bluuebunny/crossref_metadata_2025 huggingface dataset:
A spectrum of clinical severity of recessive titinopathies in prenatal
Authors: Qi Yiming , Ji Xueqi , Ding Hongke , Wang Yunan , Liu Xin , Zhang Yan , Yin Aihua
Published: January 2023

Variants in TTN are associated with a broad range of clinical phenotypes, from dominant adult-onset dilated cardiomyopathy to recessive infantile-onset myopathy. However, few foetal cases have been reported for multiple reasons. Next-generation sequencing has facilitated the prenatal identification of a growing number of suspected titinopathy variants. We investigated six affected foetuses from three families, completed the intrauterine course of the serial phenotypic spectrum of TTN, and discussed the genotype-phenotype correlations from a broader perspective. The recognizable prenatal feature onset at the second trimester was started with reduced movement, then contracture 3–6 weeks later, followed with/without hydrops, finally at late pregnancy was accompanied with polyhydramnio (major) or oligohydramnios. Two cases with typical arthrogryposis-hydrops sequences identified a meta-only transcript variant c.36203-1G>T. Deleterious transcriptional consequences of the substitution were verified by minigene splicing analysis. Case 3 identified a homozygous splicing variant in the constitutively expressed Z-disc. It presented a milder phenotype than expected, which was presumably saved by the isoform of corons. A summary of the foetal-onset titinopathy cases implied that variants in TTN present with a series of signs and a spectrum of clinical severity, which followed the dosage/positional effect; the meta-only transcript allele involvement may be a prerequisite for the development of fatal hydrops.
Prospects of microgreens as budding living functional food: Breeding and biofortification through OMICS and other approaches for nutritional security
Authors: Gupta Astha , Sharma Tripti , Singh Surendra Pratap , Bhardwaj Archana , Srivastava Deepti , Kumar Rajendra
Published: January 2023

Nutrient deficiency has resulted in impaired growth and development of the population globally. Microgreens are considered immature greens (required light for photosynthesis and growing medium) and developed from the seeds of vegetables, legumes, herbs, and cereals. These are considered “living superfood/functional food” due to the presence of chlorophyll, beta carotene, lutein, and minerals like magnesium (Mg), Potassium (K), Phosphorus (P), and Calcium (Ca). Microgreens are rich at the nutritional level and contain several phytoactive compounds (carotenoids, phenols, glucosinolates, polysterols) that are helpful for human health on Earth and in space due to their anti-microbial, anti-inflammatory, antioxidant, and anti-carcinogenic properties. Microgreens can be used as plant-based nutritive vegetarian foods that will be fruitful as a nourishing constituent in the food industryfor garnish purposes, complement flavor, texture, and color to salads, soups, flat-breads, pizzas, and sandwiches (substitute to lettuce in tacos, sandwich, burger). Good handling practices may enhance microgreens’stability, storage, and shelf-life under appropriate conditions, including light, temperature, nutrients, humidity, and substrate. Moreover, the substrate may be a nutritive liquid solution (hydroponic system) or solid medium (coco peat, coconut fiber, coir dust and husks, sand, vermicompost, sugarcane filter cake, etc.) based on a variety of microgreens. However integrated multiomics approaches alongwith nutriomics and foodomics may be explored and utilized to identify and breed most potential microgreen genotypes, biofortify including increasing the nutritional content (macro-elements:K, Ca and Mg; oligo-elements: Fe and Zn and antioxidant activity) and microgreens related other traits viz., fast growth, good nutritional values, high germination percentage, and appropriate shelf-life through the implementation of integrated approaches includes genomics, transcriptomics, sequencing-based approaches, molecular breeding, machine learning, nanoparticles, and seed priming strategiesetc.
N6-Methyladenosine-Related LncRNAs Are Potential Remodeling Indicators in the Tumor Microenvironment and Prognostic Markers in Osteosarcoma
Authors: Wu Zhongguang , Zhang Xiaobo , Chen Dongjie , Li Zian , Wu Xin , Wang Jianlong , Deng Youwen
Published: January 2023

N6-Adenosine methylation, yielding N6-methyladenosine (m6A), is a reversible epigenetic modification found in messenger RNAs and long non-coding RNAs (lncRNAs), which affects the fate of modified RNA molecules and is essential for the development and differentiation of immune cells in the tumor microenvironment (TME). Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents, and is characterized by high mortality. Currently, the possible role of m6A modifications in the prognosis of OS is unclear. In the present study, we investigated the correlation between m6A-related lncRNA expression and the clinical outcomes of OS patients via a comprehensive analysis. Clinical and workflow-type data were obtained from the Genotype-Tissue Expression Program and The Cancer Genome Atlas. We examined the relationship between m6A modifications and lncRNA expression, conducted Kyoto Encyclopedia of Genes analysis and also gene set enrichment analysis (GSEA), implemented survival analysis to investigate the association of clinical survival data with the expression of m6A-related lncRNAs, and utilized Lasso regression to model the prognosis of OS. Furthermore, we performed immune correlation analysis and TME differential analysis to investigate the infiltration levels of immune cells and their relationship with clinical prognosis. LncRNA expression and m6A levels were closely associated in co-expression analysis. The expression of m6A-related lncRNAs was quite low in tumor tissues; this appeared to be a predicting factor of OS in a prognostic model, independent of other clinical features. The NOD-like receptor signaling pathway was the most significantly enriched pathway in GSEA. In tumor tissues, SPAG4 was overexpressed while ZBTB32 and DEPTOR were downregulated. Tissues in cluster 2 were highly infiltrated by plasma cells. Cluster 2 presented higher ESTIMATE scores and stromal scores, showing a lower tumor cell purity in the TME. In conclusion, m6A-related lncRNA expression is strongly associated with the occurrence and development of OS, and can be used to as a prognostic factor of OS. Moreover, m6A-related lncRNAs and infiltrating immune cells in the TME could serve as new therapeutic targets and prognostic biomarkers for OS.
Novel insights into the immune cell landscape and gene signatures in autism spectrum disorder by bioinformatics and clinical analysis
Authors: Li Hongwei , Xu Yiran , Li Wenhua , Zhang Lingling , Zhang Xiaoli , Li Bingbing , Chen Yiwen , Wang Xiaoyang , Zhu Changlian
Published: January 2023

The pathogenesis of autism spectrum disorder (ASD) is not well understood, especially in terms of immunity and inflammation, and there are currently no early diagnostic or treatment methods. In this study, we obtained six existing Gene Expression Omnibus transcriptome datasets from the blood of ASD patients. We performed functional enrichment analysis, PPI analysis, CIBERSORT algorithm, and Spearman correlation analysis, with a focus on expression profiling in hub genes and immune cells. We validated that monocytes and nonclassical monocytes were upregulated in the ASD group using peripheral blood (30 children with ASD and 30 age and sex-matched typically developing children) using flow cytometry. The receiver operating characteristic curves (PSMC4 and ALAS2) and analysis stratified by ASD severity (LIlRB1 and CD69) showed that they had predictive value using the “training” and verification groups. Three immune cell types – monocytes, M2 macrophages, and activated dendritic cells – had different degrees of correlation with 15 identified hub genes. In addition, we analyzed the miRNA-mRNA network and agents-gene interactions using miRNA databases (starBase and miRDB) and the DSigDB database. Two miRNAs (miR-342-3p and miR-1321) and 23 agents were linked with ASD. These findings suggest that dysregulation of the immune system may contribute to ASD development, especially dysregulation of monocytes and monocyte-derived cells. ASD-related hub genes may serve as potential predictors for ASD, and the potential ASD-related miRNAs and agents identified here may open up new strategies for the prevention and treatment of ASD.
The helminth derived peptide FhHDM-1 redirects macrophage metabolism towards glutaminolysis to regulate the pro-inflammatory response
Authors: Quinteros Susel Loli , von Krusenstiern Eliana , Snyder Nathaniel W. , Tanaka Akane , O’Brien Bronwyn , Donnelly Sheila
Published: January 2023

We have previously identified an immune modulating peptide, termed FhHDM-1, within the secretions of the liver fluke, Fasciola hepatica, which is sufficiently potent to prevent the progression of type 1 diabetes and multiple sclerosis in murine models of disease. Here, we have determined that the FhHDM-1 peptide regulates inflammation by reprogramming macrophage metabolism. Specifically, FhHDM-1 switched macrophage metabolism to a dependence on oxidative phosphorylation fuelled by fatty acids and supported by the induction of glutaminolysis. The catabolism of glutamine also resulted in an accumulation of alpha ketoglutarate (α-KG). These changes in metabolic activity were associated with a concomitant reduction in glycolytic flux, and the subsequent decrease in TNF and IL-6 production at the protein level. Interestingly, FhHDM-1 treated macrophages did not express the characteristic genes of an M2 phenotype, thereby indicating the specific regulation of inflammation, as opposed to the induction of an anti-inflammatory phenotype per se. Use of an inactive derivative of FhHDM-1, which did not modulate macrophage responses, revealed that the regulation of immune responses was dependent on the ability of FhHDM-1 to modulate lysosomal pH. These results identify a novel functional association between the lysosome and mitochondrial metabolism in macrophages, and further highlight the significant therapeutic potential of FhHDM-1 to prevent inflammation.
Negative interference with antibody-dependent cellular cytotoxicity mediated by rituximab from its interactions with human serum proteins
Authors: Yanaka Saeko , Yogo Rina , Yagi Hirokazu , Onitsuka Masayoshi , Wakaizumi Natsumi , Yamaguchi Yuki , Uchiyama Susumu , Kato Koichi
Published: January 2023

Although interactions of small molecular drugs with serum proteins have been widely studied from pharmacokinetic and pharmacodynamic perspectives, there have been few reports on the effects of serum components on therapeutic antibody functions. This study reports the effect of abundant serum proteins on antibody-dependent cellular cytotoxicity (ADCC) mediated by rituximab and Fcγ receptor III (FcγRIII). Human serum albumin (HSA) and the Fab fragment from the pooled serum polyclonal IgG were found to compromise ADCC as non-competitive inhibitors. Our nuclear magnetic resonance data provided direct evidence for the interactions of HSA with both the Fab and Fc regions of rituximab and also with the extracellular region of FcγRIII (sFcγRIII). The degree of involvement in the interaction decreased in the order of rituximab-Fab > rituximab-Fc > sFcγRIII, suggesting preferential binding of HSA to net positively charged proteins. Although much less pronounced than the effect of HSA, polyclonal IgG-Fab specifically interacted with rituximab-Fc. The NMR data also showed that the serum protein interactions cover the Fc surface extensively, suggesting that they can act as pan-inhibitors against various Fc receptor-mediated functions and pharmacokinetics. Our findings highlight the importance of considering serum–protein interactions in the design and application of antibody-based drugs with increased efficacy and safety.
Macrophage differentiation is marked by increased abundance of the mRNA 3’ end processing machinery, altered poly(A) site usage, and sensitivity to the level of CstF64
Authors: Mukherjee Srimoyee , Graber Joel H. , Moore Claire L.
Published: January 2023

Regulation of mRNA polyadenylation is important for response to external signals and differentiation in several cell types, and results in mRNA isoforms that vary in the amount of coding sequence or 3’ UTR regulatory elements. However, its role in differentiation of monocytes to macrophages has not been investigated. Macrophages are key effectors of the innate immune system that help control infection and promote tissue-repair. However, overactivity of macrophages contributes to pathogenesis of many diseases. In this study, we show that macrophage differentiation is characterized by shortening and lengthening of mRNAs in relevant cellular pathways. The cleavage/polyadenylation (C/P) proteins increase during differentiation, suggesting a possible mechanism for the observed changes in poly(A) site usage. This was surprising since higher C/P protein levels correlate with higher proliferation rates in other systems, but monocytes stop dividing after induction of differentiation. Depletion of CstF64, a C/P protein and known regulator of polyadenylation efficiency, delayed macrophage marker expression, cell cycle exit, attachment, and acquisition of structural complexity, and impeded shortening of mRNAs with functions relevant to macrophage biology. Conversely, CstF64 overexpression increased use of promoter-proximal poly(A) sites and caused the appearance of differentiated phenotypes in the absence of induction. Our findings indicate that regulation of polyadenylation plays an important role in macrophage differentiation.
Multi-omics profiling and digital image analysis reveal the potential prognostic and immunotherapeutic properties of CD93 in stomach adenocarcinoma
Authors: Wu Baokang , Fu Lei , Guo Xingqi , Hu Huixin , Li Yang , Shi Yu , Zhang Yizhou , Han Shukun , Lv Chao , Tian Yu
Published: January 2023

Background

Recent evidence highlights the fact that immunotherapy has significantly improved patient outcomes. CD93, as a type I transmembrane glycoprotein, was correlated with tumor-associated angiogenesis; however, how CD93 correlates with immunotherapy in stomach adenocarcinoma (STAD) remains unclear.

Methods

TCGA, GTEx, GEO, TIMER2.0, HPA, TISIDB, TCIA, cBioPortal, LinkedOmics, and ImmuCellAI public databases were used to elucidate CD93 in STAD. Visualization and statistical analysis of data were performed by R (Version 4.1.3), GraphPad (Version 8.0.1), and QuPath (Version 0.3.2).

Results

CD93 was highly expressed in STAD compared with adjacent normal tissues. The overexpression of CD93 was significantly correlated with a poor prognosis in STAD. There was a negative correlation between CD93 expression levels with CD93 mutation and methylation in STAD. Our results revealed that CD93 expression was positively associated with most immunosuppressive genes (including PD-1, PD-L1, CTLA-4, and LAG3), immunostimulatory genes, HLA, chemokine, and chemokine receptor proteins in STAD. Furthermore, in STAD, CD93 was noticeably associated with the abundance of multiple immune cell infiltration levels. Functional HALLMARK and KEGG term enhancement analysis of CD93 through Gene Set Enrichment Analysis was correlated with the process of the angiogenesis pathway. Subsequently, digital image analysis results by QuPath revealed that the properties of CD93+ cells were statistically significant in different regions of stomach cancer and normal stomach tissue. Finally, we utilized external databases, including GEO, TISIDB, ImmuCellAI, and TCIA, to validate that CD93 plays a key role in the immunotherapy of STAD.

Conclusion

Our study reveals that CD93 is a potential oncogene and is an indicative biomarker of a worse prognosis and exerts its immunomodulatory properties and potential possibilities for immunotherapy in STAD.
Effectiveness of therapeutic patient education interventions for chronic diseases: A systematic review and meta-analyses of randomized controlled trials
Authors: Correia Jorge César , Waqas Ahmed , Assal Jean-Philippe , Davies Melanie J. , Somers Florence , Golay Alain , Pataky Zoltan
Published: January 2023

Background

Chronic disorders are highly prevalent and are a major contributor to death and disability worldwide. Evidence has shown that therapeutic patient education (TPE) interventions are effective in improving a range of biomedical and psychological outcomes for a variety of chronic disorders. This has been demonstrated in scores of randomized controlled and evidence-synthesis studies. However, no quantitative evidence has been published so far on the content and effective teaching strategies in TPE programs. The present systematic review and meta-analysis aim to bridge this gap by answering the who, what, and how of TPE programs.

Methods

Using a pretested search strategy, we searched the Web of Science, MEDLINE, CINAHL, PsycINFO, and the COCHRANE databases, from inception to August 2019. The search strategy was based on four comprehensive search concepts (patient education, chronic diseases, study design, and outcomes). After a careful screening for eligible studies, two reviewers extracted qualitative and quantitative data from the randomized controlled trials on the TPE interventions. We also developed a taxonomy of curriculum skills and intervention delivery techniques to aid the extraction of data in these domains.

Results

We found that these interventions were effective in improving biological outcomes (SMD = 0.48; 95% CI: 0.38–0.57), adherence to the treatment regimen (SMD = 0.73; 95% CI: 0.46–1.002), knowledge (SMD = 1.22; 95% CI: 0.79–1.65), self-efficacy (SMD = 0.43; 95% CI: 0.30–0.56), and psychological health (SMD = −0.41; 95% CI: −0.53 to −0.29). This effectiveness was consistent across different delivery formats (individual, group, and electronic) and delivery agents (non-specialists vs. specialists).

Conclusion

The flexibility in the choice of mode of delivery and curriculum development gives stakeholders an opportunity to scale up TPE interventions in healthcare settings.

Systematic review registration

Identifier: CRD42019141294.
The potential of facultative predatory Actinomycetota spp. and prospects in agricultural sustainability
Authors: Ibrahimi Manar , Loqman Souad , Jemo Martin , Hafidi Mohamed , Lemee Laurent , Ouhdouch Yedir
Published: January 2023

Actinomycetota in the phylum of bacteria has been explored extensively as a source of antibiotics and secondary metabolites. In addition to acting as plant growth-promoting agents, they also possess the potential to control various plant pathogens; however, there are limited studies that report the facultative predatory ability of Actinomycetota spp. Furthermore, the mechanisms that underline predation are poorly understood. We assessed the diversity of strategies employed by predatory bacteria to attack and subsequently induce the cell lysing of their prey. We revisited the diversity and abundance of secondary metabolite molecules linked to the different predation strategies by bacteria species. We analyzed the pros and cons of the distinctive predation mechanisms and explored their potential for the development of new biocontrol agents. The facultative predatory behaviors diverge from group attack “wolfpack,” cell-to-cell proximity “epibiotic,” periplasmic penetration, and endobiotic invasion to degrade host-cellular content. The epibiotic represents the dominant facultative mode of predation, irrespective of the habitat origins. The wolfpack is the second-used approach among the Actinomycetota harboring predatory traits. The secondary molecules as chemical weapons engaged in the respective attacks were reviewed. We finally explored the use of predatory Actinomycetota as a new cost-effective and sustainable biocontrol agent against plant pathogens.
Metagenome-assembled genomes indicate that antimicrobial resistance genes are highly prevalent among urban bacteria and multidrug and glycopeptide resistances are ubiquitous in most taxa
Authors: Magnúsdóttir Stefanía , Saraiva Joao Pedro , Bartholomäus Alexander , Soheili Majid , Toscan Rodolfo Brizola , Zhang Junya , Nunes da Rocha Ulisses ,   CLUE-TERRA consortium
Published: January 2023

Introduction

Every year, millions of deaths are associated with the increased spread of antimicrobial resistance genes (ARGs) in bacteria. With the increasing urbanization of the global population, the spread of ARGs in urban bacteria has become a more severe threat to human health.

Methods

In this study, we used metagenome-assembled genomes (MAGs) recovered from 1,153 urban metagenomes in multiple urban locations to investigate the fate and occurrence of ARGs in urban bacteria. Additionally, we analyzed the occurrence of these ARGs on plasmids and estimated the virulence of the bacterial species.

Results

Our results showed that multidrug and glycopeptide ARGs are ubiquitous among urban bacteria. Additionally, we analyzed the deterministic effects of phylogeny on the spread of these ARGs and found ARG classes that have a non-random distribution within the phylogeny of our recovered MAGs. However, few ARGs were found on plasmids and most of the recovered MAGs contained few virulence factors.

Discussion

Our results suggest that the observed non-random spreads of ARGs are not due to the transfer of plasmids and that most of the bacteria observed in the study are unlikely to be virulent. Additional research is needed to evaluate whether the ubiquitous and widespread ARG classes will become entirely prevalent among urban bacteria and how they spread among phylogenetically distinct species.
The fate of sulfonamide resistance genes and anthropogenic pollution marker intI1 after discharge of wastewater into a pristine river stream
Authors: Haenelt Sarah , Wang Gangan , Kasmanas Jonas Coelho , Musat Florin , Richnow Hans Hermann , da Rocha Ulisses Nunes , Müller Jochen A. , Musat Niculina
Published: January 2023

Introduction

Currently there are sparse regulations regarding the discharge of antibiotics from wastewater treatment plants (WWTP) into river systems, making surface waters a latent reservoir for antibiotics and antibiotic resistance genes (ARGs). To better understand factors that influence the fate of ARGs in the environment and to foster surveillance of antibiotic resistance spreading in such habitats, several indicator genes have been proposed, including the integrase gene intI1 and the sulfonamide resistance genes sul1 and sul2.

Methods

Here we used quantitative PCR and long-read nanopore sequencing to monitor the abundance of these indicator genes and ARGs present as class 1 integron gene cassettes in a river system from pristine source to WWTP-impacted water. ARG abundance was compared with the dynamics of the microbial communities determined via 16S rRNA gene amplicon sequencing, conventional water parameters and the concentration of sulfamethoxazole (SMX), sulfamethazine (SMZ) and sulfadiazine (SDZ).

Results

Our results show that WWTP effluent was the principal source of all three sulfonamides with highest concentrations for SMX (median 8.6 ng/l), and of the indicator genes sul1, sul2 and intI1 with median relative abundance to 16S rRNA gene of 0.55, 0.77 and 0.65%, respectively. Downstream from the WWTP, water quality improved constantly, including lower sulfonamide concentrations, decreasing abundances of sul1 and sul2 and lower numbers and diversity of ARGs in the class 1 integron. The riverine microbial community partially recovered after receiving WWTP effluent, which was consolidated by a microbiome recovery model. Surprisingly, the relative abundance of intI1 increased 3-fold over 13 km of the river stretch, suggesting an internal gene multiplication.

Discussion

We found no evidence that low amounts of sulfonamides in the aquatic environment stimulate the maintenance or even spread of corresponding ARGs. Nevertheless, class 1 integrons carrying various ARGs were still present 13 km downstream from the WWTP. Therefore, limiting the release of ARG-harboring microorganisms may be more crucial for restricting the environmental spread of antimicrobial resistance than attenuating ng/L concentrations of antibiotics.
Estimating the optimal efflux inhibitor concentration of carvacrol as a function of the bacterial physiological state
Authors: Jánosity Anna , Baranyi József , Surányi Botond Bendegúz , Možina Sonja Smole , Taczman-Brückner Andrea , Kiskó Gabriella , Klančnik Anja
Published: January 2023

Our aim was to find the optimal efflux inhibitor concentration of a natural component, carvacrol, as a function of the physiological state of Escherichia coli. Using fluorescence-based measurements with two strains of E. coli, the effect of carvacrol was assessed at 17 sub-inhibitory concentrations, at which the bacterial efflux mechanism was compromised. The efficacy of carvacrol, as an efflux inhibitor, was compared to synthetic inhibitors and we found carvacrol the most efficient one. We considered the accumulation of Ethidium Bromide (EtBr) as a proxy for drugs spreading in the cell, thus measuring the efflux activity indirectly. The change in membrane integrity caused by the exposure to carvacrol was monitored using the LIVE/DEAD BacLight Bacterial Viability kit. To find the optimal inhibitory concentration of carvacrol, we used predictive microbiology methods. This optimum varied with the bacterial physiological state, as non-growing cultures were less susceptible to the effect of carvacrol than growing cultures were. Moreover, we point out, for the first time, that the efflux-mediated resistance of untreated cultures was also stronger in the non-growing than in the growing phase at population level.
Urinary protein biomarkers based on LC–MS/MS analysis to discriminate vascular dementia from Alzheimer’s disease in Han Chinese population
Authors: Chen Ruijuan , Yi Yuanjing , Xiao Wenbiao , Zhong Bowen , Zhang Le , Zeng Yi
Published: January 2023

Objective

This study aimed to identify the potential urine biomarkers of vascular dementia (VD) and unravel the disease-associated mechanisms by applying Liquid chromatography tandem-mass spectrometry (LC–MS/MS).

Methods

LC–MS/MS proteomic analysis was applied to urine samples from 3 groups, including 14 patients with VD, 9 patients with AD, and 21 normal controls (NC). By searching the MS data by Proteome Discoverer software, analyzing the protein abundances qualitatively and quantitatively, comparing between groups, combining bioinformatics analysis using Gene Ontology (GO) and pathway crosstalk analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG), and literature searching, the differentially expressed proteins (DEPs) of VD can be comprehensively determined at last and were further quantified by receiver operating characteristic (ROC) curve methods.

Results

The proteomic findings showed quantitative changes in patients with VD compared to patients with NC and AD groups; among 4,699 identified urine proteins, 939 and 1,147 proteins displayed quantitative changes unique to VD vs. NC and AD, respectively, including 484 overlapped common DEPs. Then, 10 unique proteins named in KEGG database (including PLOD3, SDCBP, SRC, GPRC5B, TSG101/STP22/VPS23, THY1/CD90, PLCD, CDH16, NARS/asnS, AGRN) were confirmed by a ROC curve method.

Conclusion

Our results suggested that urine proteins enable detection of VD from AD and VC, which may provide an opportunity for intervention.
Loss of RAB39B does not alter MPTP-induced Parkinson’s disease-like phenotypes in mice
Authors: Wang Zijie , Yang Dingting , Jiang Yiru , Wang Yong , Niu Mengxi , Wang Chong , Luo Hong , Xu Huaxi , Li Jingwen , Zhang Yun-wu , Zhang Xian
Published: January 2023

Parkinson’s disease (PD) is a common neurodegenerative movement disorder with undetermined etiology. A major pathological hallmark of PD is the progressive degeneration of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in the RAB39B gene, which encodes a neuronal-specific small GTPase RAB39B, have been associated with X-linked intellectual disability and pathologically confirmed early-onset PD in multiple families. However, the role of RAB39B in PD pathogenesis remains elusive. In this study, we treated Rab39b knock-out (KO) mice with MPTP to explore whether RAB39B deficiency could alter MPTP-induced behavioral impairments and dopaminergic neuron degeneration. Surprisingly, we found that MPTP treatment impaired motor activity and led to loss of tyrosine hydroxylase-positive dopaminergic neurons and gliosis in both WT and Rab39b KO mice. However, RAB39B deficiency did not alter MPTP-induced impairments. These results suggest that RAB39B deficiency does not contribute to PD-like phenotypes through compromising dopaminergic neurons in mice; and its role in PD requires further scrutiny.
Sodium butyrate ameliorates gut dysfunction and motor deficits in a mouse model of Parkinson’s disease by regulating gut microbiota
Authors: Zhang Yi , Xu Shaoqing , Qian Yiwei , Mo Chengjun , Ai Penghui , Yang Xiaodong , Xiao Qin
Published: January 2023

Background

A growing body of evidence showed that gut microbiota dysbiosis might be associated with the pathogenesis of Parkinson’s disease (PD). Microbiota-targeted interventions could play a protective role in PD by regulating the gut microbiota-gut-brain axis. Sodium butyrate (NaB) could improve gut microbiota dysbiosis in PD and other neuropsychiatric disorders. However, the potential mechanism associated with the complex interaction between NaB and gut microbiota-gut-brain communication in PD needs further investigation.

Methods

C57BL/6 mice were subjected to a rotenone-induced PD model and were treated intragastrically with NaB for 4 weeks. The gut function and motor function were evaluated. The α-synuclein expression in colon and substantia nigra were detected by western blotting. Tyrosine hydroxylase (TH)-positive neurons in substantia nigra were measured by immunofluorescence. Moreover, gut microbiota composition was analyzed by 16S rRNA sequencing. Fecal short chain fatty acids (SCFAs) levels were determined by liquid chromatography tandem mass spectrometry (LC–MS). The levels of glucagon like peptide-1 (GLP-1) in tissues and serum were evaluated using enzyme-linked immunosorbent assay (ELISA).

Results

NaB ameliorated gut dysfunction and motor deficits in rotenone-induced mice. Meanwhile, NaB protected against rotenone-induced α-synuclein expression in colon and substantia nigra, and prevented the loss of TH-positive neurons. In addition, NaB could remodel gut microbiota composition, and regulate gut SCFAs metabolism, and restore GLP-1 levels in colon, serum, and substantia nigra in PD mice.

Conclusion

NaB could ameliorate gut dysfunction and motor deficits in rotenone-induced PD mice, and the mechanism might be associated with the regulation of gut microbiota dysbiosis.
Neuron arbor geometry is sensitive to the limited-range fractal properties of their dendrites
Authors: Rowland Conor , Smith Julian H. , Moslehi Saba , Harland Bruce , Dalrymple-Alford John , Taylor Richard P.
Published: January 2023

Fractal geometry is a well-known model for capturing the multi-scaled complexity of many natural objects. By analyzing three-dimensional images of pyramidal neurons in the rat hippocampus CA1 region, we examine how the individual dendrites within the neuron arbor relate to the fractal properties of the arbor as a whole. We find that the dendrites reveal unexpectedly mild fractal characteristics quantified by a low fractal dimension. This is confirmed by comparing two fractal methods—a traditional “coastline” method and a novel method that examines the dendrites’ tortuosity across multiple scales. This comparison also allows the dendrites’ fractal geometry to be related to more traditional measures of their complexity. In contrast, the arbor’s fractal characteristics are quantified by a much higher fractal dimension. Employing distorted neuron models that modify the dendritic patterns, deviations from natural dendrite behavior are found to induce large systematic changes in the arbor’s structure and its connectivity within a neural network. We discuss how this sensitivity to dendrite fractality impacts neuron functionality in terms of balancing neuron connectivity with its operating costs. We also consider implications for applications focusing on deviations from natural behavior, including pathological conditions and investigations of neuron interactions with artificial surfaces in human implants.
Positive changes to written language following phonological treatment in logopenic variant primary progressive aphasia: Case report
Authors: Nickels Katlyn , Beeson Pélagie M. , Rising Kindle , Jebahi Fatima , Kielar Aneta
Published: January 2023

Phonological impairment contributes to deficits in repetition and spoken naming in logopenic variant Primary Progressive Aphasia (lvPPA), but weakened phonology can also affect written language skills. In this experimental case report, we demonstrate phonological text agraphia in a 71-year-old woman in the early stages of lvPPA that undermined her ability to write meaningful, grammatical sentences. We investigated the therapeutic value of a rigorous treatment protocol to strengthen phonological manipulation skills coupled with transcranial direct current stimulation (tDCS). Intervention took place 5 days a week for 2 weeks with active tDCS, followed by a 2-month rest period, and then a second period of phonological treatment with sham tDCS. Over the course of treatment, our participant demonstrated improved phonological transcoding and manipulation skills as well as marked improvement in the proportion of grammatically well-formed, meaningful written narratives. Improvements in spelling and letter selection were also observed. Treatment gains were documented during phonological intervention in both active tDCS and sham treatment phases and were maintained 2 months after the conclusion of intervention. Importantly, improvements were observed in the context of a progressive disorder. These data present compelling evidence regarding the impairment-based approach that targets compromised phonological skills, presenting opportunity for improving functional written communication skills relevant to the everyday lives of individuals with lvPPA.
Gray matter asymmetry atypical patterns in subgrouping minors with autism based on core symptoms
Authors: Li Cuicui , Chen Wenxiong , Li Xiaojing , Li Tong , Chen Ying , Zhang Chunling , Ning Mingmin , Wang Ximing
Published: January 2023

Abnormal gray matter (GM) asymmetry has been verified in autism spectrum disorder (ASD), which is characterized by high heterogeneity. ASD is distinguished by three core symptom domains. Previous neuroimaging studies have offered support for divergent neural substrates of different core symptom domains in ASD. However, no previous study has explored GM asymmetry alterations underlying different core symptom domains. This study sought to clarify atypical GM asymmetry patterns underlying three core symptom domains in ASD with a large sample of 230 minors with ASD (ages 7–18 years) and 274 matched TD controls from the Autism Brain Imaging Data Exchange I (ABIDE I) repository. To this end, the scores of the revised autism diagnostic interview (ADI-R) subscales were normalized for grouping ASD into three core-symptom-defined subgroups: social interaction (SI), verbal communication (VA), and restricted repetitive behaviors (RRB). We investigated core-symptom-related GM asymmetry alterations in ASD resulting from advanced voxel-based morphometry (VBM) by general linear models. We also examined the relationship between GM asymmetry and age and between GM asymmetry and symptom severity assessed by the Autism Diagnostic Observation Schedule (ADOS). We found unique GM asymmetry alterations underlying three core-symptom-defined subgroups in ASD: more rightward asymmetry in the thalamus for SI, less rightward asymmetry in the superior temporal gyrus, anterior cingulate and caudate for VA, and less rightward asymmetry in the middle and inferior frontal gyrus for RRB. Furthermore, the asymmetry indexes in the thalamus were negatively associated with ADOS_SOCIAL scores in the general ASD group. We also showed significant correlations between GM asymmetry and age in ASD and TD individuals. Our results support the theory that each core symptom domain of ASD may have independent etiological and neurobiological underpinnings, which is essential for the interpretation of heterogeneity and the future diagnosis and treatment of ASD.
Human gastrin- releasing peptide receptor expression in women with uterine cervix cancer
Authors: Kunos Charles A. , Fabian Denise , Napier Dana , Stonecypher Mark S. , Duncan Ravyn M. , Hurt Jason
Published: January 2023

Introduction

212Pb-DOTAM-GRPR1 is a pharmaceutical radioimmunoconjugate consisiting of an α-particle-emitting radionuclide lead-212 (212Pb), a metal chelator DOTAM (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), and a gastrin-releasing peptide receptor (GRPR)-targeted antagonist currently being evaluated as therapy in uterine cervix and other cancer types. Previous studies have revealed that a variable proportion of uterine cervix cancer tumors overexpress the radiopharmaceutical target GRPR when assessed by cell proportion and staining intensity immunoreactive scores (IRS). Tumor response to 212Pb-DOTAM-GRPR1 strongly associates with GRPR overexpression, and therefore, it seems reasonable to assess uterine cervix cancer GRPR immunoreactivity for greater insight into the feasibility of using 212Pb-DOTAM-GRPR1 as a radiopharmaceutical treatment.

Methods

We examined a series of 33 uterine cervix cancer paraffin-embedded tumors in order to establish whether this tumor type overexpresses GRPR at an IRS score of 6 or higher, as 212Pb-DOTAM-GRPR1 is currently being evaluated in clinical trials against tumors showing such a level of expression.

Results

The results show that five of five (100%) primary adenocarcinomas and 10 of 16 (63%) primary squamous cell tumors overexpress GRPR at an IRS score of 6 or higher.

Discussion

The frequency of overexpression in this study suggests that 212Pb-DOTAM-GRPR1 radiopharmaceutical treatment may be useful in the management of persistent, recurrent, or metastatic uterine cervix cancer patients. A phase I clinical trial involving patients with metastatic uterine cervix cancer is currently underway (NCT05283330).
Testing the Arabic-Saudi Arabia version of the Rome IV Diagnostic Questionnaire for functional gastrointestinal disorders for Children living in Saudi Arabia
Authors: Khatib Mai A. , Aljaaly Elham A.
Published: January 2023

Functional gastrointestinal disorders (FGID) are a worldwide phenomenon described by painful, recurrent or chronic gastrointestinal (GI) symptoms. Variable types of FGID exist in a significant portion of children in Saudi Arabia (SA). While the studies and reports on child FGID are limited, the available ones show a notable significance of FGID in children in SA. The self-report Rome IV Diagnostic Questionnaire (DQ) globally recognizes the selection of symptom criteria and incidence thresholds. Using such a questionnaire would help clinicians provide a provisional diagnosis, serve as a case definition for epidemiological surveys, and identify inclusion criteria for clinical trials. This research aimed to pilot test the collective FGIDs prevalence among preschool children in Jeddah city and its countryside of Saudi Arabia, using Rome IV DQ in Arabic-SA. Of the 59 responses, 11.8% (n = 7), 5% (n = 3), 1 (1.6%), and 1 (1.6%) participants have functional dyspepsia, functional constipation, functional irritable bowel syndrome, and functional aerophagia, respectively according to the Rome IV criteria. The tested translated DQ in this study was the first translated version available in Arabic- SA, which could provide researchers and clinicians in SA with a diagnostic tool for FGIDs. However, because this study is a pilot study in a new field, the conclusions cannot be extrapolated to the demographic of the targeted population of children. The same researchers plan a larger study to use the current results and a larger calculated sample to assess FGIDs prevalence in children 4+ years old in Jeddah and its countryside, Saudi Arabia.
The effect of antibiotics on the periodontal treatment of diabetic patients with periodontitis: A systematic review and meta-analysis
Authors: Tang Ziwei , Fan Qi , Jiang Qingsong , Li Xiaolong , Wang Yan , Long Hu , Lai Wenli , Jian Fan
Published: January 2023

Background: The aim of this meta-analysis was to compare the effects of periodontal treatment with or without adjunctive antibiotic on periodontal status and blood glucose level in diabetic patients with periodontitis.

Methods: A search using electronic database (MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials) and a manual search were performed up to July 2022. Eligible 13 RCTs were included according to inclusion and exclusion criteria. Reviewers independently performed data screening, data selection, data extraction, and risk of bias. Quality assessment was performed according to the Cochrane Handbook for Systematic Reviews of Interventions. Weighted mean differences and 95% confidence intervals (CIs) for continuous outcomes were calculated using random or fixed-effects models. This review is registered in the PROSPERO database (CRD42022347803).

Results: Of the 13 included articles, eight were on the use of systemic antibiotics and five on topical antibiotics. The results showed statistically significant improvement in periodontal status (probing depth, clinical attachment loss and bleeding on probing) at 6 months with systematic antibiotics use (PD-6M p = 0.04, BOP-6M p < 0.0001, CAL-6M p = 0.002). The improvement in PD with topical antibiotics was statistically significant at 1 month (p = 0.0006). However, there was no statistically significant improvement in periodontal status at 3 months with adjuvant systemic antibiotics.

Conclusion: Antibiotics can improve the periodontal condition of diabetic patients with periodontitis to a certain extent. In clinical practice, it is necessary to comprehensively consider the balance of benefits and risks before deciding whether to use antibiotics.

Systematic Review Registration: Identifier CRD42022347803, https://www.crd.york.ac.uk/PROSPERO/.
Preclinical and clinical evidence for the treatment of non-alcoholic fatty liver disease with soybean: A systematic review and meta-analysis
Authors: Li Yubing , Deng Xinyu , Guo Xiaochuan , Zhang Fangling , Wu Hefei , Qin Xuhua , Ma Xiao
Published: January 2023

Non-alcoholic fatty liver disease (NAFLD), a prevalent public health issue, involves the accumulation of triglycerides in hepatocytes, which is generally considered to be an early lesion of liver fibrosis and cirrhosis. Thus, the development of treatments for NAFLD is urgently needed. This study explored the preclinical and clinical evidence of soybeans to alleviate NAFLD. Studies indexed in three relevant databases—Web of Science, PubMed, and Embase—between January 2002 and August 2022 were retrieved. A total of 13 preclinical studies and five RCTs that included 212 animals and 260 patients were included in the present analysis. The preclinical analysis showed that liver function indices (AST, SMD = −1.41, p < 0.0001 and ALT, SMD = −1.47, p < 0.0001) were significantly improved in the soybean group compared to the model group, and fatty liver indicators (TG, SMD = −0.78, p < 0.0001; TC, SMD = −1.38, p < 0.0001) and that oxidative stress indices (MDA, SMD = −1.09, p < 0.0001; SOD, SMD = 1.74, p = 0.022) were improved in the soybean group. However, the five RCTs were not entirely consistent with the preclinical results; however, the results confirmed the protective effect on the liver. The results of the clinical RCTs showed that soybean significantly affected liver function, fatty liver, and oxidative stress indicators (ALT, SMD = −0.42, p = 0.006; TG, SMD = −0.31, p = 0.039; MDA, SMD = −0.76, p = 0.007). The current meta-analysis combined preclinical and clinical studies and verified that soybean could protect the liver in NAFLD by regulating lipid metabolism and oxidative stress factors via the Akt/AMPK/PPARα signaling pathway. Soybean might be a promising therapeutic agent for treating non-alcoholic fatty liver disease.

Systematic Review Registration: (https://www.crd.york.ac.uk/prospero/#myprospero), identifier (CRD42022335822).
Characterization of the metabolism of eupalinolide A and B by carboxylesterase and cytochrome P450 in human liver microsomes
Authors: Li Yingzi , Liu Xiaoyan , Li Ludi , Zhang Tao , Gao Yadong , Zeng Kewu , Wang Qi
Published: January 2023

Eupalinolide A (EA; Z-configuration) and eupalinolide B (EB; E-configuration) are bioactive cis-trans isomers isolated from Eupatorii Lindleyani Herba that exert anti-inflammatory and antitumor effects. Although one pharmacokinetic study found that the metabolic parameters of the isomers were different in rats, metabolic processes relevant to EA and EB remain largely unknown. Our preliminary findings revealed that EA and EB are rapidly hydrolyzed by carboxylesterase. Here, we investigated the metabolic stability and enzyme kinetics of carboxylesterase-mediated hydrolysis and cytochrome P450 (CYP)-mediated oxidation of EA and EB in human liver microsomes (HLMs). We also explored differences in the hydrolytic stability of EA and EB in human liver microsomes and rat liver microsomes (RLMs). Moreover, cytochrome P450 reaction phenotyping of the isomers was performed via in silico methods (i.e., using a quantitative structure-activity relationship model and molecular docking) and confirmed using human recombinant enzymes. The total normalized rate approach was considered to assess the relative contributions of five major cytochrome P450s to EA and EB metabolism. We found that EA and EB were eliminated rapidly, mainly by carboxylesterase-mediated hydrolysis, as compared with cytochrome P450-mediated oxidation. An inter-species difference was observed as well, with faster rates of EA and EB hydrolysis in rat liver microsomes. Furthermore, our findings confirmed EA and EB were metabolized by multiple cytochrome P450s, among which CYP3A4 played a particularly important role.
Gallic acid ameliorates dextran sulfate sodium-induced ulcerative colitis in mice via inhibiting NLRP3 inflammasome
Authors: Yu Tian-Yuan , Feng Yi-Ming , Kong Wei-Song , Li Shan-Ni , Sun Xue-Jiao , Zhou Gui , Xie Rui-Fang , Zhou Xin
Published: January 2023

Background: Ulcerative colitis (UC) is a chronic recurrent inflammatory bowel disease (IBD). The conventional drugs for UC may induce severe side effects. Herbal medicine is considered as a complementary and alternative choice for UC.

Purpose: This study aims to estimate the effect of natural polyphenol gallic acid (GA) on the NLRP3 inflammasome with dextran sulfate sodium (DSS)-induced colitis in mice.

Study design: The body weights and symptoms of BALB/c mice were recorded. Histological evaluation, ELISA, q-PCR, immunohistochemistry, and western blotting were carried out to observe the morphology, cytokine contents, mRNA expressions, and protein expressions, respectively. Lipopolysaccharide (LPS)-induced RAW264.7 macrophage was used to probe GA’s effect on relative protein expression.

Results: GA attenuated weight loss (p < 0.05), relieved symptoms, and ameliorated colonic morphological injury (p < 0.05) in mice with colitis induced by DSS. GA also lowered the contents of TNF-α, IL-1β, IL-18, IL-33, and IFN-γ in the serum and colon of mice, which were elevated by DSS, downregulated protein, and mRNA expressions of the NLRP3 pathway in the colon tissue. Furthermore, GA downregulated the expressions of NLRP3 (p < 0.05), iNOS (p < 0.01), COX2 (p < 0.01), and P-p65 (p < 0.05), and suppressed NO release (p < 0.001) in LPS-induced RAW264.7 cells.

Conclusion: GA ameliorated DSS-induced UC in mice via inhibiting the NLRP3 inflammasome. These findings furnish evidence for the anti-inflammatory effect of herbal medicines containing GA on UC.