGSEA was performed to analyze the immune microenvironment in DN. Wilcoxon test and LASSO regression were used to determine the core immune signatures. The correlation between biomarkers and crucial immune signatures was calculated by Spearman analysis. Finally, cMap was used to explore potential drugs treating renal tubule injury in DN patients.

Results

A total of 509 DEGs, including 338 upregulated and 171 downregulated genes, were screened out. “chemokine signaling pathway” and “cell adhesion molecules” were enriched in both GSEA and KEGG analysis. CCR2, CX3CR1, and SELP, especially for the combination model of the three genes, were identified as core biomarkers with high diagnostic capabilities with striking AUC, sensitivity, and specificity in both merged and validated datasets and IHC validation. Immune infiltration analysis showed a notable infiltration advantage for APC co-stimulation, CD8+ T cells, checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation in the DN group. In addition, the correlation analysis showed that CCR2, CX3CR1, and SELP were strongly and positively correlated with checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation in the DN group. Finally, dilazep was screened out as an underlying compound for DN analyzed by CMap.

Conclusions

CCR2, CX3CR1, and SELP are underlying diagnostic biomarkers for DN, especially in their combination. APC co-stimulation, CD8+ T cells, checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation may participate in the occurrence and development of DN. At last, dilazep may be a promising drug for treating DN.
Case report: Targeting the PD-1 receptor and genetic mutations validated in primary histiocytic sarcoma with hemophagocytic lymphohistiocytosis
Authors: Zhao Yan , Deng Yating , Jiang Yi , Zheng Wenli , Tan Yanlin , Yang Zhiwu , Wang Zhihua , Xu Feng , Cheng Zhao , Yuan Lingli , Peng Hongling
Published: March 2023

Histiocytic sarcoma (HS) is a rare hematological malignancy with limited treatment options, and it is also prone to complications such as hemophagocytic lymphohistiocytosis (HLH) in the later stages of the disease, leading to difficulties in treatment and poor prognosis. It highlights the importance of developing novel therapeutic agents. Herein, we present a case of a 45-year-old male patient who was diagnosed with PD-L1-positive HS with HLH. The patient was admitted to our hospital with recurrent high fever, multiple skin rashes with pruritus throughout the body and enlarged lymph nodes. Subsequently, pathological biopsy of the lymph nodes revealed high expression of CD163, CD68, S100, Lys and CD34 in the tumor cells and no expression of CD1a and CD207, confirming this rare clinical diagnosis. Concerning the low remission rate by conventional treatment in this disease, the patient was administered with sintilimab (an anti-programmed cell death 1 [anti-PD-1] monoclonal antibody) at 200 mg/d combined with a first-line chemotherapy regimen for one cycle. Further exploration of pathological biopsy by using next-generation gene sequencing led to the use of targeted therapy of chidamide. After one cycle of combination therapy (chidamide+sintilimab, abbreviated as CS), the patient achieved a favorable response. The patient showed remarkable improvement in the general symptoms and laboratory examination results (e.g., elevated indicators of inflammation); even the clinical benefits was not persistent, he survived one more month after his cessation of treatment by himself due to economic difficulty. Our case suggests that PD-1 inhibitor coupled with targeted therapy might constitute a potential therapeutic option for primary HS with HLH.
Pre-existing immunity to SARS-CoV-2 before the COVID-19 pandemic era in Cameroon: A comparative analysis according to HIV-status
Authors: Aissatou Abba , Fokam Joseph , Semengue Ezechiel Ngoufack Jagni , Takou Désiré , Ka’e Aude Christelle , Ambe Collins Chenwi , Nka Alex Durand , Djupsa Sandrine Claire , Beloumou Grâce , Ciaffi Laura , Tchouaket Michel Carlos Tommo , Nayang Audrey Rachel Mundo , Pabo Willy Leroi Togna , Essomba René Ghislain , Halle Edie G. E. , Okomo Marie-Claire , Bissek Anne-Cecile ZK. , Leke Rose , Boum Yap , Mballa Georges Alain Etoundi , Montesano Carla , Perno Carlo-Federico , Colizzi Vittorio , Ndjolo Alexis
Published: March 2023

Background

The lower burden of COVID-19 in tropical settings may be due to preexisting cross-immunity, which might vary according to geographical locations and potential exposure to other pathogens. We sought to assess the overall prevalence of SARS-CoV-2 antibodies and determine SARS-CoV-2 seropositivity according to HIV-status before the COVID-19 pandemic era.

Methods

A cross-sectional and comparative study was conducted at the Chantal BIYA International Reference Centre (CIRCB) on 288 stored plasma samples (163 HIV-positive versus 125 HIV-negative); all collected in 2017-2018, before the COVID-19 pandemic era. Abbott Panbio™ COVID-19 IgG/IgM assay was used for detecting SARS-CoV-2 immunoglobulin G (IgG) and M (IgM). Among people living with HIV (PLHIV), HIV-1 viral load and TCD4 cell count (LTCD4) were measured using Abbott Real Time PCR and BD FACSCalibur respectively. Statistical analyses were performed, with p<0.05 considered statistically significant.

Results

The median [IQR] age was 25 [15-38] years. Overall seropositivity to SARS-CoV-2 antibodies was 13.5% (39/288) of which 7.3% (21) was IgG, 7.3% (21) IgM and 1.0% (3) IgG/IgM. According to HIV-status in the study population, SARS-CoV-2 seropositivity was 11.0% (18/163) among HIV-positive versus 16.8% (21/125) among HIV-negative respectively, p=0.21. Specifically, IgG was 6.1% (10/163) versus 8.8% (11/125), p=0.26; IgM was 5.5% (9/163) versus 9.6%, (12/125), p=0.13 and IgG/IgM was 0.6% (1/163) versus 1.6% (2/125) respectively. Among PLHIV, SARS-CoV-2 seropositivity according to CD4 count was 9.2% (≥500 cells/µL) versus 1.8% (200-499 cells/µL), (OR=3.5; p=0.04) and 0.6% (<200 cells/µL), (OR=17.7; p<0.01). According to viral load, SARS-CoV-2 seropositivity was 6.7% (≥40 copies/mL) versus 4.9% (<40 copies/mL), (OR= 3.8; p<0.01).

Conclusion

Before COVID-19 in Cameroon, cross-reactive antibodies to SARS-CoV-2 were in circulation, indicating COVID-19 preexisting immunity. This preexisting immunity may contribute in attenuating disease severity in tropical settings like Cameroon. Of relevance, COVID-19 preexisting immunity is lower with HIV-infection, specifically with viral replication and poor CD4-cell count. As poor CD4-count leads to lower cross-reactive antibodies (regardless of viral load), people living with HIV appear more vulnerable to COVID-19 and should be prioritized for vaccination.
Comprehensive evaluation of corroded grounding electrodes considering the impulse characteristics
Authors: Wang Xuemeng , Xiong Lan , Zhang Zhanlong , Dan Yihua , Deng Jun
Published: March 2023

The grounding electrodes are buried in a harsh soil environment, which will cause corrosion. Corroded grounding electrodes directly affect the safe and stable operation of the power system. Therefore, it is particularly important to detect the corrosion degree of the grounding electrodes accurately. The existing methods have the following problems: 1) Power-frequency grounding resistance is used as a single criterion, and lack of considering the impulse characteristics, which is difficult to accurately judge the corrosion degree and could cause a potential safety hazard. 2) Lacking considering the environmental PH value, water content, salt content, and other factors of the buried soil, which is easy to lead to misjudgment of corrosion degree. To solve the problems, this paper studies a comprehensive evaluation of corroded grounding electrodes considering impulse characteristics. Based on thermal stability, impulse characteristics, and power frequency characteristics, the minimum safety diameter of grounding electrodes and the factors that affect the corrosion of the soil environment are studied. According to the relationship between each evaluation factors and corrosivity, the membership is calculated and combined with the comprehensive weight determined by the sum of the squares of deviation. The fuzzy evaluation method is adopted to obtain the corrosive evaluation matrix Y, and the corrosive index C is proposed to quantify the corrosive strength. Combined with the minimum safety diameter, the residual life range of the grounding electrodes is predicted and the corrosion degree is divided. Finally, a comprehensive corrosion evaluation algorithm considering impulse characteristics is proposed. The results show that this method not only considers the soil environmental factors but also considers the grounding characteristics of the grounding electrodes, especially the impulse characteristics. This method is more comprehensive than other evaluation methods which only consider the soil environment and can realize trenchless corrosion detection of grounding electrodes. Therefore, the contribution of this work is of great significance to the operation and maintenance of tower grounding electrodes.
Facile fabrication of flexible and adhesive micro-supercapacitor tapes from conducting polymer solution for self-powered wearable sensing system
Authors: Yuan Wenxiong , Zhao Chen , Zhang Xiaoxian , Min Yonggang , Shu Kewei
Published: March 2023

Flexible micro-supercapacitor (MSC) with in-plane electrodes has attracted significant attention as microscale energy storage device. Especially, flexible MSCs with adhesion properties are of great interest for wearable electronics. Here, we demonstrate a facile and cost-effective mask-assisted drop-casting method to fabricate adhesive MSC on medical tape using dimethyl sulfoxide (DMSO) doped poly (3,4-ethylenedioxythiophene):poly (styrenesulfonate) (PEDOT:PSS) aqueous solution. The fabricated MSC with poly (vinyl alcohol)/H3PO4 gel electrolyte exhibits an areal specific capacitance of 10.96 mF cm−2 at a current density of 0.1 mA cm−2 with excellent mechanical flexibility. The MSC can be attached on various substrates due to the stickiness of the medical tape. For practical application, the MSC can be coupled with a solar cell to achieve a stand-alone power supply system for a flex senor in monitoring finger movements. Therefore, we believe that the mask-assisted drop-casting method paves a new way to develop flexible and adhesive MSCs for self-powered integrated wearable electronics.
First comparative genomic characterization of the MSSA ST398 lineage detected in aquaculture and other reservoirs
Authors: Salgueiro Vanessa , Manageiro Vera , Bandarra Narcisa M. , Ferreira Eugénia , Clemente Lurdes , Caniça Manuela
Published: March 2023

Staphylococcus aureus ST398 can cause diseases in several different animals. In this study we analyzed ten S. aureus ST398 previously collected in three different reservoirs in Portugal (humans, gilthead seabream from aquaculture and dolphin from a zoo). Strains tested against sixteen antibiotics, by disk diffusion or minimum inhibitory concentration, showed decreased susceptibility to benzylpenicillin (all strains from gilthead seabream and dolphin) and to erythromycin with an iMLSB phenotype (nine strains), and susceptibility to cefoxitin (methicillin-susceptible S. aureus, MSSA). All strains from aquaculture belonged to the same spa type, t2383, whereas strains from the dolphin and humans belonged to spa type t571. A more detailed analysis using single nucleotide polymorphisms (SNPs)-based tree and a heat map, showed that all strains from aquaculture origin were highly related with each other and the strains from dolphin and humans were more distinct, although they were very similar in ARG, VF and MGE content. Mutations F3I and A100V in glpT gene and D278E and E291D in murA gene were identified in nine fosfomycin susceptible strains. The blaZ gene was also detected in six of the seven animal strains. The study of the genetic environment of erm(T)-type (found in nine S. aureus strains) allowed the identification of MGE (rep13-type plasmids and IS431R-type), presumably involved in the mobilization of this gene. All strains showed genes encoding efflux pumps from major facilitator superfamily (e.g., arlR, lmrS-type and norA/B-type), ATP-binding cassettes (ABC; mgrA) and multidrug and toxic compound extrusion (MATE; mepA/R-type) families, all associated to decreased susceptibility to antibiotics/disinfectants. Moreover, genes related with tolerance to heavy metals (cadD), and several VF (e.g., scn, aur, hlgA/B/C and hlb) were also identified. Insertion sequences, prophages, and plasmids made up the mobilome, some of them associated with ARG, VF and genes related with tolerance to heavy metals. This study highlights that S. aureus ST398 can be a reservoir of several ARG, heavy metals resistance genes and VF, which are essential in the adaption and survival of the bacterium in the different environments and an active agent in its dissemination. It makes an important contribution to understanding the extent of the spread of antimicrobial resistance, as well as the virulome, mobilome and resistome of this dangerous lineage.
Alterations in the gut microbiome and metabolome profiles of septic mice treated with Shen FuHuang formula
Authors: He Shasha , Zhao Chunxia , Guo Yuhong , Zhao Jingxia , Xu Xiaolong , Hu Yahui , Lian Bo , Ye Haoran , Wang Ning , Luo Lianxiang , Liu Qingquan
Published: March 2023

Sepsis has a high mortality rate, and treating sepsis remains a significant challenge worldwide. In former studies, our group found that traditional Chinese medicine, Shen FuHuang formula (SFH), is a promising medicine in treating coronavirus disease 2019 (COVID-19) patients with the septic syndrome. However, the underlying mechanisms remain elusive. In the present study, we first investigated the therapeutic effects of SFH on septic mice. To investigate the mechanisms of SFH-treated sepsis, we identified the gut microbiome profile and exploited untargeted metabolomics analyses. The results demonstrated that SFH significantly enhanced the mice’s 7-day survival rate and hindered the release of inflammatory mediators, i.e., TNF-α, IL-6, and IL-1β. 16S rDNA sequencing further deciphered that SFH decreased the proportion of Campylobacterota and Proteobacteria at the phylum level. LEfSe analysis revealed that the treatment of SFH enriched Blautia while decreased Escherichia_Shigella. Furthermore, serum untargeted metabolomics analysis indicated that SFH could regulate the glucagon signaling pathway, PPAR signaling pathway, galactose metabolism, and pyrimidine metabolism. Finally, we found the relative abundance of Bacteroides, Lachnospiraceae_NK4A136_group, Escherichia_Shigella, Blautia, Ruminococcus, and Prevotella were closely related to the enrichment of the metabolic signaling pathways, including L-tryptophan, uracil, glucuronic acid, protocatechuic acid, and gamma-Glutamylcysteine. In conclusion, our study demonstrated that SFH alleviated sepsis by suppressing the inflammatory response and hence reduced mortality. The mechanism of SFH for treating sepsis may be ascribed to the enrichment of beneficial gut flora and modulation in glucagon signaling pathway, PPAR signaling pathway, galactose metabolism, and pyrimidine metabolism. To sum up, these findings provide a new scientific perspective for the clinical application of SFH in treating sepsis.
Rapid visualization of Clostridioides difficile toxins A and B by multiplex RPA combined with CRISPR-Cas12a
Authors: Jiang Tong , Hu Xinyi , Lin Chunhui , Xia Zhaoxin , Yang Wensu , Zhu Yi , Xu Huaming , Tang Hao , Shen Jilu
Published: March 2023

Purpose

Clostridioides difficile (C. difficile) infection is the most common cause of nosocomial infection, which is a severe challenge in modern medical care. Currently, many laboratory diagnostic methods for C. difficile are available, such as PCR, culture-based tests, and antigen-based tests. However, these methods are not suitable for rapid point-of-care testing (POCT). Therefore, it is of great significance to develop a rapid, sensitive, and cost-effective method to detect C. difficile toxin genes.

Methods

Recently, the development of clustered regularly interspaced short palindromic repeats (CRISPR) technology has emerged as a promising tool for rapid POCT. In this study, we developed a rapid and specific detection platform for dual C. difficile toxins by combining recombinase polymerase amplification (RPA) and CRISPR/Cas12a.

Results

The platform includes multiplex RPA-cas12a-fluorescence assay and multiplex RPA-cas12a-LFS (Lateral flow strip) assay, through which the detection limit for tcdA and tcdB was 10 copies/μL and 1 copy/μL, respectively. The results can be more clearly distinguished using a violet flashlight, which realized a portable visual readout. The platform can be tested within 50 min. Furthermore, our method did not cross-react with other pathogens that cause intestinal diarrhea. The results of 10 clinical samples using our method was 100% consistent with those from real-time PCR detection.

Conclusion

In conclusion, the CRISPR-based double toxin gene detection platform for C. difficile is an effective, specific, and sensitive detection method, which can be used as a powerful on-site detection tool for POCT in the future.
Analysis of synonymous codon usage patterns in mitochondrial genomes of nine Amanita species
Authors: Li Qiang , Luo Yingyong , Sha Ajia , Xiao Wenqi , Xiong Zhuang , Chen Xiaodie , He Jing , Peng Lianxin , Zou Liang
Published: March 2023

Introduction

Codon basis is a common and complex natural phenomenon observed in many kinds of organisms.

Methods

In the present study, we analyzed the base bias of 12 mitochondrial core protein-coding genes (PCGs) shared by nine Amanita species.

Results

The results showed that the codons of all Amanita species tended to end in A/T, demonstrating the preference of mitochondrial codons of Amanita species for a preference for this codon. In addition, we detected the correlation between codon base composition and the codon adaptation index (CAI), codon bias index (CBI), and frequency of optimal codons (FOP) indices, indicating the influence of base composition on codon bias. The average effective number of codons (ENC) of mitochondrial core PCGs of Amanita is 30.81, which is <35, demonstrating the strong codon preference of mitochondrial core PCGs of Amanita. The neutrality plot analysis and PR2-Bias plot analysis further demonstrated that natural selection plays an important role in Amanita codon bias. In addition, we obtained 5–10 optimal codons (ΔRSCU > 0.08 and RSCU > 1) in nine Amanita species, and GCA and AUU were the most widely used optimal codons. Based on the combined mitochondrial sequence and RSCU value, we deduced the genetic relationship between different Amanita species and found large variations between them.

Discussion

This study promoted the understanding of synonymous codon usage characteristics and evolution of this important fungal group.
Extracellular matrix stiffness—The central cue for skin fibrosis
Authors: Wang Kang , Wen Dongsheng , Xu Xuewen , Zhao Rui , Jiang Feipeng , Yuan Shengqin , Zhang Yifan , Gao Ya , Li Qingfeng
Published: March 2023

Skin fibrosis is a physiopathological process featuring the excessive deposition of extracellular matrix (ECM), which is the main architecture that provides structural support and constitutes the microenvironment for various cellular behaviors. Recently, increasing interest has been drawn to the relationship between the mechanical properties of the ECM and the initiation and modulation of skin fibrosis, with the engagement of a complex network of signaling pathways, the activation of mechanosensitive proteins, and changes in immunoregulation and metabolism. Simultaneous with the progression of skin fibrosis, the stiffness of ECM increases, which in turn perturbs mechanical and humoral homeostasis to drive cell fate toward an outcome that maintains and enhances the fibrosis process, thus forming a pro-fibrotic “positive feedback loop”. In this review, we highlighted the central role of the ECM and its dynamic changes at both the molecular and cellular levels in skin fibrosis. We paid special attention to signaling pathways regulated by mechanical cues in ECM remodeling. We also systematically summarized antifibrotic interventions targeting the ECM, hopefully enlightening new strategies for fibrotic diseases.
Using mass spectrometry imaging to visualize age-related subcellular disruption
Authors: Hogan Kelly A. , Zeidler Julianna D. , Beasley Heather K. , Alsaadi Abrar I. , Alshaheeb Abdulkareem A. , Chang Yi-Chin , Tian Hua , Hinton Antentor O. , McReynolds Melanie R.
Published: March 2023

Metabolic homeostasis balances the production and consumption of energetic molecules to maintain active, healthy cells. Cellular stress, which disrupts metabolism and leads to the loss of cellular homeostasis, is important in age-related diseases. We focus here on the role of organelle dysfunction in age-related diseases, including the roles of energy deficiencies, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, changes in metabolic flux in aging (e.g., Ca2+ and nicotinamide adenine dinucleotide), and alterations in the endoplasmic reticulum-mitochondria contact sites that regulate the trafficking of metabolites. Tools for single-cell resolution of metabolite pools and metabolic flux in animal models of aging and age-related diseases are urgently needed. High-resolution mass spectrometry imaging (MSI) provides a revolutionary approach for capturing the metabolic states of individual cells and cellular interactions without the dissociation of tissues. mass spectrometry imaging can be a powerful tool to elucidate the role of stress-induced cellular dysfunction in aging.
Prognostic role of the pretreatment systemic immune-inflammation index in patients with glioma: A meta-analysis
Authors: Zhang Sunhuan , Ni Qunqin
Published: March 2023

Background

The systemic immune-inflammation index (SII) has been recognized as the indicator that reflects the status of immune responses. The SII is related to the prognostic outcome of many malignancies, whereas its role in gliomas is controversial. For patients with glioma, we, therefore, conducted a meta-analysis to determine if the SII has a prognostic value.

Methods

Studies relevant to this topic were searched from 16 October 2022 in several databases. In patients with glioma, the relation of the SII level with the patient prognosis was analyzed based on hazard ratios (HRs) as well as corresponding 95% confidence intervals (CIs). Moreover, subgroup analysis was conducted to examine a possible heterogeneity source.

Results

There were eight articles involving 1,426 cases enrolled in the present meta-analysis. The increased SII level predicted the dismal overall survival (OS) (HR = 1.81, 95% CI = 1.55–2.12, p < 0.001) of glioma cases. Furthermore, an increased SII level also predicted the prognosis of progression-free survival (PFS) (HR = 1.87, 95% CI = 1.44–2.43, p < 0.001) in gliomas. An increased SII was significantly associated with a Ki-67 index of ≥30% (OR = 1.72, 95% CI = 1.10–2.69, p = 0.017). However, a high SII was not correlated with gender (OR = 1.05, 95% CI = 0.78–1.41, p = 0.734), KPS score (OR = 0.64, 95% CI = 0.17–2.37, p = 0.505), or symptom duration (OR 1.22, 95% CI 0.37–4.06, p = 0.745).

Conclusion

There was a significant relation between an increased SII level with poor OS and the PFS of glioma cases. Moreover, patients with glioma with a high SII value have a positive relationship with a Ki-67 of ≥30%.
Long-term neuropsychological outcomes in children with febrile infection-related epilepsy syndrome (FIRES) treated with anakinra
Authors: Shrestha Anima , Wood E. Lynne , Berrios-Siervo Gretchen , Stredny Coral M. , Boyer Katrina , Vega Clemente , Nangia Srishti , Muscal Eyal , Eschbach Krista
Published: March 2023

Background

Febrile-infection related epilepsy syndrome (FIRES) is a rare epilepsy syndrome in which a previously healthy individual develops refractory status epilepticus in the setting of a preceding febrile illness. There are limited data regarding detailed long-term outcomes. This study aims to describe the long-term neuropsychological outcomes in a series of pediatric patients with FIRES.

Methods

This is a retrospective multi-center case series of pediatric patients with a diagnosis of FIRES treated acutely with anakinra who had neuropsychological testing at least 12 months after status epilepticus onset. Each patient underwent comprehensive neuropsychological evaluation as part of routine clinical care. Additional data collection included the acute seizure presentation, medication exposures, and outcomes.

Results

There were six patients identified with a median age of 11.08 years (IQR: 8.19–11.23) at status epilepticus onset. Anakinra initiation was a median of 11 days (IQR: 9.25–13.50) after hospital admission. All patients had ongoing seizures and none of the patients returned to baseline cognitive function with a median follow-up of 40 months (IQR 35–51). Of the five patients with serial full-scale IQ testing, three demonstrated a decline in scores over time. Testing results revealed a diffuse pattern of deficits across domains and all patients required special education and/or accommodations for academic learning.

Conclusions

Despite treatment with anakinra, neuropsychological outcomes in this series of pediatric patients with FIRES demonstrated ongoing diffuse neurocognitive impairment. Future research will need to explore the predictors of long-term neurocognitive outcomes in patients with FIRES and to evaluate if acute treatment interventions improve these outcomes.
Evidence of polygenic regulation of the physiological presence of neurofilament light chain in human serum
Authors: Herrera-Rivero Marisol , Hofer Edith , Maceski Aleksandra , Leppert David , Benkert Pascal , Kuhle Jens , Schmidt Reinhold , Khalil Michael , Wiendl Heinz , Stoll Monika , Berger Klaus
Published: March 2023

Introduction

The measurement of neurofilament light chain (NfL) in blood is a promising biomarker of neurological injury and disease. We investigated the genetic factors that underlie serum NfL levels (sNfL) of individuals without neurological conditions.

Methods

We performed a discovery genome-wide association study (GWAS) of sNfL in participants of the German BiDirect Study (N = 1,899). A secondary GWAS for meta-analysis was performed in a small Austrian cohort (N = 287). Results from the meta-analysis were investigated in relation with several clinical variables in BiDirect.

Results

Our discovery GWAS identified 12 genomic loci at the suggestive threshold ((p < 1 × 10−5). After meta-analysis, 7 loci were suggestive of an association with sNfL. Genotype-specific differences in sNfL were observed for the lead variants of meta-analysis loci (rs34523114, rs114956339, rs529938, rs73198093, rs34372929, rs10982883, and rs1842909) in BiDirect participants. We identified potential associations in meta-analysis loci with markers of inflammation and renal function. At least 6 protein-coding genes (ACTG2, TPRKB, DMXL1, COL23A1, NAT1, and RIMS2) were suggested as genetic factors contributing to baseline sNfL levels.

Discussion

Our findings suggest that polygenic regulation of neuronal processes, inflammation, metabolism and clearance modulate the variability of NfL in the circulation. These could aid in the interpretation of sNfL measurements in a personalized manner.
Prediction of ground reaction forces and moments during walking in children with cerebral palsy
Authors: Kloeckner Julie , Visscher Rosa M. S. , Taylor William R. , Viehweger Elke , De Pieri Enrico
Published: March 2023

Introduction

Gait analysis is increasingly used to support clinical decision-making regarding diagnosis and treatment planning for movement disorders. As a key part of gait analysis, inverse dynamics can be applied to estimate internal loading conditions during movement, which is essential for understanding pathological gait patterns. The inverse dynamics calculation uses external kinetic information, normally collected using force plates. However, collection of external ground reaction forces (GRFs) and moments (GRMs) can be challenging, especially in subjects with movement disorders. In recent years, a musculoskeletal modeling-based approach has been developed to predict external kinetics from kinematic data, but its performance has not yet been evaluated for altered locomotor patterns such as toe-walking. Therefore, the goal of this study was to investigate how well this prediction method performs for gait in children with cerebral palsy.

Methods

The method was applied to 25 subjects with various forms of hemiplegic spastic locomotor patterns. Predicted GRFs and GRMs, in addition to associated joint kinetics derived using inverse dynamics, were statistically compared against those based on force plate measurements.

Results

The results showed that the performance of the predictive method was similar for the affected and unaffected limbs, with Pearson correlation coefficients between predicted and measured GRFs of 0.71–0.96, similar to those previously reported for healthy adults, despite the motor pathology and the inclusion of toes-walkers within our cohort. However, errors were amplified when calculating the resulting joint moments to an extent that could influence clinical interpretation.

Conclusion

To conclude, the musculoskeletal modeling-based approach for estimating external kinetics is promising for pathological gait, offering the possibility of estimating GRFs and GRMs without the need for force plate data. However, further development is needed before implementation within clinical settings becomes possible.
Binocular dynamic visual acuity in dry eye disease patients
Authors: Ren Xiaotong , Wang Yuexin , Wu Tingyi , Jing Dalan , Li Xuemin
Published: March 2023

Purpose

To investigate binocular dynamic visual acuity (DVA) for patients with dry eye disease (DED).

Methods

The prospective study included DED patients. The binocular DVA at 40 and 80 degrees per second (dps), Ocular Surface Disease Index (OSDI), tear meniscus height (TMH), tear film break-up time first (TBUTF), corneal fluorescein staining (CFS), eyelid margin abnormalities and meibomian gland (MG) abnormalities morphology and function were evaluated. A deep learning model was applied to quantify the MG area proportion. The correlation between DVA and DED parameters was analyzed.

Results

A total of 73 DED patients were enrolled. The age, OSDI, CFS, MG expressibility, secretion quality, and eyelid margin abnormalities were significantly positively correlated with the DVA for 40 and 80 dps (all P < 0.05). The MG area proportion in the upper eyelid was negatively correlated with DVA at 40 dps (R = −0.293, P < 0.001) and at 80 dps (R = −0.304, P < 0.001). Subgroup analysis by MG grade demonstrated that the DVA of patients with severe MG dropout (<25% of the total area) was significantly worse than other mild and moderate groups, both in 40 and 80 dps (all P < 0.05). The patients with CFS showed worse 40 (P < 0.001) and 80 dps (P < 0.001) DVA than the patients without CFS.

Conclusion

Binocular DVA is significantly associated with DED symptoms and signs. The DED patients with CFS and severe MG dropout and dysfunction have worse DVA.
Sex differences in hippocampal β-amyloid accumulation in the triple-transgenic mouse model of Alzheimer’s disease and the potential role of local estrogens
Authors: Hu Yu-Ting , Chen Xin-Lu , Zhang Ya-Nan , McGurran Hugo , Stormmesand Jochem , Breeuwsma Nicole , Sluiter Arja , Zhao Juan , Swaab Dick , Bao Ai-Min
Published: March 2023

Introduction

Epidemiological studies show that women have a higher prevalence of Alzheimer’s disease (AD) than men. Peripheral estrogen reduction during aging in women is proposed to play a key role in this sex-associated prevalence, however, the underlying mechanism remains elusive. We previously found that transcription factor early growth response-1 (EGR1) significantly regulates cholinergic function. EGR1 stimulates acetylcholinesterase (AChE) gene expression and is involved in AD pathogenesis. We aimed to investigate whether the triple-transgenic AD (3xTg-AD) mice harboring PS1M146V, APPSwe, and TauP301L show sex differences in β-amyloid (Aβ) and hyperphosphorylated tau (p-Tau), the two primary AD hallmarks, and how local 17β-estradiol (E2) may regulate the expression of EGR1 and AChE.

Methods

We first sacrificed male and female 3xTg-AD mice at 3–4, 7–8, and 11–12 months and measured the levels of Aβ, p-Tau, EGR1, and AChE in the hippocampal complex. Second, we infected SH-SY5Y cells with lentivirus containing the amyloid precursor protein construct C99, cultured with or without E2 administration we measured the levels of extracellular Aβ and intracellular EGR1 and AChE.

Results

Female 3xTg-AD mice had higher levels of Aβ compared to males, while no p-Tau was found in either group. In SH-SY5Y cells infected with lentivirus containing the amyloid precursor protein construct C99, we observed significantly increased extracellular Aβ and decreased expression of intracellular EGR1 and AChE. By adding E2 to the culture medium, extracellular Aβ(1–42) was significantly decreased while intracellular EGR1 and AChE expression were elevated.

Discussion

This data shows that the 3xTg-AD mouse model can be useful for studying the human sex differences of AD, but only in regards to Aβ. Furthermore, in vitro data shows local E2 may be protective for EGR1 and cholinergic functions in AD while suppressing soluble Aβ(1–42) levels. Altogether, this study provides further in vivo and in vitro data supporting the human epidemiological data indicating a higher prevalence of AD in women is related to changes in brain estrogen levels.
Effects of television viewing on brain structures and risk of dementia in the elderly: Longitudinal analyses
Authors: Takeuchi Hikaru , Kawashima Ryuta
Published: March 2023

Introduction

TV viewing in the elderly and in children is associated with subsequent greater decline of various cognitive functions including verbal working memory, but results of its association with subsequent risk of dementia were divided.

Methods

In this longitudinal cohort study of UK Biobank, we investigated the associations of TV viewing length with subsequent risk of dementia and longitudinal changes of brain structural measures after corrections of a wide range of potential confounders.

Results

Our results showed longer TV viewing was associated with increased risk of subsequent onset of dementia, as well as subsequent greater decline in intracellular volume fraction (ICVF) in the extensive areas of right lateral temporal cortex and the right medial temporal cortex, in the area around the left middle and inferior temporal cortex as well as the left fusiform gyrus, and the area adjacent to the left inferior frontal gyrus, and left insula.

Discussion

These results may suggest prolonged TV viewing was associated with decline in density of neurites (axon, dendrites) in areas particularly implicated in language, communication, and memory, which are altered in dementia.
Palmitoylation controls the stability of 190 kDa ankyrin-G in dendritic spines and is regulated by ZDHHC8 and lithium
Authors: Piguel Nicolas H. , Sanders Shaun S. , De Simone Francesca I. , Martin-de-Saavedra Maria D. , McCoig Emmarose , Dionisio Leonardo E. , Smith Katharine R. , Thomas Gareth M. , Penzes Peter
Published: March 2023

Introduction

AnkG, encoded by the ANK3 gene, is a multifunctional scaffold protein with complex isoform expression: the 480 and 270 kDa isoforms have roles at the axon initial segment and node of Ranvier, whereas the 190 kDa isoform (AnkG-190) has an emerging role in the dendritic shaft and spine heads. All isoforms of AnkG undergo palmitoylation, a post-translational modification regulating protein attachment to lipid membranes. However, palmitoylation of AnkG-190 has not been investigated in dendritic spines. The ANK3 gene and altered expression of AnkG proteins are associated with a variety of neuropsychiatric and neurodevelopmental disorders including bipolar disorder and are implicated in the lithium response, a commonly used mood stabilizer for bipolar disorder patients, although the precise mechanisms involved are unknown.

Result

Here, we showed that Cys70 palmitoylation stabilizes the localization of AnkG-190 in spine heads and at dendritic plasma membrane nanodomains. Mutation of Cys70 impairs AnkG-190 function in dendritic spines and alters PSD-95 scaffolding. Interestingly, we find that lithium reduces AnkG-190 palmitoylation thereby increasing its mobility in dendritic spines. Finally, we demonstrate that the palmitoyl acyl transferase ZDHHC8, but not ZDHHC5, increases AnkG-190 stability in spine heads and is inhibited by lithium.

Discussion

Together, our data reveal that palmitoylation is critical for AnkG-190 localization and function and a potential ZDHHC8/AnkG-190 mechanism linking AnkG-190 mobility to the neuronal effects of lithium.
Anti-cancer potential of synergistic phytochemical combinations is influenced by the genetic profile of prostate cancer cell lines
Authors: Gano Carol A. , Fatima Shadma , Failes Timothy W. , Arndt Gregory M. , Sajinovic Mila , Mahns David , Saedisomeolia Ahmad , Coorssen Jens R. , Bucci Joseph , de Souza Paul , Vafaee Fatemeh , Scott Kieran F.
Published: March 2023

Introduction

Despite strong epidemiological evidence that dietary factors modulate cancer risk, cancer control through dietary intervention has been a largely intractable goal for over sixty years. The effect of tumour genotype on synergy is largely unexplored.

Methods

The effect of seven dietary phytochemicals, quercetin (0–100 μM), curcumin (0–80 μM), genistein, indole-3-carbinol (I3C), equol, resveratrol and epigallocatechin gallate (EGCG) (each 0–200 μM), alone and in all paired combinations om cell viability of the androgen-responsive, pTEN-null (LNCaP), androgen-independent, pTEN-null (PC-3) or androgen-independent, pTEN-positive (DU145) prostate cancer (PCa) cell lines was determined using a high throughput alamarBlue® assay. Synergy, additivity and antagonism were modelled using Bliss additivism and highest single agent equations. Patterns of maximum synergy were identified by polygonogram analysis. Network pharmacology approaches were used to identify interactions with known PCa protein targets.

Results

Synergy was observed with all combinations. In LNCaP and PC-3 cells, I3C mediated maximum synergy with five phytochemicals, while genistein was maximally synergistic with EGCG. In contrast, DU145 cells showed resveratrol-mediated maximum synergy with equol, EGCG and genistein, with I3C mediating maximum synergy with only quercetin and curcumin. Knockdown of pTEN expression in DU145 cells abrogated the synergistic effect of resveratrol without affecting the synergy profile of I3C and quercetin.

Discussion

Our study identifies patterns of synergy that are dependent on tumour cell genotype and are independent of androgen signaling but are dependent on pTEN. Despite evident cell-type specificity in both maximally-synergistic combinations and the pathways that phytochemicals modulate, these combinations interact with similar prostate cancer protein targets. Here, we identify an approach that, when coupled with advanced data analysis methods, may suggest optimal dietary phytochemical combinations for individual consumption based on tumour molecular profile.
Incorporating risk preferences of patients in the valuation of immune checkpoint inhibitors for non-small cell lung cancer
Authors: Zaim Remziye , Redekop W. Ken , Uyl-de Groot Carin A.
Published: March 2023

Immunotherapy offers a distinctive mechanism of action compared to traditional treatments, arising from additional value dimensions that may not be captured in standard health technology assessments. Cancer patients may have the expectation that immunotherapy provides durable, long-term survival gains. Moreover, some patients may be willing to take a ‘risk’ to undergo immunotherapy to achieve better survival outcomes. We reviewed quantitative methods that explored patients’ risk preferences in their non-small cell lung cancer (NSCLC) treatment choices, in PubMed (MEDLINE), from January 1, 2015, until July 1, 2022. The consideration of a value dimension (‘hope’) based on patients’ risk-seeking preferences is specifically addressed for the valuation of immune checkpoint inhibitors in NSCLC. We reported that the quantitative methods that aim to measure patients’ risk preferences or ‘hope’ empirically are emerging. Value assessments should not only comprise survival improvements for the mean or median patient but also consider methods that reflect durable, long-term overall survival gains for risk-seeking patients. However, the published evidence for incorporating ‘hope’ based on patients’ stated preferences for uncertain treatment profiles is not strong, and future research could strengthen this evidence base. We encourage further research on the development and validation of quantification methods to incorporate ‘hope’ and risk preferences of patients treated with immunotherapy for NSCLC and beyond.
A novel risk score model based on gamma-aminobutyric acid signature predicts the survival prognosis of patients with breast cancer
Authors: Yang Liping , Zhu Jin , Wang Lieliang , He Longbo , Gong Yi , Luo Qingfeng
Published: March 2023

Background

Gamma-aminobutyric acid (GABA) participates in the migration, differentiation, and proliferation of tumor cells. However, the GABA-related risk signature has never been investigated. Hence, we aimed to develop a reliable gene signature based on GABA pathways-related genes (GRGs) to predict the survival prognosis of breast cancer patients.

Methods

GABA-related gene sets were acquired from the MSigDB database, while mRNA gene expression profiles and corresponding clinical data of breast cancer patients were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Univariate Cox regression analysis was used to identify prognostic-associated GRGs. Subsequently, LASSO analysis was applied to establish a risk score model. We also constructed a clinical nomogram to perform the survival evaluation. Besides, ESTIMATE and ssGSEA algorithms were used to assess the immune cell infiltration among the risk score subgroups.

Results

A GRGs-related risk score model was constructed in the TCGA cohort, and validated in the GSE21653 cohort. The risk score was significantly related to the overall survival of breast cancer patients, which could predict the survival prognosis of breast cancer patients independently of other clinical features. Breast cancer patients in the low-risk score group exhibited higher immune cell infiltration levels.

Conclusion

A novel prognostic model containing five GRGs could accurately predict the survival prognosis and immune infiltration of breast cancer patients. Our findings provided a novel insight into investigating the immunoregulation roles of GRGs.
Comprehensive analysis of microbiota signature across 32 cancer types
Authors: Yang Xia , An Huimin , He Yongtao , Fu Guoxiang , Jiang Zhinong
Published: March 2023

Microbial communities significantly inhabit the human body. Evidence shows the interaction between the human microbiome and host cells plays a central role in multiple physiological processes and organ microenvironments. However, the majority of related studies focus on gut microbiota or specific tissues/organs, and the component signature of intratumor microbiota across various cancer types remains unclear. Here, we systematically analyzed the correlation between intratumor microbial signature with survival outcomes, genomic features, and immune profiles across 32 cancer types based on the public databases of Bacteria in Cancer (BIC) and The Cancer Genome Atlas (TCGA). Results showed the relative abundance of microbial taxa in tumors compared to normal tissues was observed as particularly noticeable. Survival analysis found that specific candidate microbial taxa were correlated with prognosis across various cancers. Then, a microbial-based scoring system (MS), which was composed of 64 candidate prognostic microbes, was established. Further analyses showed significant differences in survival status, genomic function, and immune profiles among the distinct MS subgroups. Taken together, this study reveals the diversity and complexity of microbiomes in tumors. Classifying cancer into different subtypes based on intratumor microbial signatures might reasonably reflect genomic characteristics, immune features, and survival status.