bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and validation of an inflammation-related lncRNAs signature for improving outcomes of patients in colorectal cancer
Authors: Huang Mengjia , Ye Yuqing , Chen Yi , Zhu Junkai , Xu Li , Cheng Wenxuan , Lu Xiaofan , Yan Fangrong
Published: September 2022

Background: Colorectal cancer is the fourth most deadly cancer worldwide. Although current treatment regimens have prolonged the survival of patients, the prognosis is still unsatisfactory. Inflammation and lncRNAs are closely related to tumor occurrence and development in CRC. Therefore, it is necessary to establish a new prognostic signature based on inflammation-related lncRNAs to improve the prognosis of patients with CRC.

Methods: LASSO-penalized Cox analysis was performed to construct a prognostic signature. Kaplan-Meier curves were used for survival analysis and ROC curves were used to measure the performance of the signature. Functional enrichment analysis was conducted to reveal the biological significance of the signature. The R package “maftool” and GISTIC2.0 algorithm were performed for analysis and visualization of genomic variations. The R package “pRRophetic”, CMap analysis and submap analysis were performed to predict response to chemotherapy and immunotherapy.

Results: An effective and independent prognostic signature, IRLncSig, was constructed based on sixteen inflammation-related lncRNAs. The IRLncSig was proved to be an independent prognostic indicator in CRC and was superior to clinical variables and the other four published signatures. The nomograms were constructed based on inflammation-related lncRNAs and detected by calibration curves. All samples were classified into two groups according to the median value, and we found frequent mutations of the TP53 gene in the high-risk group. We also found some significantly amplificated regions in the high-risk group, 8q24.3, 20q12, 8q22.3, and 20q13.2, which may regulate the inflammatory activity of cancer cells in CRC. Finally, we identified chemotherapeutic agents for high-risk patients and found that these patients were more likely to respond to immunotherapy, especially anti-CTLA4 therapy.

Conclusion: In short, we constructed a new signature based on sixteen inflammation-related lncRNAs to improve the outcomes of patients in CRC. Our findings have proved that the IRLncSig can be used as an effective and independent marker for predicting the survival of patients with CRC.
Gene-specific machine learning model to predict the pathogenicity of BRCA2 variants
Authors: Khandakji Mohannad N. , Mifsud Borbala
Published: September 2022

Background: Existing BRCA2-specific variant pathogenicity prediction algorithms focus on the prediction of the functional impact of a subtype of variants alone. General variant effect predictors are applicable to all subtypes, but are trained on putative benign and pathogenic variants and do not account for gene-specific information, such as hotspots of pathogenic variants. Local, gene-specific information have been shown to aid variant pathogenicity prediction; therefore, our aim was to develop a BRCA2-specific machine learning model to predict pathogenicity of all types of BRCA2 variants.

Methods: We developed an XGBoost-based machine learning model to predict pathogenicity of BRCA2 variants. The model utilizes general variant information such as position, frequency, and consequence for the canonical BRCA2 transcript, as well as deleteriousness prediction scores from several tools. We trained the model on 80% of the expert reviewed variants by the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium and tested its performance on the remaining 20%, as well as on an independent set of variants of uncertain significance with experimentally determined functional scores.

Results: The novel gene-specific model predicted the pathogenicity of ENIGMA BRCA2 variants with an accuracy of 99.9%. The model also performed excellently on predicting the functional consequence of the independent set of variants (accuracy was up to 91.3%).

Conclusion: This new, gene-specific model is an accurate method for interpreting the pathogenicity of variants in the BRCA2 gene. It is a valuable addition for variant classification and can prioritize unreviewed variants for functional analysis or expert review.
CFAP300 mutation causing primary ciliary dyskinesia in Finland
Authors: Schultz Rüdiger , Elenius Varpu , Fassad Mahmoud R. , Freke Grace , Rogers Andrew , Shoemark Amelia , Koistinen Tiina , Mohamed Mai A. , Lim Jacqueline S. Y. , Mitchison Hannah M. , Sironen Anu I.
Published: September 2022

Primary ciliary dyskinesia (PCD) is a rare genetic condition characterized by chronic respiratory tract infections and in some cases laterality defects and infertility. The symptoms of PCD are caused by malfunction of motile cilia, hair-like organelles protruding out of the cell that are responsible for removal of mucus from the airways and organizing internal organ positioning during embryonic development. PCD is caused by mutations in genes coding for structural or assembly proteins in motile cilia. Thus far mutations in over 50 genes have been identified and these variants explain around 70% of all known cases. Population specific genetics underlying PCD has been reported, thus highlighting the importance of characterizing gene variants in different populations for development of gene-based diagnostics. In this study, we identified a recurrent loss-of-function mutation c.198_200delinsCC in CFAP300 causing lack of the protein product. PCD patients homozygous for the identified CFAP300 mutation have immotile airway epithelial cilia associated with missing dynein arms in their ciliary axonemes. Furthermore, using super resolution microscopy we demonstrate that CFAP300 is transported along cilia in normal human airway epithelial cells suggesting a role for CFAP300 in dynein complex transport in addition to preassembly in the cytoplasm. Our results highlight the importance of CFAP300 in dynein arm assembly and improve diagnostics of PCD in Finland.
Aberrant lncRNA–mRNA expression profile and function networks during the adipogenesis of mesenchymal stem cells from patients with ankylosing spondylitis
Authors: Cen Shuizhong , Cai Mingxi , Wang Yihan , Lu Xiuyi , Chen Zhipeng , Chen Haobo , Fang Yingdong , Wu Changping , Qiu Sujun , Liu Zhenhua
Published: September 2022

Objective: We have already demonstrated that mesenchymal stem cells from patients with ankylosing spondylitis (ASMSCs) exhibited greater adipogenic differentiation potential than those from healthy donors (HDMSCs). Here, we further investigated the expression profile of long noncoding RNA (lncRNA) and mRNA, aiming to explore the underlying mechanism of abnormal adipogenic differentiation in ASMSCs.

Methods: HDMSCs and ASMSCs were separately isolated and induced with adipogenic differentiation medium for 10 days. Thereafter, lncRNAs and mRNAs that were differentially expressed (DE) between HDMSCs and ASMSCs were identified via high-throughput sequencing and confirmed by quantitative real-time PCR (qRT–PCR) assays. Then, the DE genes were annotated and enriched by GO analysis. In addition, protein interaction network was constructed to evaluate the interactions between DE mRNAs and to find hub nodes and study cliques. Besides, co-expression network analysis was carried out to assess the co-expressions between DE mRNA and DE lncRNAs, and competing endogenous RNA (ceRNA) network analysis were conducted to predict the relationships among lncRNAs, mRNAs and miRNAs. The signaling pathways based on the DE genes and the predicted DE genes were enriched by KEGG analysis.

Results: A total of 263 DE lncRNAs and 1376 DE mRNAs were found during adipogenesis in ASMSCs. qRT–PCR indicated that the expression of the top 20 mRNAs and the top 10 lncRNAs was consistent with the high-throughput sequencing data. Several lncRNAs (NR_125386.1, NR_046473.1 and NR_038937.1) and their target genes (SPN and OR1AIP2), together with the significantly co-expressed pairs of DE lncRNAs and DE mRNAs (SLC38A5-ENST00000429588.1, TMEM61-ENST00000400755.3 and C5orf46-ENST00000512300.1), were closely related to the enhanced adipogenesis of ASMSCs by modulating the PPAR signaling pathway.

Conclusion: Our study analyzed the expression profiles of DE lncRNAs and DE mRNAs during adipogenesis in ASMSCs and HDMSCs. Several DE lncRNAs, DE mRNAs and signaling pathways that probably participate in the aberrant adipogenesis of ASMSCs were selected for future study. These results will likely provide potential targets for our intervention on fat metaplasia and subsequent new bone formation in patients with AS in the future.
Phosphate and IL-10 concentration as predictors of long-covid in hemodialysis patients: A Brazilian study
Authors: Corrêa Hugo L. , Deus Lysleine A. , Araújo Thaís B. , Reis Andrea L. , Amorim Carlos E. N. , Gadelha André B. , Santos Rafael L. , Honorato Fernando S. , Motta-Santos Daisy , Tzanno-Martins Carmen , Neves Rodrigo V. P. , Rosa Thiago S.
Published: September 2022

Background

The global burden of persistent COVID-19 in hemodialysis (HD) patients is a worrisome scenario worth of investigation for the critical care of chronic kidney disease (CKD). We performed an exploratory post-hoc study from the trial U1111-1237-8231 with two specific aims: i) to investigate the prevalence of COVID-19 infection and long COVID symptoms from our Cohort of 178 Brazilians HD patients. ii) to identify whether baseline characteristics should predict long COVID in this sample.

Methods

247 community-dwelling older (>60 years) patients (Men and women) undergoing HD (glomerular filtration rate < 15 mL/min/1.73m2) with arteriovenous fistula volunteered for this study. All patients presented hypertension and diabetes. Patients were divided in two groups: without long-COVID and with long-COVID. Body composition, handgrip strength, functional performance, iron metabolism, phosphate, and inflammatory profile were assessed. Patients were screened for 11-months after COVID-19 infection. Results were considered significant at P < 0.05.

Results

We found that more than 85% of the COVID-19 infected patients presented a severe condition during the infection. In our sample, the mortality rate over 11-month follow was relatively low (8.4%) when compared to worldwide (approximately 36%). Long COVID was highly prevalent in COVID-19 survivors representing more than 80% of all cases. Phosphate and IL-10 were higher in the long COVID group, but only phosphate higher than 5.35 mg/dL appears to present an increased prevalence of long COVID, dyspnea, and fatigue.

Conclusion

There was a high prevalence of COVID-19 infection and long COVID in HD patients from the Brazilian trial ‘U1111-1237-8231’. HD clinics should be aware with phosphate range in HD patients as a possible target for adverse post-COVID events.
Reestablish immune tolerance in rheumatoid arthritis
Authors: Shuai Ziqiang , Zheng Shuang , Wang Kang , Wang Jian , Leung Patrick S. C. , Xu Bin
Published: September 2022

Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease. Despite the wide use of conventional synthetic, targeted and biologic disease modifying anti-rheumatic drugs (DMARDs) to control its radiological progress, nearly all DMARDs are immunologically non-selective and do not address the underlying immunological mechanisms of RA. Patients with RA often need to take various DMARDs long-term or even lifelong and thus, face increased risks of infection, tumor and other adverse reactions. It is logical to modulate the immune disorders and restore immune balance in patients with RA by restoring immune tolerance. Indeed, approaches based on stem cell transplantation, tolerogenic dendritic cells (tolDCs), and antigen-based tolerogenic vaccination are under active investigation, and some have already transformed from wet bench research to clinical investigation during the last decade. Among them, clinical trials on stem cell therapy, especially mesenchymal stem cells (MSCs) transplantation are most investigated and followed by tolDCs in RA patients. On the other hand, despite active laboratory investigations on the use of RA-specific peptide-/protein-based tolerogenic vaccines for T cell, clinical studies on RA patients are much limited. Overall, the preliminary results of these clinical studies are promising and encouraging, demonstrating their safety and effectiveness in the rebalancing of T cell subsets; particular, the recovery of RA-specific Treg with increasing anti-inflammatory cytokines and reduced proinflammatory cytokines. Future studies should focus on the optimization of transplanted stem cells, the preparation of tolDCs, and tolerogenic vaccines with RA-specific protein or peptide, including their dosage, course, and route of administration with well-coordinated multi-center randomized clinical control researches. With the progress of experimental and clinical studies, generating and restoring RA-specific immune tolerance may bring revolutionary changes to the clinical management of RA in the near future.
AIM2 as a putative target in acute kidney graft rejection
Authors: Franchon Marques Tejada Nathália , Ziroldo Lopes João Vitor , Duarte Gonçalves Luis Eduardo , Mamede Costa Andrade da Conceição Izabela , Franco Glória Regina , Ghirotto Bruno , Câmara Niels Olsen Saraiva
Published: September 2022

Acute rejection (AR) is a process triggered via the recognition of grafted organ-derived antigens by the immune system, which could present as a life-threatening condition. In the context of a kidney transplant, despite improvement with immunosuppressive therapies, AR maintains a significant incidence of 10%, and currently available drugs generally act in similar and canonical pathways of lymphocyte activation. This prompted the research for different approaches to identify potential novel targets that could improve therapeutic interventions. Here, we conducted a transcriptome analysis comparing groups of acute rejection (including T cell-mediated rejection and antibody-mediated rejection) to stable grafts that included differentially expressed genes, transcription factor and kinase enrichment, and Gene Set Enrichment Analysis. These analyses revealed inflammasome enhancement in rejected grafts and AIM2 as a potential component linked to acute rejection, presenting a positive correlation to T-cell activation and a negative correlation to oxidative phosphorylation metabolism. Also, the AIM2 expression showed a global accuracy in discerning acute rejection grafts (area under the curve (AUC) = 0.755 and 0.894, p < 0.0001), and meta-analysis comprising different studies indicated a considerable enhancement of AIM2 in rejection (standardized mean difference (SMD) = 1.45, [CI 95%, 1.18 to 1.71]), especially for T cell-mediated rejection (TCMR) (SMD = 2.01, [CI 95%, 1.58 to 2.45]). These findings could guide future studies of AIM2 as either an adjuvant target for immunosuppression or a potential biomarker for acute rejection and graft survival.
Metabolic-related gene pairs signature analysis identifies ABCA1 expression levels on tumor-associated macrophages as a prognostic biomarker in primary IDHWT glioblastoma
Authors: Wang Shiqun , Li Lu , Zuo Shuguang , Kong Lingkai , Wei Jiwu , Dong Jie
Published: September 2022

Background

Although isocitrate dehydrogenase (IDH) mutation serves as a prognostic signature for routine clinical management of glioma, nearly 90% of glioblastomas (GBM) patients have a wild-type IDH genotype (IDHWT) and lack reliable signatures to identify distinct entities.

Methods

To develop a robust prognostic signature for IDHWT GBM patients, we retrospectively analyzed 4 public datasets of 377 primary frozen tumor tissue transcriptome profiling and clinical follow-up data. Samples were divided into a training dataset (204 samples) and a validation (173 samples) dataset. A prognostic signature consisting of 21 metabolism-related gene pairs (MRGPs) was developed based on the relative ranking of single-sample gene expression levels. GSEA and immune subtype analyses were performed to reveal differences in biological processes between MRGP risk groups. The single-cell RNA-seq dataset was used to examine the expression distribution of each MRG constituting the signature in tumor tissue subsets. Finally, the association of MRGs with tumor progression was biologically validated in orthotopic GBM models.

Results

The metabolic signature remained an independent prognostic factor (hazard ratio, 5.71 [3.542-9.218], P < 0.001) for stratifying patients into high- and low-risk levels in terms of overall survival across subgroups with MGMTp methylation statuses, expression subtypes, and chemo/ratio therapies. Immune-related biological processes were significantly different between MRGP risk groups. Compared with the low-risk group, the high-risk group was significantly enriched in humoral immune responses and phagocytosis processes, and had more monocyte infiltration and less activated DC, NK, and γδ T cell infiltration. scRNA-seq dataset analysis identified that the expression levels of 5 MRGs (ABCA1, HMOX1, MTHFD2, PIM1, and PTPRE) in TAMs increased with metabolic risk. With tumor progression, the expression level of ABCA1 in TAMs was positively correlated with the population of TAMs in tumor tissue. Downregulation of ABCA1 levels can promote TAM polarization towards an inflammatory phenotype and control tumor growth.

Conclusions

The metabolic signature is expected to be used in the individualized management of primary IDHWT GBM patients.
Pyroptosis and respiratory diseases: A review of current knowledge
Authors: Sun Jialiang , Li Yanan
Published: September 2022

Pyroptosis is a relatively newly discovered programmed cell death accompanied by an inflammatory response. In the classical view, pyroptosis is mediated by caspases-1,-4,-5,-11 and executed by GSDMD, however, recently it was demonstrated that caspase-3 and-8 also participate in the process of pyroptosis, by cleaving GSDMD/E and GSDMD respectively. Different from autophagy and apoptosis, many pores are formed on the cell membrane during pyroptosis, which makes the cell membrane lose its integrity, eventually leading to the release of cytokines interleukin(IL)-1β and IL-18. When the body is infected with pathogens or exposed to some stimulations, pyroptosis could play an immune defense role. It is found that pyroptosis exists widely in infectious and inflammatory respiratory diseases such as acute lung injury, bronchial dysplasia, chronic obstructive pulmonary disease, and asthma. Excessive pyroptosis may accompany airway inflammation, tissue injury, and airway damage, and induce an inflammatory reaction, leading to more serious damage and poor prognosis of respiratory diseases. This review summarizes the relationship between pyroptosis and related respiratory diseases.
Exhaust the exhausters: Targeting regulatory T cells in the tumor microenvironment
Authors: McRitchie Bayley R. , Akkaya Billur
Published: September 2022

The concept of cancer immunotherapy has gained immense momentum over the recent years. The advancements in checkpoint blockade have led to a notable progress in treating a plethora of cancer types. However, these approaches also appear to have stalled due to factors such as individuals’ genetic make-up, resistant tumor sub-types and immune related adverse events (irAE). While the major focus of immunotherapies has largely been alleviating the cell-intrinsic defects of CD8+T cells in the tumor microenvironment (TME), amending the relationship between tumor specific CD4+T cells and CD8+T cells has started driving attention as well. A major roadblock to improve the cross-talk between CD4+T cells and CD8+T cells is the immune suppressive action of tumor infiltrating T regulatory (Treg) cells. Despite their indispensable in protecting tissues against autoimmune threats, Tregs have also been under scrutiny for helping tumors thrive. This review addresses how Tregs establish themselves at the TME and suppress anti-tumor immunity. Particularly, we delve into factors that promote Treg migration into tumor tissue and discuss the unique cellular and humoral composition of TME that aids survival, differentiation and function of intratumoral Tregs. Furthermore, we summarize the potential suppression mechanisms used by intratumoral Tregs and discuss ways to target those to ultimately guide new immunotherapies.
A novel cuproptosis-related molecular pattern and its tumor microenvironment characterization in colorectal cancer
Authors: Zhu Zhonglin , Zhao Qiuyan , Song Wang , Weng Junyong , Li Shanbao , Guo Tianan , Zhu Congcong , Xu Ye
Published: September 2022

Cuproptosis, or copper-induced cell death, has been reported as a novel noncanonical form of cell death in recent times. However, the potential roles of cuproptosis in the alteration of tumor clinicopathological features and the formation of a tumor microenvironment (TME) remain unclear. In this study, we comprehensively analyzed the cuproptosis-related molecular patterns of 1,274 colorectal cancer samples based on 16 cuproptosis regulators. The consensus clustering algorithm was conducted to identify cuproptosis-related molecular patterns and gene signatures. The ssGSEA and ESTIMATE algorithms were used to evaluate the enrichment levels of the infiltrated immune cells and tumor immune scores, respectively. The cuproptosis score was established to assess the cuproptosis patterns of individuals with principal component analysis algorithms based on the expression of cuproptosis-related genes. Three distinct cuproptosis patterns were confirmed and demonstrated to be associated with distinguishable biological processes and clinical prognosis. Interestingly, the three cuproptosis patterns were revealed to be consistent with three immune infiltration characterizations: immune-desert, immune-inflamed, and immune-excluded. Enhanced survival, activation of immune cells, and high tumor purity were presented in patients with low cuproptosisScore, implicating the immune-inflamed phenotype. In addition, low scores were linked to high tumor mutation burden, MSI-H and high CTLA4 expression, showing a higher immune cell proportion score (IPS). Taken together, our study revealed a novel cuproptosis-related molecular pattern associated with the TME phenotype. The formation of cuproptosisScore will further strengthen our understanding of the TME feature and instruct a more personalized immunotherapy schedule in colorectal cancer.
Distinct spatial distribution and roles of Kupffer cells and monocyte-derived macrophages in mouse acute liver injury
Authors: Flores Molina Manuel , Abdelnabi Mohamed N. , Mazouz Sabrina , Villafranca-Baughman Deborah , Trinh Vincent Quoc-Huy , Muhammad Shafi , Bédard Nathalie , Osorio Laverde David , Hassan Ghada S. , Di Polo Adriana , Shoukry Naglaa H.
Published: September 2022

Macrophages are key regulators of inflammation and repair, but their heterogeneity and multiple roles in the liver are not fully understood. We aimed herein to map the intrahepatic macrophage populations and their function(s) during acute liver injury. We used flow cytometry, gene expression analysis, multiplex-immunofluorescence, 3D-reconstruction, and spatial image analysis to characterize the intrahepatic immune landscape in mice post-CCl4-induced acute liver injury during three distinct phases: necroinflammation, and early and late repair. We observed hepatocellular necrosis and a reduction in liver resident lymphocytes during necroinflammation accompanied by the infiltration of circulating myeloid cells and upregulation of inflammatory cytokines. These parameters returned to baseline levels during the repair phase while pro-repair chemokines were upregulated. We identified resident CLEC4F+ Kupffer cells (KCs) and infiltrating IBA1+CLEC4F- monocyte-derived macrophages (MoMFs) as the main hepatic macrophage populations during this response to injury. While occupying most of the necrotic area, KCs and MoMFs exhibited distinctive kinetics, distribution and morphology at the site of injury. The necroinflammation phase was characterized by low levels of KCs and a remarkable invasion of MoMFs suggesting their potential role in phagoctosing necrotic hepatocytes, while opposite kinetics/distribution were observed during repair. During the early repair phase, yolksac - derived KCs were restored, whereas MoMFs diminished gradually then dissipated during late repair. MoMFs interacted with hepatic stellate cells during the necroinflammatory and early repair phases, potentially modulating their activation state and influencing their fibrogenic and pro-repair functions that are critical for wound healing. Altogether, our study reveals novel and distinct spatial and temporal distribution of KCs and MoMFs and provides insights into their complementary roles during acute liver injury.
Comparative genomics of Staphylococcus capitis reveals species determinants
Authors: Chong Charlotte E. , Bengtsson Rebecca J. , Horsburgh Malcolm James
Published: September 2022

Staphylococcus capitis is primarily described as a human skin commensal but is now emergent as an opportunistic pathogen isolated from the bloodstream and prosthetic joint infections, and neonatal intensive care unit (NICU)-associated sepsis. We used comparative genomic analyses of S. capitis to provide new insights into commensal scalp isolates from varying skin states (healthy, dandruff lesional, and non-lesional), and to expand our current knowledge of the species populations (scalp isolates, n = 59; other skin isolates, n = 7; publicly available isolates, n = 120). A highly recombinogenic population structure was revealed, with genomes including the presence of a range of previously described staphylococcal virulence factors, cell wall-associated proteins, and two-component systems. Genomic differences between the two described S. capitis subspecies were explored, which revealed the determinants associated exclusively with each subspecies. The subspecies ureolyticus was distinguished from subspecies capitis based on the differences in antimicrobial resistance genes, β-lactam resistance genes, and β-class phenol soluble modulins and gene clusters linked to biofilm formation and survival on skin. This study will aid further research into the classification of S. capitis and virulence-linked phylogroups to monitor the spread and evolution of S. capitis.
Long non-coding RNA NBAT1, TUG1, miRNA-335, and miRNA-21 as potential biomarkers for acute ischemic stroke and their possible correlation to thyroid hormones
Authors: Mohammed Asmaa , Shaker Olfat G. , Khalil Mahmoud A. F. , Gomaa Mohammed , Fathy Shaimaa A. , Abu-El-Azayem Abeer K. , Samy Amira , Aboelnor Mahmoud I. , Gomaa Mohamed S. , Zaki Othman M. , Erfan Randa
Published: September 2022

Objective: RNA-based mechanisms of epigenetic modification related to acute ischemic stroke (AIS) have been widely studied recently. The current work aimed to determine the potential roles of four ncRNAs (TUG1 and its target miR-21, NBAT1, and miR-335) as promising diagnostic biomarkers in AIS as well as their involvement in the disease pathogenesis.

Methods: The levels of the studied lncRNAs and miRNAs were measured in the serum for two different groups, including patients with AIS (60) and healthy controls (60). All individuals were subjected to a full history investigation and clinical examination. Blood samples were tested for FBS, 2HPP, TAG, HDL, LDL, TSH, T3, and T4 levels.

Results: The serum levels of TUG1 were significantly increased in AIS patients compared to control subjects. It is worthwhile to note that serum TUG1 levels were positively correlated with cholesterol, triglycerides, LDL, carotid IMT (Intima-media thickness), and miR-21, while they were negatively correlated with HDL levels. Our study showed that NBAT1 serum expression levels were elevated in AIS patients compared to controls. NBAT1 expression levels were observed to be positively correlated with triglycerides, TUG1, and miR-21. NBAT1 could distinguish between AIS patients and controls with a sensitivity of 100% and specificity of 100% at a cut-off point of 1.45. Regarding miR-335, we found that its expression levels were downregulated in AIS patients compared with healthy controls. It could distinguish between AIS patients and controls with a sensitivity of 73.3% and a specificity of 100% at a cut-off point of 0.796.

Conclusion: Our results revealed that serum TUG1, miR-21, NBAT1, and miR-335 could be promising molecular diagnostic markers for AIS as these biomarkers could discriminate between AIS patients and healthy controls.
Impaired ankle inversion proprioception during walking is associated with fear of falling in older adults
Authors: Shao Xuerong , Wang Zheng , Luan Lijiang , Sheng Yilan , Yu Ruoni , Pranata Adrian , Adams Roger , Zhang Anren , Han Jia
Published: September 2022

Background

Ankle proprioception plays a critical role in lower limb movement control. However, the relationship between ankle proprioception and fear of falling (FOF) in older people is still unclear.

Objective

(1) This study aims to develop a new device for measuring ankle inversion proprioceptive discrimination sensitivity during walking, i.e., the Ankle Inversion Discrimination Apparatus–Walking (AIDAW), and assess the test–retest reliability of the AIDAW in both young and older adults; (2) to evaluate the discriminant validity of the measure by comparing ankle proprioception during walking between the two groups; and (3) to explore convergent validity by determining to what extent the AIDAW proprioceptive scores correlate with Fall Efficacy Scale-International (FES-I) scores.

Materials and methods

The AIDAW was purpose-built to test ankle inversion proprioceptive discrimination sensitivity during walking. The area under the receiver operating curve (AUC) was calculated as the proprioceptive discrimination score. In total, 54 adults volunteered. Test–retest reliability was evaluated in 12 young and 12 older adults, and another 15 young and 15 older adults completed the comparison study. FOF was assessed by using the FES-I.

Results

The test–retest reliability intraclass correlation coefficient ICC (3,1) value for the whole group was 0.76 (95% CI: 0.52–0.89). The ICC values of the young and older groups were 0.81 (95% CI: 0.46–0.94) and 0.71 (95% CI: 0.26–0.91), respectively. The Minimal Detectable Change with 90% confidence (MDC90) values for the young and older groups were 0.03 and 0.11, respectively. There was a significant difference between the AIDAW proprioceptive sensitivity scores for the young and older groups (0.78 ± 0.04 vs. 0.72 ± 0.08, F = 5.06, p = 0.033). Spearman’s correlation analysis showed that the FES-I scores were significantly and negatively correlated with the AIDAW scores (rho = −0.61, p = 0.015), with higher FOF associated with worse ankle proprioception.

Conclusion

The AIDAW is a reliable and valid device for measuring ankle proprioception during walking in both young and older adults. Ankle inversion proprioceptive discrimination sensitivity during walking was found to be impaired in the elderly compared to young adults. This impairment was found to be strongly associated with FOF, suggesting that assessment and intervention for ankle proprioception in this population are needed to reduce the risk of falls.
Characterization of white matter over 1–2 years in small vessel disease using MR-based quantitative susceptibility mapping and free-water mapping
Authors: Sun Yawen , Hu Ying , Qiu Yage , Zhang Yuyao , Jiang Changhao , Lu Peiwen , Xu Qun , Shi Yuting , Wei Hongjiang , Zhou Yan
Published: September 2022

Purpose

The aim of this study was to investigate alterations in white matter lesions (WMLs) and normal-appearing white matter (NAWM) with small vessel disease (SVD) over 1–2 years using quantitative susceptibility mapping (QSM) and free-water (FW) mapping.

Methods

Fifty-one SVD patients underwent MRI brain scans and neuropsychological testing both at baseline and follow-up. The main approach for treating these patients is the management of risk factors. Quantitative susceptibility (QS), fractional anisotropy (FA), mean diffusivity (MD), FW, FW-corrected FA (FAT), and FW-corrected MD (MDT) maps within WMLs and NAWM were generated. Furthermore, the JHU-ICBM-DTI label atlas was used as an anatomic guide, and the measurements of the segmented NAWMs were calculated. The average regional values were extracted, and a paired t-test was used to analyze the longitudinal change. Partial correlations were used to assess the relationship between the MRI indices changes (e.g., ΔQSfollowup − baseline/QSbaseline) and the cognitive function changes (e.g., ΔMoCAfollowup − baseline/MoCAbaseline).

Results

After SVD risk factor control, no gradual cognitive decline occurred during 1–2 years. However, we still found that the QS values (index of demyelination) increased in the NAWM at follow-up, especially in the NAWM part of the left superior frontal blade (SF), left occipital blade, right uncinate fasciculus, and right corticospinal tract (CST). FW (index of neuroinflammation/edema) analysis revealed that the follow-up group differed from the baseline group in the NAWM part of the right CST and inferior frontal blade (IF). Decreased FAT (index of axonal loss) was observed in the NAWM part of the right SF and IF at follow-up. In addition, the FAT changes in the NAWM part of the right IF were associated with overall cognitive performance changes. In contrast, no significant differences were found in the WMLs.

Conclusion

The NAWM was still in the progressive injury process over time, while WMLs remained relatively stable, which supports the notion that SVD is a chronic progressive disease. The process of axonal loss in the NAWM part of the prefrontal lobe might be a biomarker of cognitive changes in the evolution of SVD.
Thirty-six months recurrence after acute ischemic stroke among patients with comorbid type 2 diabetes: A nested case-control study
Authors: Wang Lu , Li Hongyun , Hao Jiheng , Liu Chao , Wang Jiyue , Feng Jingjun , Guo Zheng , Zheng Yulu , Zhang Yanbo , Li Hongxiang , Zhang Liyong , Hou Haifeng
Published: September 2022

Background

Stroke patients have to face a high risk of recurrence, especially for those with comorbid T2DM, which usually lead to much more serious neurologic damage and an increased likelihood of death. This study aimed to explore determinants of stroke relapse among patients with comorbid T2DM.

Materials and methods

We conducted this case-control study nested a prospective cohort of ischemic stroke (IS) with comorbid T2DM. During 36-month follow-up, the second stroke occurred in 84 diabetic IS patients who were allocated into the case group, while 613 patients without recurrence were the controls. We collected the demographic data, behaviors and habits, therapies, and family history at baseline, and measured the variables during follow-up. LASSO and Logistic regression analyses were carried out to develop a prediction model of stroke recurrence. The receiver operator characteristic (ROC) curve was employed to evaluate the performance of the prediction model.

Results

Compared to participants without recurrence, the higher levels of pulse rate (78.29 ± 12.79 vs. 74.88 ± 10.93) and hypertension (72.6 vs. 61.2%) were recorded at baseline. Moreover, a lower level of physical activity (77.4 vs. 90.4%), as well as a higher proportion of hypoglycemic therapy (36.9 vs. 23.3%) was also observed during 36-month follow-up. Multivariate logistic regression revealed that higher pulse rate at admission (OR = 1.027, 95 %CI = 1.005–1.049), lacking physical activity (OR = 2.838, 95% CI = 1.418–5.620) and not receiving hypoglycemic therapy (OR = 1.697, 95% CI = 1.013–2.843) during follow-up increased the risk of stroke recurrence. We developed a prediction model using baseline pulse rate, hypoglycemic therapy, and physical activity, which produced an area under ROC curve (AUC) of 0.689.

Conclusion

Physical activity and hypoglycemic therapy play a protective role for IS patients with comorbid diabetes. In addition to targeted therapeutics, the improvement of daily-life habit contributes to slowing the progress of the IS.
Cellular autophagy, the compelling roles in hearing function and dysfunction
Authors: Wan Huanzhi , Zhang Yuanyuan , Hua Qingquan
Published: September 2022

Sensorineural hearing loss (SNHL) is currently a major health issue. As one of the most common neurodegenerative diseases, SNHL is associated with the degradation of hair cells (HCs), spiral ganglion neurons (SGNs), the stria vascularis, supporting cells and central auditory system cells. Autophagy is a highly integrated cellular system that eliminates impaired components and replenishes energy to benefit cellular homeostasis. Etiological links between autophagy alterations and neurodegenerative diseases, such as SNHL, have been established. The hearing pathway is complex and depends on the comprehensive functions of many types of tissues and cells in auditory system. In this review, we discuss the roles of autophagy in promoting and inhibiting hearing, paying particular attention to specific cells in the auditory system, as discerned through research. Hence, our review provides enlightening ideas for the role of autophagy in hearing development and impairment.
Urinary sodium excretion is low prior to acute kidney injury in patients in the intensive care unit
Authors: de Morais David Gomes , Sanches Talita Rojas Cunha , Santinho Mirela Aparecida Rodrigues , Yada Eduardo Yuki , Segura Gabriela Cardoso , Lowe Diogo , Navarro Guilherme , Seabra Victor Faria , Taniguchi Leandro Utino , Malbouisson Luiz Marcelo Sá , de André Carmen Diva Saldiva , Andrade Lúcia , Rodrigues Camila Eleuterio
Published: September 2022

Background

The incidence of acute kidney injury (AKI) is high in intensive care units (ICUs), and a better understanding of AKI is needed. Early chronic kidney disease is associated with urinary concentration inability and AKI recovery with increased urinary solutes in humans. Whether the inability of the kidneys to concentrate urine and excrete solutes at appropriate levels could occur prior to the diagnosis of AKI is still uncertain, and the associated mechanisms have not been studied.

Methods

In this single-center prospective observational study, high AKI risk in ICU patients was followed up for 7 days or until ICU discharge. They were grouped as “AKI” or “No AKI” according to their AKI status throughout admission. We collected daily urine samples to measure solute concentrations and osmolality. Data were analyzed 1 day before AKI, or from the first to the fifth day of admission in the “No AKI” group. We used logistic regression models to evaluate the influence of the variables on future AKI diagnosis. The expression of kidney transporters in urine was evaluated by Western blotting.

Results

We identified 29 patients as “No AKI” and 23 patients as “AKI,” the latter being mostly low severity AKI. Urinary sodium excretion was lower in “AKI” patients prior to AKI diagnosis, particularly in septic patients. The expression of Na+/H+ exchanger (NHE3), a urinary sodium transporter, was higher in “AKI” patients.

Conclusions

Urinary sodium excretion is low before an AKI episode in ICU patients, and high expressions of proximal tubule sodium transporters might contribute to this.
Clinical and genetic characterization of a Taiwanese cohort with spastic paraparesis combined with cerebellar involvement
Authors: Lan Min-Yu , Lu Chin-Song , Wu Shey-Lin , Chen Ying-Fa , Sung Yueh-Feng , Tu Min-Chien , Chang Yung-Yee
Published: September 2022

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders clinically characterized by progressive lower-limb spasticity. Cerebellar ataxia commonly co-occurs with complicated HSPs. HSP with concurrent cerebellar ataxia has significant clinical and genetic overlaps with hereditary cerebellar ataxia (HCA) and other inherited neurological diseases, adding to the challenge of planning genetic testing for the disease. In this study, we characterized clinical features of a cohort of 24 patients (male/female: 15/9) from 22 families who presented spastic paraparesis combined with cerebellar involvement, with a median disease onset age 20.5 (range 5–53) years. Aside from the core phenotype, 18 (75%) patients had additional neuropsychiatric and systemic manifestations. A stepwise genetic testing strategy stratified by mode of inheritance, distinct neuroimaging features (e.g., thin corpus callosum), population-specific prevalence and whole-exome sequencing was utilized to investigate the genetic etiology. Causative mutations in up to 10 genes traditionally related to HSP, HCA and other neurogenetic diseases (autosomal recessive spastic ataxia of Charlevoix-Saguenay, neurodegeneration with brain iron accumulation, and progressive encephalopathy with brain atrophy and thin corpus callosum) were detected in 16 (73%) of the 22 pedigrees. Our study revealed the genetic complexity of HSP combined with cerebellar involvement. In contrast to the marked genetic diversity, the functions of the causative genes are restricted to a limited number of physiological themes. The functional overlap might reflect common underlying pathogenic mechanisms, to which the corticospinal tract and cerebellar neuron circuits may be especially vulnerable.
Roles of fMRI and Wada tests in the presurgical evaluation of language functions in temporal lobe epilepsy
Authors: Massot-Tarrús Andreu , Mirsattari Seyed M.
Published: September 2022

Surgical treatment of pharmacoresistant temporal lobe epilepsy (TLE) carries risks for language function that can significantly affect the quality of life. Predicting the risks of decline in language functions before surgery is, consequently, just as important as predicting the chances of becoming seizure-free. The intracarotid amobarbital test, generally known as the Wada test (WT), has been traditionally used to determine language lateralization and to estimate their potential decline after surgery. However, the test is invasive and it does not localize the language functions. Therefore, other noninvasive methods have been proposed, of which functional magnetic resonance (fMRI) has the greatest potential. Functional MRI allows localization of language areas. It has good concordance with the WT for language lateralization, and it is of predictive value for postsurgical naming outcomes. Consequently, fMRI has progressively replaced WT for presurgical language evaluation. The objective of this manuscript is to review the most relevant aspects of language functions in TLE and the current role of fMRI and WT in the presurgical evaluation of language. First, we will provide context by revising the language network distribution and the effects of TLE on them. Then, we will assess the functional outcomes following various forms of TLE surgery and measures to reduce postoperative language decline. Finally, we will discuss the current indications for WT and fMRI and the potential usefulness of the resting-state fMRI technique.
Case report: Blepharospasm in peak-dose dyskinesia may benefit from amantadine in Parkinson's disease
Authors: Fan Qian-Ya , Zhang Xiao-Dong , Hu Ze-Di , Huang Shi-Shi , Zhu Shi-Guo , Chen Cai-Ping , Zhang Xiong , Wang Jian-Yong
Published: September 2022

Introduction

Blepharospasm is uncommon in Parkinson's disease, especially in the peak-dose dyskinesia period.

Case presentation

We herein present the case of a patient with PD who developed blepharospasm in the peak-dose dyskinesia period. The symptom was improved by taking amantadine.

Conclusion

The current report expands the phenomenology of peak-dose dykinesia in PD to include dystonic blepharospasm. This complication of levodopa therapy may respond to amantadine despite the dystonic appearance of movements.
Effects of age and sex on outcomes of the Q-Motor speeded finger tapping and grasping and lifting tests-findings from the population-based BiDirect Study
Authors: Teismann Henning , Schubert Robin , Reilmann Ralf , Berger Klaus
Published: September 2022

Background

Q-Motor is a suite of motor tests originally designed to assess motor symptoms in Huntington's disease. Among others, Q-Motor encompasses a finger tapping task and a grasping and lifting task. To date, there are no systematic investigations regarding effects of variables which may affect the performance in specific Q-Motor tests per se, and normative Q-Motor data based on a large population-based sample are not yet available.

Objective

We investigated effects of age and sex on five selected Q-Motor outcomes representing the two core Q-Motor tasks speeded finger tapping and grasping and lifting in a community sample of middle-aged to elderly adults. Furthermore, we explored effects of the potentially mediating variables educational attainment, alcohol consumption, smoking status, and depressive symptoms. Moreover, we explored inter-examiner variability. Finally, we compared the findings to findings for the Purdue Pegboard test.

Methods

Based on a sample of 726 community-dwelling adults and using multiple (Gaussian) regression analysis, we modeled the motor outcomes using age, sex, years in full-time education, depressive symptoms in the past seven days, alcohol consumption in the past seven days, and smoking status as explanatory variables.

Results

With regard to the Q-Motor tests, we found that more advanced age was associated with reduced tapping speed, male sex was associated with increased tapping speed and less irregularity, female sex was associated with less involuntary movement, more years of education were associated with increased tapping speed and less involuntary movement, never smoking was associated with less involuntary movement compared to current smoking, and more alcohol consumed was associated with more involuntary movement.

Conclusion

The present results show specific effects of age and sex on Q-Motor finger tapping and grasping and lifting performance. In addition, besides effects of education, there also were specific effects of smoking status and alcohol consumption. Importantly, the present study provides normative Q-Motor data based on a large population-based sample. Overall, the results are in favor of the feasibility and validity of Q-Motor finger tapping and grasping and lifting for large observational studies. Due to their low task-complexity and lack of placebo effects, Q-Motor tests may generate additional value in particular with regard to clinical conditions such as Huntington's or Parkinson's disease.
Increased PRR14 and VCAM-1 level in serum of patients with Parkinson's disease
Authors: Zheng Huimin , Wang Tai , Shi Changhe , Fan Liyuan , Su Yun , Fan Yu , Li Xinwei , Yang Jing , Mao Chengyuan , Xu Yuming
Published: September 2022

Background

Regarding the complexity of Parkinson's disease (PD), the identification of reliable biomarkers is of great significance for improving the accuracy of diagnosis and monitoring disease progression. Recently, some studies suggested that serum proline-rich protein 14 (PRR14), vascular cell adhesion molecule-1 (VCAM-1), and soluble CD163 (sCD163) factors may be associated with PD, even as potential biomarkers. However, the role of these serum factors is still unclear.

Objectives

This study aimed to explore the alterations of serum PRR14, VCAM-1, and sCD163 levels during PD progression, and their association with disease-related variables of PD.

Methods

We performed the assessment of scale tests and the detection of serum samples in patients with PD (n = 100) and healthy controls (HCs, n = 100). Furthermore, we investigated the association between serum factors and sex, cognitive impairments, H&Y (Hohn and Yahr), age at onset (AAO), and other variables in patients with PD.

Results

Patients with PD exhibited increased PRR14 and VCAM-1 serum levels compared with HCs. No significant differences were found in serum levels of sCD163. Subgroup analysis uncovered increased VCAM-1 in the female and male subgroups (PD and HCs). Among patients with PD, decreased PRR14 and increased VCAM-1 were associated with severer cognitive impairments and severer PD (H&Y), respectively. Bivariate correlation analysis revealed that there was a positive correlation between VCAM-1 and AAO.

Conclusions

Increased serum levels of PRR14 and VCAM-1 suggest that inflammation and defective autophagy may play vital roles in the pathogenesis of PD. However, the potential mechanisms remain to be elucidated.