bluuebunny/crossref_metadata_2025 huggingface dataset:
Urinary Angiotensinogen-Melatonin Ratio in Gestational Diabetes and Preeclampsia
Authors: Valias Gabriela Ribeiro , Gomes Patricia Rodrigues Lourenço , Amaral Fernanda G. , Alnuaimi Saif , Monteiro Daniela , O'Sullivan Siobhán , Zangaro Renato , Cipolla-Neto José , Acuna Juan , Baltatu Ovidiu Constantin , Campos Luciana Aparecida
Published: March 2022

Background: A large research portfolio indicates that an activated renal renin-angiotensin system or a deficit on melatonin is associated with several cardiovascular pathologies. In this observational clinical study, we hypothesized that alterations in urinary melatonin or angiotensinogen levels may be altered in two common conditions, preeclampsia and gestational diabetes. Our study’s primary objective was to assess melatonin and angiotensinogen as novel disease biomarkers detectable and quantifiable in the urine of pregnant women with or without pregnancy complications.

Methods: This was a concurrent cohort study of pregnant women with selected obstetric pathologies (gestational diabetes, preeclampsia, hypertension and obesity with hypertension). A group of healthy controls was also included. Urinary 6-sulfatoxymelatonin and angiotensinogen were measured by sensitive and specific ELISAs in first morning void urine samples. The patients were included in the cohort consecutively, and the diagnosis was blinded at the level of urine collection. Urinary 6-sulfatoxymelatonin and angiotensinogen levels were investigated in the patients included in the cohort.

Results: Urinary levels of angiotensinogen were significantly higher in the gestational diabetes [angiotensinogen/creatinine ratio median (25th, 75th): 0.11 (0.07, 0.18)] and preeclampsia [0.08 (0.06, 0.18)] groups than in those with healthy pregnancy [0.05(0.04, 0.06]; 6-sulfatoxymelatonin levels were significantly lower in the gestational diabetes [ug/h: median (25th, 75th): 0.12(0.08, 0.17)] and preeclampsia [0.12 (0.09, 0.15)] groups than in those with healthy pregnancy [0.20 (0.15, 0.27]. Neither morning void protein/creatinine ratio nor 24-h urine protein estimate were significantly different between the study groups.

Conclusion: These results suggest that urinary angiotensinogen levels may indicate an intrarenal RAS activation while melatonin production appears to be defective in gestational diabetes or hypertension. An angiotensinogen/melatonin ratio is suggested as an early biomarker for identification of gestational diabetes or hypertension. This report provides a basis for the potential use of melatonin for the treatment of preeclampsia. A prospective study in a larger number of patients to determine the operative characteristics of these markers as potential diagnostic tests is justified.
Molecular and Clinical Repercussions of GABA Transporter 1 Variants Gone Amiss: Links to Epilepsy and Developmental Spectrum Disorders
Authors: Fischer Florian P. , Kasture Ameya S. , Hummel Thomas , Sucic Sonja
Published: March 2022

The human γ-aminobutyric acid (GABA) transporter 1 (hGAT-1) is the first member of the solute carrier 6 (SLC6) protein superfamily. GAT-1 (SLC6A1) is one of the main GABA transporters in the central nervous system. Its principal physiological role is retrieving GABA from the synapse into neurons and astrocytes, thus swiftly terminating neurotransmission. GABA is a key inhibitory neurotransmitter and shifts in GABAergic signaling can lead to pathological conditions, from anxiety and epileptic seizures to schizophrenia. Point mutations in the SLC6A1 gene frequently give rise to epilepsy, intellectual disability or autism spectrum disorders in the afflicted individuals. The mechanistic routes underlying these are still fairly unclear. Some loss-of-function variants impair the folding and intracellular trafficking of the protein (thus retaining the transporter in the endoplasmic reticulum compartment), whereas others, despite managing to reach their bona fide site of action at the cell surface, nonetheless abolish GABA transport activity (plausibly owing to structural/conformational defects). Whatever the molecular culprit(s), the physiological aftermath transpires into the absence of functional transporters, which in turn perturbs GABAergic actions. Dozens of mutations in the kin SLC6 family members are known to exhort protein misfolding. Such events typically elicit severe ailments in people, e.g., infantile parkinsonism-dystonia or X-linked intellectual disability, in the case of dopamine and creatine transporters, respectively. Flaws in protein folding can be rectified by small molecules known as pharmacological and/or chemical chaperones. The search for such apt remedies calls for a systematic investigation and categorization of the numerous disease-linked variants, by biochemical and pharmacological means in vitro (in cell lines and primary neuronal cultures) and in vivo (in animal models). We here give special emphasis to the utilization of the fruit fly Drosophila melanogaster as a versatile model in GAT-1-related studies. Jointly, these approaches can portray indispensable insights into the molecular factors underlying epilepsy, and ultimately pave the way for contriving efficacious therapeutic options for patients harboring pathogenic mutations in hGAT-1.
The Interplay Between Brain Vascular Calcification and Microglia
Authors: Maheshwari Upasana , Huang Sheng-Fu , Sridhar Sucheta , Keller Annika
Published: March 2022

Vascular calcifications are characterized by the ectopic deposition of calcium and phosphate in the vascular lumen or wall. They are a common finding in computed tomography scans or during autopsy and are often directly related to a pathological condition. While the pathogenesis and functional consequences of vascular calcifications have been intensively studied in some peripheral organs, vascular calcification, and its pathogenesis in the central nervous system is poorly characterized and understood. Here, we review the occurrence of vessel calcifications in the brain in the context of aging and various brain diseases. We discuss the pathomechanism of brain vascular calcification in primary familial brain calcification as an example of brain vessel calcification. A particular focus is the response of microglia to the vessel calcification in the brain and their role in the clearance of calcifications.
Transcranial Direct-Current Stimulation as an Adjunct to Verb Network Strengthening Treatment in Post-stroke Chronic Aphasia: A Double-Blinded Randomized Feasibility Study
Authors: Matar Shereen J. , Newton Caroline , Sorinola Isaac O. , Pavlou Marousa
Published: March 2022

Background

Difficulties in discourse production are common in post-stroke chronic aphasia. Previous studies have found that speech and language therapy combined with transcranial direct-current stimulation (tDCS) may improve language skills like naming and enhance aphasia treatment outcomes. However, very few studies have investigated the effect of tDCS when combined with interventions for improving higher level language skills such as the Verb Network Strengthening Treatment (VNeST).

Aims

This study aimed to determine the feasibility of anodal tDCS as an adjunct to VNeST to improve discourse production in post-stroke chronic aphasia.

Methods

Six people with post-stroke chronic aphasia took part in this double-blinded randomized feasibility study. Participants were randomly allocated to either the experimental group receiving a 6-week block of once weekly VNeST sessions combined with active tDCS over the left inferior frontal gyrus (LIFG) or a control group that received VNeST with sham stimulation. Feasibility outcomes included screening, eligibility, retention, and completion rates, and adverse events. Preliminary response to intervention was also examined using discourse production, functional communication, quality of life, psychological state, and cognition outcomes.

Results

Overall 19 individuals were screened and ten met the inclusion criteria. Six individuals provided consent and participated in the study giving a consent rate of 60%. Participant retention and completion rates were 100% and no adverse effects were reported. Exploratory analyses revealed promising changes (i.e., estimated large effect size) in discourse production measures across discourse language tasks and functional communication for the active tDCS group.

Conclusions

Our results support the feasibility of tDCS as an adjunct to VNeST. Preliminary findings provide motivation for future large-scale studies to better understand the potential of tDCS as a safe and economical tool for enhancing rehabilitation in chronic aphasia.
Identification of Stroke and TIA in Patients With Acute Dizziness, Vertigo or Imbalance in Emergency Departments of Primary Care Hospitals: Early Experiences With a Network-Based Telemedical Approach
Authors: Müller-Barna Peter , Leinweber Christina , Pfaffenrath Julia , Schütt-Becker Nina , von Martial Rascha , Greck Susanne , Hubert Nikolai , Rambold Holger , Haberl Roman , Hubert Gordian Jan
Published: March 2022

Background

Acute dizziness, vertigo, and imbalance are frequent and difficult to interpret symptoms in the emergency department (ED). Primary care hospitals often lack the expertise to identify stroke or TIA as underlying causes. A telemedical approach based on telestroke networks may offer adequate diagnostics and treatment.

Aim

The aim of this study is to evaluate the accuracy of a novel ED algorithm in differentiating between peripheral and central vestibular causes.

Methods

Within the Telemedical Project for Integrative Stroke Care (TEMPiS), a telemedical application including a videooculography (VOG) system was introduced in 2018 in 19 primary care spoke hospitals. An ED triage algorithm was established for all patients with acute dizziness, vertigo, or imbalance of unknown cause (ADVIUC) as a leading complaint. In three predefined months, all ADVIUC cases were prospectively registered and discharge letters analyzed. Accuracy of the ED triage algorithm in differentiation between central and peripheral vestibular cases was analyzed by comparison of ED diagnoses to final discharge diagnoses. The rate of missed strokes was calculated in relation to all cases with a suitable brain imaging. Acceptance of teleconsultants and physicians in spoke hospitals was assessed by surveys.

Results

A total number of 388 ADVIUC cases were collected, with a median of 12 cases per months and hospital (IQR 8–14.5). The most frequent hospital discharge diagnoses are vestibular neuritis (22%), stroke/TIA (18%), benign paroxysmal positioning vertigo (18%), and dizziness due to internal medicine causes (15%). Detection of a central vestibular cause by the ED triage algorithm has a high sensitivity (98.6%), albeit poor specificity (45.9%). One stroke out of 32 verified by brain scan was missed (3.1%). User satisfaction, helpfulness of the project, improvement of care, personal competence, and satisfaction about handling of the VOG systems were rated consistently positive.

Discussion

The concept shows good acceptance for a telemedical and network-based approach to manage ADVIUC cases in the ED of primary care hospitals. Identification of stroke cases is accurate, while specificity needs further improvement. The concept could be a major step toward a broadly available state of the art diagnostics and therapy for patients with ADVIUC in primary care hospitals.
Influence of Treadmill Design on Gait: Does Treadmill Size Affect Muscle Activation Amplitude? A Musculoskeletal Calculation With Individualized Input Parameters of Gait Analysis
Authors: Woiczinski Matthias , Lehner Carolin , Esser Thekla , Kistler Manuel , Azqueta Monica , Leukert Johannes , Bauer Leandra , Kraft Eduard
Published: March 2022

With increasing age, gait changes often occur, leading to mobility problems and thus a higher risk of falling. Interest in training at home or at retirement homes has led to the development of “mobile treadmills.” A difference in treadmill surface length may influence walking parameters (i.e., step length) and therefore may affect muscle activation. This led to the question: Does the treadmill size affect the muscle activation, i.e., with the length of the walking surface. The study aimed to investigate the influence of treadmill size, i.e., length of the walking surface, on gait pattern and to determine differences in the amplitude of muscle activation using a participant-specific musculoskeletal model (AnyBody Technology A/S, Aalborg, Denmark). For a prospective, randomized study gait parameters were collected from 47 healthy participants (aged 50.19 ± 20.58 years) while walking on two different treadmills, a small mobile treadmill (walking surface length 100 cm) and a conventional treadmill (walking surface length 150 cm), at their preferred speed, 2 km/h, and 4 km/h. Muscle activation amplitude patterns were similar between treadmills (M. gastrocnemius medialis: rmean = 0.94, M. gastrocnemius lateralis: rmean = 0.92, M. gluteus medius rmean = 0.90, M. gluteus minimus rmean = 0.94). However, the gait analysis showed a decreased preferred velocity (p < 0.001, z = 4.54), reduced stride length (preferred velocity: p = 0.03, z = −2.17; 2 km/h: p = 0.36, z = 2.10; 4 km/h: p = 0.006, z = 2.76), shorter stride time (2 km/h: p < 0.001, z = 4.65; 4 km/h: p < 0.001, z = 4.15), and higher cadence (2 km/h: p < 0.001, z = −4.20; 4 km/h: p = 0.029, z = −2.18) on the mobile treadmill than on the conventional treadmill. Our observations suggest that the treadmill design (e.g., a 50 cm difference in walking surface length) may not influence muscle activity amplitude during walking. However, the design of the treadmill may influence gait characteristics (e.g., stride length, cadence) of walking.
Visual Perturbation Suggests Increased Effort to Maintain Balance in Early Stages of Parkinson’s to be an Effect of Age Rather Than Disease
Authors: Student Justus , Engel David , Timmermann Lars , Bremmer Frank , Waldthaler Josefine
Published: March 2022

Postural instability marks a prevalent symptom of Parkinson’s disease (PD). It often manifests in increased body sway, which is commonly assessed by tracking the Center of Pressure (CoP). Yet, in terms of postural control, the body’s Center of Mass (CoM), and not CoP is what is regulated in a gravitational field. The aim of this study was to explore the effect of early- to mid-stage PD on these measures of postural control in response to unpredictable visual perturbations. We investigated three cohorts: (i) 18 patients with early to mid-stage PD [Hoehn & Yahr stage (1–3); 1.94 ± 0.70]; (ii) a group of 15 age-matched controls (ECT); and (iii) a group of 12 young healthy adults (YCT). Participants stood on a force plate to track their CoP, while the movement of their entire body was recorded with a video-based motion tracking system to monitor their CoM. A moving room paradigm was applied through a head-mounted virtual reality headset. The stimulus consisted of a virtual tunnel that stretched in the anterior-posterior direction which either remained static or moved back and forth in an unpredictable fashion.We found differences in mean sway amplitude (MSA) and mean velocities of CoP and CoM between the groups under both conditions, with higher MSA of CoP and CoM for PD and higher mean velocities of both variables for PD and ECT when compared with YCT. Visual perturbation increased mean CoP velocity in all groups but did not have effects on mean CoM velocity or MSA. While being significantly lower for the young adults, the net effect of visual perturbation on mean CoP velocity was similar between patients with PD and age-matched controls. There was no effect of the visual perturbation on mean CoM velocity for any of the groups.Our simultaneous assessment of CoP and CoM revealed that postural control is reflected differently in CoM and CoP. As the motion of CoM remained mostly unaffected, all groups successfully counteracted the perturbation and maintained their balance. Higher CoP velocity for PD and ECT revealed increased corrective motion needed to achieve this, which however was similar in both groups. Thus, our results suggest increased effort, expressed in CoP velocity, to be an effect of age rather than disease in earlier stages of PD.
RealNeuralNetworks.jl: An Integrated Julia Package for Skeletonization, Morphological Analysis, and Synaptic Connectivity Analysis of Terabyte-Scale 3D Neural Segmentations
Authors: Wu Jingpeng , Turner Nicholas , Bae J. Alexander , Vishwanathan Ashwin , Seung H. Sebastian
Published: March 2022

Benefiting from the rapid development of electron microscopy imaging and deep learning technologies, an increasing number of brain image datasets with segmentation and synapse detection are published. Most of the automated segmentation methods label voxels rather than producing neuron skeletons directly. A further skeletonization step is necessary for quantitative morphological analysis. Currently, several tools are published for skeletonization as well as morphological and synaptic connectivity analysis using different computer languages and environments. Recently the Julia programming language, notable for elegant syntax and high performance, has gained rapid adoption in the scientific computing community. Here, we present a Julia package, called RealNeuralNetworks.jl, for efficient sparse skeletonization, morphological analysis, and synaptic connectivity analysis. Based on a large-scale Zebrafish segmentation dataset, we illustrate the software features by performing distributed skeletonization in Google Cloud, clustering the neurons using the NBLAST algorithm, combining morphological similarity and synaptic connectivity to study their relationship. We demonstrate that RealNeuralNetworks.jl is suitable for use in terabyte-scale electron microscopy image segmentation datasets.
Repetitive Restricted Behaviors in Autism Spectrum Disorder: From Mechanism to Development of Therapeutics
Authors: Tian Junbin , Gao Xuping , Yang Li
Published: March 2022

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social communication, social interaction, and repetitive restricted behaviors (RRBs). It is usually detected in early childhood. RRBs are behavioral patterns characterized by repetition, inflexibility, invariance, inappropriateness, and frequent lack of obvious function or specific purpose. To date, the classification of RRBs is contentious. Understanding the potential mechanisms of RRBs in children with ASD, such as neural connectivity disorders and abnormal immune functions, will contribute to finding new therapeutic targets. Although behavioral intervention remains the most effective and safe strategy for RRBs treatment, some promising drugs and new treatment options (e.g., supplementary and cell therapy) have shown positive effects on RRBs in recent studies. In this review, we summarize the latest advances of RRBs from mechanistic to therapeutic approaches and propose potential future directions in research on RRBs.
Looking for “fNIRS Signature” in Autism Spectrum: A Systematic Review Starting From Preschoolers
Authors: Conti Eugenia , Scaffei Elena , Bosetti Chiara , Marchi Viviana , Costanzo Valeria , Dell’Oste Valerio , Mazziotti Raffaele , Dell’Osso Liliana , Carmassi Claudia , Muratori Filippo , Baroncelli Laura , Calderoni Sara , Battini Roberta
Published: March 2022

Accumulating evidence suggests that functional Near-Infrared Spectroscopy (fNIRS) can provide an essential bridge between our current understanding of neural circuit organization and cortical activity in the developing brain. Indeed, fNIRS allows studying brain functions through the measurement of neurovascular coupling that links neural activity to subsequent changes in cerebral blood flow and hemoglobin oxygenation levels. While the literature offers a multitude of fNIRS applications to typical development, only recently this tool has been extended to the study of neurodevelopmental disorders (NDDs). The exponential rise of scientific publications on this topic during the last years reflects the interest to identify a “fNIRS signature” as a biomarker of high translational value to support both early clinical diagnosis and treatment outcome. The purpose of this systematic review is to describe the updating clinical applications of fNIRS in NDDs, with a specific focus on preschool population. Starting from this rationale, a systematic search was conducted for relevant studies in different scientific databases (Pubmed, Scopus, and Web of Science) resulting in 13 published articles. In these studies, fNIRS was applied in individuals with Autism Spectrum Disorder (ASD) or infants at high risk of developing ASD. Both functional connectivity in resting-state conditions and task-evoked brain activation using multiple experimental paradigms were used in the selected investigations, suggesting that fNIRS might be considered a promising method for identifying early quantitative biomarkers in the autism field.
Diffusion Tensor Imaging Revealed Microstructural Changes in Normal-Appearing White Matter Regions in Relapsing–Remitting Multiple Sclerosis
Authors: Bao Jianfeng , Tu Hui , Li Yijia , Sun Jubao , Hu Zhigang , Zhang Fengshou , Li Jinghua
Published: March 2022

Background

Axons and myelin sheaths are the physical foundation for white matter (WM) to perform normal functions. Our previous study found the metabolite abnormalities in frontal, parietal, and occipital normal-appearing white matter (NAWM) regions in relapsing–remitting multiple sclerosis (RRMS) patients by applying a 2D 1H magnetic resonance spectroscopic imaging method. Since the metabolite changes may associate with the microstructure changes, we used the diffusion tensor imaging (DTI) method to assess the integrity of NAWM in this study.

Method

Diffusion tensor imaging scan was performed on 17 clinically definite RRMS patients and 21 age-matched healthy controls on a 3.0-T scanner. DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were extracted from 19 predefined regions of interest (ROIs), which were generated by removing a mask of manually drawn probabilistic lesion map from the Johns Hopkins University white-matter atlas. The mean values of FA, MD, AD, and RD were compared between different groups in the same ROIs.

Results

A probabilistic lesion map was successfully generated, and the lesion regions were eliminated from the WM atlas. We found that the RRMS patients had significantly lower FA in the entire corpus callosum (CC), bilateral of anterior corona radiata, and right posterior thalamic radiation (PTR). At the same time, RRMS patients showed significantly higher MD in the bilateral anterior corona radiata and superior corona radiata. Moreover, all AD values increased, and the bilateral external capsule, PTR, and left tapetum NAWM show statistical significance. What is more, all NAWM tracts showed increasing RD values in RRMS patients, and the bilateral superior corona radiata, the anterior corona radiata, right PTR, and the genu CC reach statistical significance.

Conclusion

Our study revealed widespread microstructure changes in NAWM in RRMS patients through a ready-made WM atlas and probabilistic lesion map. These findings support the hypothesis of demyelination, accumulation of inflammatory cells, and axonal injury in NAWM for RRMS. The DTI-based metrics could be considered as potential non-invasive biomarkers of disease severity.
Altered Intra- and Inter-Network Functional Connectivity in Patients With Crohn’s Disease: An Independent Component Analysis-Based Resting-State Functional Magnetic Resonance Imaging Study
Authors: Li Lu , Ma Jie , Hua Xuyun , Zhou Yan , Qiu Yage , Zhu Zhen , Zheng Yanling , Xie Qian , Liang Zonghui , Xu Jianguang
Published: March 2022

Background

Many studies have reported changes in the structure and function of several brain areas in patients with Crohn’s disease (CD). However, little is known about whether the possible functional connectivity of resting-state networks (RSNs) is altered in CD patients.

Purpose

Aim to investigate the intra- and inter-network alterations between related RSNs in patients with CD and the potential relationships between altered neuroimaging and CD clinical indices.

Materials and Methods

In this study, 20 CD patients and 22 age- and sex-matched healthy controls were included. All participants underwent functional magnetic resonance imaging examination. We used independent component analysis (ICA) to explore the changes in RSNs and evaluated functional connectivity between different RSNs using functional network connectivity (FNC) analysis, and Pearson correlation analysis was performed between altered intra- and inter-network functional connectivity and CD clinical index.

Results

Six CD-related RSNs were identified via ICA, namely the high visual, prime visual, language, dorsal default mode, posterior insula, and precuneus networks. Compared to healthy controls, patients with CD showed significant changes in prime visual and language networks. Additionally, the functional connectivity (FC) values of the left calcarine within the prime visual network were negatively correlated with CD duration. The inter-alterations showed that a significantly increased FNC existed between the language and dorsal default mode networks.

Conclusion

The results showed CD-related changes in brain functional networks. This evidence provides more insights into the pathophysiological mechanisms of brain plasticity in CD.
Identifying Changes of Brain Regional Homogeneity and Cingulo-Opercular Network Connectivity in First-Episode, Drug-Naïve Depressive Patients With Suicidal Ideation
Authors: He Mengxin , Ping Liangliang , Chu Zhaosong , Zeng Chunqiang , Shen Zonglin , Xu Xiufeng
Published: March 2022

Objective

Adult patients with major depressive disorder (MDD) may not actively reveal their suicidal ideation (SI). Therefore, this study is committed to finding the alterations in the cingulo-opercular network (CON) that are closely related to SI with multi-imaging methods, thus providing neuroimaging basis for SI.

Method

A total of 198 participants (129 MDD patients and 69 healthy controls) were recruited and evaluated with the Montgomery–Asberg Depression Rating Scale (MADRS). The healthy individuals formed the HC group, while the MDD patients were subdivided into no SI MDD (NSI, n = 32), mild SI MDD (MSI, n = 64), and severe SI MDD (SSI, n = 33) according to their MADRS item 10. We obtained MRI data of all participants and applied regional homogeneity (ReHo) analysis to verify a previous finding that links CON abnormality to SI. In addition, we employed the structural covariance network (SCN) analysis to investigate the correlation between abnormal structural connectivity of CON and SI severity.

Results

Compared to those of the HC group, MDD ReHo values and gray matter volume (GMV) were consistently found abnormal in CON. ReHo values and GMV of the right orbital inferior frontal gyrus (ORBinf.R) in the MDD group decreased with the increase of SI. Compared to the HC group, the MDD patients showed enhanced structural connectivity of three pairs of brain regions in CON [ACC.L–left superior frontal gyrus (SFG.L), SFG.L–left middle temporal gyrus (MTG.L), and the SFG.L–left post-central gyrus (PoCG.L)]. Compared with that of the NSI and MSI groups, the structural connectivity of three pairs of brain regions in CON is enhanced in the SSI groups [ORBinf.L–right ventral posterior cingulate gyrus (VPCC.R), VPCC.R–SFG.R, and SFG.R–PoCG.R].

Conclusion

Our findings showed the distinctive ReHo, GMV, and SCN pattern of CON in MDD patients with SI; and with the severity of suicide, abnormal brain regions increased. Our finding suggested that MDD patients with different severity of SI have different neuroimaging changes.
Blood SSR1: A Possible Biomarker for Early Prediction of Parkinson’s Disease
Authors: Zhang Wen , Shen Jiabing , Wang Yuhui , Cai Kefu , Zhang Qi , Cao Maohong
Published: March 2022

Parkinson’s disease (PD) is the second most common neurodegenerative disease associated with age. Early diagnosis of PD is key to preventing the loss of dopamine neurons. Peripheral-blood biomarkers have shown their value in recent years because of their easy access and long-term monitoring advantages. However, few peripheral-blood biomarkers have proven useful. This study aims to explore potential peripheral-blood biomarkers for the early diagnosis of PD. Three substantia nigra (SN) transcriptome datasets from the Gene Expression Omnibus (GEO) database were divided into a training cohort and a test cohort. We constructed a protein–protein interaction (PPI) network and a weighted gene co-expression network analysis (WGCNA) network, found their overlapping differentially expressed genes and studied them as the key genes. Analysis of the peripheral-blood transcriptome datasets of PD patients from GEO showed that three key genes were upregulated in PD over healthy participants. Analysis of the relationship between their expression and survival and analysis of their brain expression suggested that these key genes could become biomarkers. Then, animal models were studied to validate the expression of the key genes, and only SSR1 (the signal sequence receptor subunit1) was significantly upregulated in both animal models in peripheral blood. Correlation analysis and logistic regression analysis were used to analyze the correlation between brain dopaminergic neurons and SSR1 expression, and it was found that SSR1 expression was negatively correlated with dopaminergic neuron survival. The upregulation of SSR1 expression in peripheral blood was also found to precede the abnormal behavior of animals. In addition, the application of artificial intelligence technology further showed the value of SSR1 in clinical PD prediction. The three classifiers all showed that SSR1 had high predictability for PD. The classifier with the best prediction accuracy was selected through AUC and MCC to construct a prediction model. In short, this research not only provides potential biomarkers for the early diagnosis of PD but also establishes a possible artificial intelligence model for predicting PD.
Statistical Perspective on Functional and Causal Neural Connectomics: A Comparative Study
Authors: Biswas Rahul , Shlizerman Eli
Published: March 2022

Representation of brain network interactions is fundamental to the translation of neural structure to brain function. As such, methodologies for mapping neural interactions into structural models, i.e., inference of functional connectome from neural recordings, are key for the study of brain networks. While multiple approaches have been proposed for functional connectomics based on statistical associations between neural activity, association does not necessarily incorporate causation. Additional approaches have been proposed to incorporate aspects of causality to turn functional connectomes into causal functional connectomes, however, these methodologies typically focus on specific aspects of causality. This warrants a systematic statistical framework for causal functional connectomics that defines the foundations of common aspects of causality. Such a framework can assist in contrasting existing approaches and to guide development of further causal methodologies. In this work, we develop such a statistical guide. In particular, we consolidate the notions of associations and representations of neural interaction, i.e., types of neural connectomics, and then describe causal modeling in the statistics literature. We particularly focus on the introduction of directed Markov graphical models as a framework through which we define the Directed Markov Property—an essential criterion for examining the causality of proposed functional connectomes. We demonstrate how based on these notions, a comparative study of several existing approaches for finding causal functional connectivity from neural activity can be conducted. We proceed by providing an outlook ahead regarding the additional properties that future approaches could include to thoroughly address causality.
Significance of Postprandial Insulin and Triglycerides to Evaluate the Metabolic Response of Composite Meals Differing in Nutrient Composition – A Randomized Cross-Over Trial
Authors: Thota Rohith N. , Moughan Paul J. , Singh Harjinder , Garg Manohar L.
Published: March 2022

Background and aims

GlucoTRIG, based on postprandial plasma insulin and triglyceride concentrations, has been recently developed as a novel index to determine the postprandial metabolic response to the meals. This study aimed to test GlucoTRIG as a measure for ranking composite meals for their metabolic effects.

Methods

In a randomized cross-over trial, healthy adult volunteers (both males and females; n = 10 for each meal) consumed three is caloric (2000 kj) test meals (meal 1, meal 2, meal 3) of varying macronutrient composition. Postmeal consumption, venous blood samples were collected to determine plasma insulin and plasma triglycerides for estimating the GlucoTRIG value using (Triglycerides180min × Insulin180min) - (Triglycerides0min × Insulin0min).

Results

The GlucoTRIG values differed significantly (p = 0.0085) across meals. The statistical significance remains even after adjusting for confounding variables such as baseline diet, insulin, and triglycerides. The meal (M3) with a high fiber, low total fat content and containing less refined foods (fruits, beans, vegetables, plain yogurt) exhibited a significantly (p = 0.007) lower GlucoTRIG value (10 ± 7.7) compared to the other two meals, M1 (77 ± 19.8) and M2 (38 ± 12.1) which contained low processed foods, and were relatively high in fat and low in fiber meals. No statistically significant differences were observed between M1 and M2 meal.

Conclusions

GlucoTRIG is a physiologically based index that may be useful to rank composite meals for reducing the risk of metabolic diseases. Further research focusing on the application of GlucoTRIG to foods, meals, and diets is warranted.

ACTRN12619000973112 (Australian New Zealand Clinical Trials Registry, ANZCTR).
Polysaccharide-Zein Composite Nanoparticles for Enhancing Cellular Uptake and Oral Bioavailability of Curcumin: Characterization, Anti-colorectal Cancer Effect, and Pharmacokinetics
Authors: Liu Lu , Yang Shufang , Chen Feng , Cheng Ka-Wing
Published: March 2022

Curcumin (CUR) has demonstrated promising potential as a therapeutic agent against colorectal cancer (CRC). However, its intrinsic shortcomings, including oxidative instability, sensitivity to gastrointestinal (GI) hydrolytic/enzymatic action, and susceptibility to biotransformation and systemic elimination, have greatly undermined its value for application in clinical settings. The development of carriers, in particular oral formulations, for its efficient delivery has remained an important direction in nutraceutical research. In the present work, CUR-encapsulated nanoparticles were fabricated with zein alone (Zein-CUR) and with zein and a polysaccharide (PS) [gum Arabic (GA), hyaluronic acid (HA) and pectin (PC), respectively] (PS-Zein-CUR). Their physicochemical and biological properties were evaluated in a series of in vitro and in vivo assays. Dynamic light scattering analysis showed an increase in the particle size of the nanoparticles from 129.0 nm (Zein-CUR) to 188.8–346.4 nm (PS-Zein-CUR). The three PS-Zein-CUR formulations had significantly higher (17–22%) CUR encapsulation efficiency (EE) than Zein-CUR. Among them, HA-Zein-CUR exhibited the highest EE and loading capacity. Zeta potential and FTIR spectra indicated the involvement of electrostatic and hydrophobic interactions and hydrogen bonds in the formation of the PS-Zein-CUR. In human CRC cell lines (HCT8, HCT29, and HCT116), the three PS-Zein-CUR and CUR all effectively inhibited cell viability and colony formation (HA-Zein-CUR > PC-Zein-CUR > GA-Zein-CUR/CUR). HA-Zein-CUR and PC-Zein-CUR also resulted in significantly higher cellular uptake of CUR than GA-Zein-CUR and CUR. Simulated GI-digestion assay demonstrated significantly improved controlled-release properties of these two formulations. Further pharmacokinetics and tissue distribution assays in a CRC subcutaneous xenograft model in nude mice corroborated the enhanced pharmacokinetic properties of intragastric administration of HA-Zein-CUR compared with that of free CUR (3 times higher Cmax and 9.18 times higher plasma AUC). HA-Zein-CUR also led to enhanced delivery and accumulation of CUR in major organs/tissues, in particular CRC tumors and colon. These results together support that HA-Zein-CUR has promising potential as an oral agent for the control of CRC.
Identification and Validation of N6-Methyladenosine-Related Biomarkers for Bladder Cancer: Implications for Immunotherapy
Authors: Deng Hongyu , Tang Faqing , Zhou Ming , Shan Dongyong , Chen Xingyu , Cao Ke
Published: March 2022

N6-methyladenosine (m6A) has emerged as one of the most important modifications of RNA. Based on the expression of 23 different modes of m6A regulatory factors, we identified three different m6A modification patterns in bladder cancer. The effects of the three different modes of m6A modification on clinicopathological characteristics, immune cell infiltration levels and expression levels of immune checkpoint genes were comprehensively analyzed. In addition, the effects of different modes of m6A modification on the therapeutic efficacy of anti-PD-L1 immunotherapy (atezolizumab) are also discussed. Our results confirm that m6A methylation plays an important role in immune cell recruitment in the tumor microenvironment of bladder cancer, which influences the efficacy of anti-PD-L1 therapy for bladder cancer. We further confirmed the important role of FTO protein in the biological function of bladder cancer cells by performing in vitro experiments. FTO functions as an oncogene in bladder cancer cells, and upon FTO knockdown, the level of m6A enzyme activity in bladder cancer cells was significantly increased, apoptosis was increased, and cell proliferation and cell invasion were reduced. In addition, our study also confirmed that K216H and K216E are probably important targets for regulating FTO. We provide new insights into the regulatory pathways of the immune microenvironment and the methylation function of m6A in bladder cancer, which will help in designing novel diagnostic methods, prognostic tools, and therapeutic targets.
Glioblastoma Microenvironment: From an Inviolable Defense to a Therapeutic Chance
Authors: Di Nunno Vincenzo , Franceschi Enrico , Tosoni Alicia , Gatto Lidia , Bartolini Stefania , Brandes Alba Ariela
Published: March 2022

Glioblastoma is an aggressive tumor and is associated with a dismal prognosis. The availability of few active treatments as well as the inexorable recurrence after surgery are important hallmarks of the disease. The biological behavior of glioblastoma tumor cells reveals a very complex pattern of genomic alterations and is partially responsible for the clinical aggressiveness of this tumor. It has been observed that glioblastoma cells can recruit, manipulate and use other cells including neurons, glial cells, immune cells, and endothelial/stromal cells. The final result of this process is a very tangled net of interactions promoting glioblastoma growth and progression. Nonetheless, recent data are suggesting that the microenvironment can also be a niche in which glioblastoma cells can differentiate into glial cells losing their tumoral phenotype. Here we summarize the known interactions between micro-environment and glioblastoma cells highlighting possible therapeutic implications.
A Classifier for Improving Early Lung Cancer Diagnosis Incorporating Artificial Intelligence and Liquid Biopsy
Authors: Ye Maosong , Tong Lin , Zheng Xiaoxuan , Wang Hui , Zhou Haining , Zhu Xiaoli , Zhou Chengzhi , Zhao Peige , Wang Yan , Wang Qi , Bai Li , Cai Zhigang , Kong Feng-Ming (Spring) , Wang Yuehong , Li Yafei , Feng Mingxiang , Ye Xin , Yang Dawei , Liu Zilong , Zhang Quncheng , Wang Ziqi , Han Shuhua , Sun Lihong , Zhao Ningning , Yu Zubin , Zhang Juncheng , Zhang Xiaoju , Katz Ruth L. , Sun Jiayuan , Bai Chunxue
Published: March 2022

Lung cancer is the leading cause of cancer-related deaths worldwide and in China. Screening for lung cancer by low dose computed tomography (LDCT) can reduce mortality but has resulted in a dramatic rise in the incidence of indeterminate pulmonary nodules, which presents a major diagnostic challenge for clinicians regarding their underlying pathology and can lead to overdiagnosis. To address the significant gap in evaluating pulmonary nodules, we conducted a prospective study to develop a prediction model for individuals at intermediate to high risk of developing lung cancer. Univariate and multivariate logistic analyses were applied to the training cohort (n = 560) to develop an early lung cancer prediction model. The results indicated that a model integrating clinical characteristics (age and smoking history), radiological characteristics of pulmonary nodules (nodule diameter, nodule count, upper lobe location, malignant sign at the nodule edge, subsolid status), artificial intelligence analysis of LDCT data, and liquid biopsy achieved the best diagnostic performance in the training cohort (sensitivity 89.53%, specificity 81.31%, area under the curve [AUC] = 0.880). In the independent validation cohort (n = 168), this model had an AUC of 0.895, which was greater than that of the Mayo Clinic Model (AUC = 0.772) and Veterans’ Affairs Model (AUC = 0.740). These results were significantly better for predicting the presence of cancer than radiological features and artificial intelligence risk scores alone. Applying this classifier prospectively may lead to improved early lung cancer diagnosis and early treatment for patients with malignant nodules while sparing patients with benign entities from unnecessary and potentially harmful surgery.

Clinical Trial Registration Number

ChiCTR1900026233, URL: http://www.chictr.org.cn/showproj.aspx?proj=43370.
The Research Progress of Exosomes in Osteoarthritis, With Particular Emphasis on the Therapeutic Effect
Authors: Xian Bo Shang , Chen Wang , Chang Liu , Hao Ran Yu , Hui Hui Guo , Ya Kun Zhu , Wu Kun Xie , Hai Tao Fan , Wen Dan Cheng
Published: March 2022

Exosomes participate in many physiological and pathological processes by regulating cell-to-cell communication. This affects the etiology and development of diseases, such as osteoarthritis (OA). Although exosomes in the OA tissue microenvironment are involved in the progression of OA, exosomes derived from therapeutic cells represent a new therapeutic strategy for OA treatment. Recent studies have shown that exosomes participate in OA treatment by regulating the proliferation, apoptosis, inflammation, and extracellular matrix synthesis of chondrocytes. However, studies in this field are scant. This review summarizes the therapeutic properties of exosomes on chondrocytes in OA and their underlying molecular mechanisms. We also discuss the challenges and prospects of exosome-based OA treatment.
Mercury and Mercury-Containing Preparations: History of Use, Clinical Applications, Pharmacology, Toxicology, and Pharmacokinetics in Traditional Chinese Medicine
Authors: Zhao Meiling , Li Yi , Wang Zhang
Published: March 2022

Historically, mercury and mercury-containing preparations have been widely used in traditional Chinese medicine and applied in many clinical practices mainly in the form of mercury sulfides. The clinical application, toxicity manifestations, and symptoms of these preparations largely depend on the route of administration and the dosage form. Commonly used mercury-containing medicinal materials and preparations in traditional Chinese medicine include Cinnabar, an excellent medicine for tranquilizing the nerves; Hongsheng Dan and Baijiang Dan, which have antibacterial, anti-inflammatory, promotion of tissue repair and regeneration and other pharmacological effects. Tibetan medicine commonly uses Zaotai and Qishiwei Zhenzhu pills, which have pharmacological effects such as sedation, anti-inflammatory, anti-convulsant, and improvement of cerebral apoplexy. Menggen Wusu Shibawei pills, commonly used in Mongolian traditional medicine, have the muscle growth and astringent effects. In India and Europe, mercury is often used for treating syphilis. This article summarizes the history, clinical application, pharmacology, toxicology, and pharmacokinetics of mercury and mercury-containing preparations in traditional medicines. In terms of clinical application, it provides suggestions for the rational use and safety of mercury-containing drugs in clinical practices and in public health issues. It will further provide a reference for formulation strategies related to mercury risk assessment and management.
AMPK Activator O304 Protects Against Kidney Aging Through Promoting Energy Metabolism and Autophagy
Authors: Zhu Mingsheng , Shen Weiwei , Li Jiemei , Jia Nan , Xiong Yabing , Miao Jinhua , Xie Chao , Chen Qiyan , Shen Kunyu , Meng Ping , Li Xiaolong , Wu Qinyu , Zhou Shan , Wang Maosheng , Kong Yaozhong , Zhou Lili
Published: March 2022

Aging is an important risk factor for kidney injury. Energy homeostasis plays a key role in retarding aging, and mitochondria are responsible for energy production. In the kidney, renal tubular cells possess high abundance of mitochondria to meet the high energy consumption. AMPK is an evolutionarily conserved serine/threonine kinase which plays a central role in maintaining energy homeostasis and mitochondrial homeostasis. Besides that, AMPK also commands autophagy, a clearing and recycling process to maintain cellular homeostasis. However, the effect of AMPK activators on kidney aging has not been fully elucidated. To this end, we testified the effects of O304, a novel direct AMPK activator, in naturally aging mice model and D-Galactose (D-Gal)-treated renal tubular cell culture. We identified that O304 beneficially protects against cellular senescence and aged-related fibrosis in kidneys. Also, O304 restored energy metabolism, promoted autophagy and preserved mitochondrial homeostasis. Transcriptomic sequencing also proved that O304 induced fatty acid metabolism, mitochondrial biogenesis and ATP process, and downregulated cell aging, DNA damage response and collagen organization. All these results suggest that O304 has a strong potential to retard aged kidney injury through regulating AMPK-induced multiple pathways. Our results provide an important therapeutic approach to delay kidney aging.