bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Diverse Functions of Electrical Synapses
Authors: Vaughn Mitchell J. , Haas Julie S.
Published: June 2022

Electrical synapses are the neurophysiological product of gap junctional pores between neurons that allow bidirectional flow of current between neurons. They are expressed throughout the mammalian nervous system, including cortex, hippocampus, thalamus, retina, cerebellum, and inferior olive. Classically, the function of electrical synapses has been associated with synchrony, logically following that continuous conductance provided by gap junctions facilitates the reduction of voltage differences between coupled neurons. Indeed, electrical synapses promote synchrony at many anatomical and frequency ranges across the brain. However, a growing body of literature shows there is greater complexity to the computational function of electrical synapses. The paired membranes that embed electrical synapses act as low-pass filters, and as such, electrical synapses can preferentially transfer spike after hyperpolarizations, effectively providing spike-dependent inhibition. Other functions include driving asynchronous firing, improving signal to noise ratio, aiding in discrimination of dissimilar inputs, or dampening signals by shunting current. The diverse ways by which electrical synapses contribute to neuronal integration merits furthers study. Here we review how functions of electrical synapses vary across circuits and brain regions and depend critically on the context of the neurons and brain circuits involved. Computational modeling of electrical synapses embedded in multi-cellular models and experiments utilizing optical control and measurement of cellular activity will be essential in determining the specific roles performed by electrical synapses in varying contexts.
Dopamine Increases the Intrinsic Excitability of Parvalbumin-Expressing Fast-Spiking Cells in the Piriform Cortex
Authors: Potts Yasmin , Bekkers John M.
Published: June 2022

The piriform cortex (PCx) is essential for the adaptive processing of olfactory information. Neuromodulatory systems, including those utilizing serotonin, acetylcholine, noradrenaline, and dopamine, innervate and regulate neuronal activity in the PCx. Previous research has demonstrated the importance of acetylcholine, noradrenaline and serotonin in odor learning and memory. In contrast, the role of dopamine in the PCx remains under-explored. Here we examined how dopamine modulates the intrinsic electrical properties of identified classes of neurons in the PCx. We found that dopamine had no consistent effect on the intrinsic electrical properties of two types of glutamatergic neurons (semilunar and superficial pyramidal cells) or three types of GABAergic interneurons (horizontal, neurogliaform and somatastatin-expressing regular-spiking cells). However, dopamine had a striking effect on the intrinsic excitability of the parvalbumin-expressing fast-spiking (FS) class of GABAergic interneuron. Dopamine depolarized the resting potential, increased the input resistance and increased the firing frequency of FS cells. Co-application of dopamine with the D1-class dopamine receptor antagonist SCH 23390 blocked the effects of dopamine modulation on FS cells. Conversely, co-application of dopamine with the D2-class antagonist RS-(±)-sulpiride had no effect on dopamine modulation of these cells. Our results indicate that dopamine binds to D1-class dopamine receptors to increase the intrinsic excitability of FS cells. These findings suggest that dopamine has a highly targeted effect in the PCx and reveal how dopamine may modulate the balance between excitation and inhibition, with consequences for odor processing. In addition, our findings provide clues for understanding why neurodegenerative disorders that modify the dopamine system, such as Parkinson’s disease, have a deleterious effect on the sense of smell, and may suggest novel diagnostics for the early detection of such disorders.
A Nomogram for Predicting Patent Foramen Ovale-Related Stroke Recurrence
Authors: Wu Zhuonan , Zhang Chuanjing , Liu Nan , Xie Wenqing , Yang Jinjin , Guo Hangyuan , Chi Jufang
Published: June 2022

Background

The high prevalence of patent foramen ovale (PFO) in cryptogenic stroke suggested a stroke-causing role for PFO. As risk factors for recurrence of such stroke are not recognized, clinicians cannot sufficiently identify, treat, and follow-up high-risk patients. Therefore, this study aimed to establish a prediction model for PFO-related stroke recurrence.

Methods

This study included 392 patients with PFO-related stroke in a training set and 164 patients with PFO-related stroke in an independent validation set. In the training set, independent risk factors for recurrence identified using forward stepwise Cox regression were included in nomogram 1, and those identified using least absolute shrinkage and selection operator(LASSO)regression were included in nomogram 2. Nomogram performance and discrimination were assessed using the concordance index (C-index), area under the curve (AUC), calibration curve, and decision curve analyses (DCA). The results were also validated in the validation set.

Results

Nomogram 1 was based on homocysteine (Hcy), high-sensitivity C-reactive protein (hsCRP), and albumin (ALB), and nomogram 2 was based on age, diabetes, hypertension, right-to-left shunt, ALB, prealbumin, hsCRP, and Hcy. The C-index of nomogram 1 was 0.861, which was not significantly different from that of nomogram 2 (0.893). The 2- and 5-year AUCs of nomogram 1 were 0.863 and 0.777, respectively. In the validation set, nomogram 1 still had good discrimination (C-index, 0.862; 2-year AUC, 0.839; 5-year AUC, 0.990). The calibration curve showed good homogeneity between the prediction by nomogram 1 and the actual observation. DCA demonstrated that nomogram 1 was clinically useful. Moreover, patients were successfully divided into two distinct risk groups (low and high risk) for recurrence rate by nomogram 1.

Conclusions

Nomogram 1, based on Hcy, hsCRP, and ALB levels, provided a more clinically realistic prognostic prediction for patients with PFO-related stroke. This model could help patients with PFO-related stroke to facilitate personalized prognostic evaluations.
Short Chain Fatty Acids Protect the Cognitive Function of Sepsis Associated Encephalopathy Mice via GPR43
Authors: Liao Hongsen , Li Haojia , Bao Hongguang , Jiang Li , Du Jiayue , Guo Yaoyi , Si Yanna
Published: June 2022

Objective

This study aims to analyze the changes of fecal short chain fatty acids (SCFAs) content and gut microbiota composition in sepsis associated encephalopathy (SAE) mice, further evaluating the effect of SCFAs on cognitive function and the underlying mechanism in SAE mice.

Methods

A total of 55 male adult C57BL/6 mice (2–3 months of age, 20–25 g) were divided into four groups randomly: sham group (n = 10), cecal ligation and puncture group (CLP group, n = 15), CLP+SCFAs group (n = 15), and CLP+SCFAs+GLPG0974 group (n = 15). Seven days after surgery, fecal samples were collected for microbiota composition and SCFA analysis from 6 mice in each group randomly. Behavioral test was applied to assess cognitive impairment at the same time. After that, mice were sacrificed and brain tissue was harvested for inflammatory cytokines analysis.

Results

The levels of acetic acid (.57 ± 0.09 vs 2.00 ± 0.24, p < 0.001) and propionic acid (.32 ± 0.06 vs .66 ± 0.12, p = 0.002) were significantly decreased in the CLP group compared with the sham group. The administration of SCFAs significantly increased the levels of acetic acid (1.51 ± 0.12 vs. 0.57 ± 0.09, p < 0.001) and propionic acid (0.54 ± 0.03 vs. 0.32 ± 0.06, p = 0.033) in CLP+SCFAs group compared with CLP group. Relative abundance of SCFAs-producing bacteria, including Allobaculum (0.16 ± 0.14 vs. 15.21 ± 8.12, p = 0.037), Bacteroides (1.82 ± 0.38 vs. 15.21 ± 5.95, p = 0.002) and Bifidobacterium (0.16 ± 0.06 vs. 2.24 ± 0.48, p = 0.002), significantly decreased in the CLP group compared with the sham group. The behavioral tests suggested that cognitive function was impaired in SAE mice, which could be alleviated by SCFAs pretreatment. ELISA tests indicated that the levels of IL-1β, IL-6, and TNF-α were elevated in SAE mice and SCFAs could lower them. However, the GPR43 antagonist, GLPG0974, could reverse the cognitive protective effect and anti-neuroinflammation effect of SCFAs.

Conclusion

Our study suggested that in SAE, the levels of acetate and propionate decreased significantly, accompanied by gut microbiota dysbiosis, particularly a decrease in SCFAs-producing bacteria. GPR43 was essential for the anti-neuroinflammation and cognitive protective effect of SCFAs in SAE.
Mechanism of Ferroptosis and Its Role in Spinal Cord Injury
Authors: Li Fei , Wang Haifan , Chen Hao , Guo Jianing , Dang Xiaoqian , Ru Yi , Wang Haoyu
Published: June 2022

Ferroptosis is a non-necrotic form of regulated cell death (RCD) that is primarily characterized by iron-dependent membrane lipid peroxidation and is regulated by cysteine transport, glutathione synthesis, and glutathione peroxidase 4 function as well as other proteins including ferroptosis suppressor protein 1. It has been found that ferroptosis played an important role in many diseases, such as neurodegenerative diseases and ischemia-reperfusion injury. Spinal cord injury (SCI), especially traumatic SCI, is an urgent problem worldwide due to its high morbidity and mortality, as well as the destruction of functions of the human body. Various RCDs, including ferroptosis, are found in SCI. Different from necrosis, since RCD is a form of cell death regulated by various molecular mechanisms in cells, the study of the role played by RCD in SCI will contribute to a deeper understanding of the pathophysiological process, as well as the treatment and functional recovery. The present review mainly introduces the main mechanism of ferroptosis and its role in SCI, so as to provide a new idea for further exploration.
Post-error Slowing Reflects the Joint Impact of Adaptive and Maladaptive Processes During Decision Making
Authors: Fievez Fanny , Derosiere Gerard , Verbruggen Frederick , Duque Julie
Published: June 2022

Errors and their consequences are typically studied by investigating changes in decision speed and accuracy in trials that follow an error, commonly referred to as “post-error adjustments”. Many studies have reported that subjects slow down following an error, a phenomenon called “post-error slowing” (PES). However, the functional significance of PES is still a matter of debate as it is not always adaptive. That is, it is not always associated with a gain in performance and can even occur with a decline in accuracy. Here, we hypothesized that the nature of PES is influenced by one’s speed-accuracy tradeoff policy, which determines the overall level of choice accuracy in the task at hand. To test this hypothesis, we had subjects performing a task in two distinct contexts (separate days), which either promoted speed (hasty context) or cautiousness (cautious context), allowing us to consider post-error adjustments according to whether subjects performed choices with a low or high accuracy level, respectively. Accordingly, our data indicate that post-error adjustments varied according to the context in which subjects performed the task, with PES being solely significant in the hasty context (low accuracy). In addition, we only observed a gain in performance after errors in a specific trial type, suggesting that post-error adjustments depend on a complex combination of processes that affect the speed of ensuing actions as well as the degree to which such PES comes with a gain in performance.
Feasibility of Markerless Motion Capture for Three-Dimensional Gait Assessment in Community Settings
Authors: McGuirk Theresa E. , Perry Elliott S. , Sihanath Wandasun B. , Riazati Sherveen , Patten Carolynn
Published: June 2022

Three-dimensional (3D) kinematic analysis of gait holds potential as a digital biomarker to identify neuropathologies, monitor disease progression, and provide a high-resolution outcome measure to monitor neurorehabilitation efficacy by characterizing the mechanisms underlying gait impairments. There is a need for 3D motion capture technologies accessible to community, clinical, and rehabilitation settings. Image-based markerless motion capture (MLMC) using neural network-based deep learning algorithms shows promise as an accessible technology in these settings. In this study, we assessed the feasibility of implementing 3D MLMC technology outside the traditional laboratory environment to evaluate its potential as a tool for outcomes assessment in neurorehabilitation. A sample population of 166 individuals aged 9–87 years (mean 43.7, S.D. 20.4) of varied health history were evaluated at six different locations in the community over a 3-month period. Participants walked overground at self-selected (SS) and fastest comfortable (FC) speeds. Feasibility measures considered the expansion, implementation, and practicality of this MLMC system. A subset of the sample population (46 individuals) walked over a pressure-sensitive walkway (PSW) concurrently with MLMC to assess agreement of the spatiotemporal gait parameters measured between the two systems. Twelve spatiotemporal parameters were compared using mean differences, Bland-Altman analysis, and intraclass correlation coefficients for agreement (ICC2,1) and consistency (ICC3,1). All measures showed good to excellent agreement between MLMC and the PSW system with cadence, speed, step length, step time, stride length, and stride time showing strong similarity. Furthermore, this information can inform the development of rehabilitation strategies targeting gait dysfunction. These first experiments provide evidence for feasibility of using MLMC in community and clinical practice environments to acquire robust 3D kinematic data from a diverse population. This foundational work enables future investigation with MLMC especially its use as a digital biomarker of disease progression and rehabilitation outcome.
Network-Based Transcranial Direct Current Stimulation May Modulate Gait Variability in Young Healthy Adults
Authors: Zhou Rong , Zhou Junhong , Xiao Yanwen , Bi Jiawei , Biagi Maria Chiara , Ruffini Giulio , Gouskova Natalia A. , Manor Brad , Liu Yu , Lü Jiaojiao , Lo On-Yee
Published: June 2022

Purpose

Previous studies have linked gait variability to resting-state functional connectivity between the dorsal attention network (DAN) and the default network (DN) in the brain. The purpose of this study was to examine the effects of a novel transcranial direct current stimulation (tDCS) paradigm designed to simultaneously facilitate the excitability of the DAN and suppress the excitability of the DN (i.e., DAN+/DN-tDCS) on gait variability and other gait characteristics in young healthy adults.

Methods

In this double-blinded randomized and sham-controlled study, 48 healthy adults aged 22 ± 2 years received one 20-min session of DAN+/DN-tDCS (n = 24) or no stimulation (the Sham group, n = 24). Immediately before and after stimulation, participants completed a gait assessment under three conditions: walking at self-selected speed (i.e., normal walking), walking as fast as possible (i.e., fast walking), and walking while counting backward (i.e., dual-task walking). Primary outcomes included gait stride time variability and gait stride length variability in normal walking conditions. Secondary outcomes include gait stride time and length variability in fast and dual-task conditions, and other gait metrics derived from the three walking conditions.

Results

Compared to the Sham group, DAN+/DN-tDCS reduced stride length variability in normal and fast walking conditions, double-limb support time variability in fast and dual-task walking conditions, and step width variability in fast walking conditions. In contrast, DAN+/DN-tDCS did not alter average gait speed or the average value of any other gait metrics as compared to the sham group.

Conclusion

In healthy young adults, a single exposure to tDCS designed to simultaneously modulate DAN and DN excitability reduced gait variability, yet did not alter gait speed or other average gait metrics, when tested just after stimulation. These results suggest that gait variability may be uniquely regulated by these spatially-distinct yet functionally-connected cortical networks. These results warrant additional research on the short- and longer-term effects of this type of network-based tDCS on the cortical control of walking in younger and older populations.
Advanced Cross-Correlation Function Application to Identify Arterial Baroreflex Sensitivity Variations From Healthy to Diabetes Mellitus
Authors: Yeh Shoou-Jeng , Lung Chi-Wen , Jan Yih-Kuen , Liau Ben-Yi
Published: June 2022

Diabetes mellitus (DM) is a chronic disease characterized by elevated blood glucose levels, which leads over time to serious damage to the heart, blood vessels, eyes, kidneys, and nerves. DM is of two types–types 1 or 2. In type 1, there is a problem with insulin secretion, and in type 2–insulin resistance. About 463 million people worldwide have diabetes, and 80% of the majority live in low- and middle-income countries, and 1.5 million deaths are directly attributed to diabetes each year. Autonomic neuropathy (AN) is one of the common diabetic complications, leading to failure in blood pressure (BP) control and causing cardiovascular disease. Therefore, early detection of AN becomes crucial to optimize treatment. We propose an advanced cross-correlation function (ACCF) between BP and heart rate with suitable threshold parameters to analyze and detect early changes in baroreflex sensitivity (BRS) in DM with AN (DM+). We studied heart rate (HR) and systolic BP responses during tilt in 16 patients with diabetes mellitus only (DM−), 19 diabetes mellitus with autonomic dysfunction (DM+), and 10 healthy subjects. The ACCF analysis revealed that the healthy and DM groups had different filtered percentages of significant maximum cross-correlation function (CCF) value (p < 0.05), and the maximum CCF value after thresholds was significantly reduced during tilt in the DM+ group (p < 0.05). The maximum CCF index, a parameter for the phase between HR and BP, separated the healthy group from the DM groups (p < 0.05). Due to the maximum CCF index in DM groups being located in the positive range and significantly different from healthy ones, it could be speculated that BRS dysfunction in DM and AN could cause a phase change from lead to lag. ACCF could detect and separate DM+ from DM groups. This fact could represent an advantage of the ACCF algorithm. A common cross-correlation analysis was not easy to distinguish between DM− and DM+. This pilot study demonstrates that ACCF analysis with suitable threshold parameters could explore hidden changes in baroreflex control in DM+ and DM−. Furthermore, the superiority of this ACCF algorithm is useful in distinguishing whether AN is present or not in DM.
Effects of Alcohol Withdrawal on Sleep Macroarchitecture and Microarchitecture in Female and Male Rats
Authors: Jones Marissa R. , Brandner Adam J. , Vendruscolo Leandro F. , Vendruscolo Janaina C. M. , Koob George F. , Schmeichel Brooke E.
Published: June 2022

The prevalence of sleep disruptions is higher among people with alcohol use disorder (AUD), particularly during alcohol withdrawal, compared to non-AUD individuals. Although women generally have a higher risk of developing sleep disorders, few studies have investigated sex differences in sleep disruptions following chronic alcohol exposure. The present study examined sleep macroarchitecture (time spent asleep or awake and sleep onset latency) and microarchitecture (bout rate and duration and sleep spindle characterization) prior to alcohol vapor exposure (baseline), during acute withdrawal, and through protracted abstinence in female and male rats. Females and males showed reduced time in rapid eye movement (REM) sleep during acute withdrawal, which returned to baseline levels during protracted abstinence. REM sleep onset latency was decreased during protracted abstinence in females only. Furthermore, there was a sex difference observed in overall REM sleep bout rate. Although there were no changes in non-REM sleep time, or to non-REM sleep bout rate or duration, there was an increase in non-REM sleep intra-spindle frequency during acute withdrawal in both females and males. Finally, there was increased wakefulness time and bout duration during acute withdrawal in both females and males. The results demonstrate both macroarchitectural and microarchitectural changes in sleep following chronic alcohol exposure, particularly during acute withdrawal, suggesting the need for therapeutic interventions for sleep disturbances during withdrawal in individuals with AUD. Furthermore, sex differences were observed in REM sleep, highlighting the importance of including both sexes in future alcohol-related sleep studies.
Male and Female C57BL/6 Mice Respond Differently to Awake Magnetic Resonance Imaging Habituation
Authors: Lindhardt Thomas Beck , Gutiérrez-Jiménez Eugenio , Liang Zhifeng , Hansen Brian
Published: June 2022

Traditionally, preclinical magnetic resonance imaging (MRI) has been performed in anesthetized animals. However, anesthesia has been shown to perturb normal brain function and physiology. Such effects limit our ability to detect subtle physiological alterations in disease models and treatment studies, thus hampering discovery and compromising generality of findings. Therefore, methods for awake animal MRI are needed to study the rodent brain in its natural physiological state, free of anesthetics. Current setups for awake animal MRI rely on restraining systems to avoid animal movement during scanning. To reduce restraint stress, animals are habituated to the scanner environment prior to MRI data collection. To date, however, most awake MRI studies employ male rodents only. This is a fundamental limitation as results obtained may be pertinent only to half of the population. We characterized training and habituation responses of male and female mice to provide improved, sex-dependent training procedures for awake mouse MRI. We recorded heart rate, monitored behavioral responses (body weight and fecal boli weight) and fecal corticosterone levels (FCM) as indicators of wellbeing and stress during a 14-day progressive habituation protocol. In addition, we also assessed discomfort levels and anxiety using the mouse grimace scale (MGS) and light/dark test (LDT), respectively. All scores were compared between both groups. We found that heart rate was significantly decreased after 10 and 11 days of training for both males and females, respectively. However, the specific time course for this decrease was significantly different between males and females, and females exhibited higher anxiety levels during habituation and 14 days after habituation than males. Lastly, we also found that mean FCM levels for both groups were decreased after 11 days of MRI habituation. The present work shows that mice can be successfully trained for extended MRI sessions which is necessary for many (particularly non-fMRI) studies. Importantly, we find that males and females differ in their response to awake MRI habituation, which should be considered in future awake MRI studies that aim to include male and female mice.
The Effect of Vocal Intonation Therapy on Vocal Dysfunction in Patients With Cervical Spinal Cord Injury: A Randomized Control Trial
Authors: Zhang Xiaoying , Song Yi-Chuan , Yang De-Gang , Liu Hong-Wei , Liu Song-Huai , Li Xiao-Bing , Li Jian-Jun
Published: June 2022

In this study, the vocal intonation therapy (VIT) was compared with the standard respiratory therapy for people suffering from respiratory dysfunction as a result of cervical spinal cord injury (CSCI) to observe its effect on vocal quality. Thirty patients with vocal dysfunction after CSCI with the injury time of more than 3 months were screened for inclusion in the trial, and 18 patients completed the 12-weeks, each participant had 60 sessions in total in the clinical trial. All patients were allocated to the intervention group or the control group. The intervention group received VIT training and the control group received respiratory phonation therapy. Both groups were trained by professional therapists, and the training time was 30 min/day, 5 days/week, for 60 sessions for each group in a total of 12 weeks. In the Baseline (T0), mid-intervention period (after 6 weeks, T1), and after intervention (after 12 weeks, T2), the vocal quality of the two groups of patients was tested with a computer-aided real-time audio analyzer 2.1.6 (Adobe Systems, United States) for Sing-SPL (p < 0.0001), Speech-SPL (p < 0.0001), SNL (p < 0.0001), and F0 (p < 0.0001) of the intervention group were significantly improved compared with the control group. In comparing the spectrometry analysis of vocal quality for the 2 groups of participants, there was a significant difference in the results of Sing-SPL and Speech-SPL acoustic analysis in the intervention group of patients at T2 (after 12 weeks) compared to the control group. Vocal intonation therapy—music therapy can improve the speech sound quality of cervical CSCI patients and provide CSCI patients with a practical, highly operable treatment that has both functional training effects and can bring a pleasant experience that can be promoted in the medical field. This study was approved by the Ethics Committee of China Rehabilitation Research Center (CRRC) (approval No. 2019-83-1) on May 20th, 2019. It was registered with the National Health Security Information Platform, medical research registration, and filing information system (Registration No. MR-11-21-011802) on January 28th, 2021.
A Glitch in the Matrix: The Role of Extracellular Matrix Remodeling in Opioid Use Disorder
Authors: Ray Madelyn H. , Williams Benjamin R. , Kuppe Madeline K. , Bryant Camron D. , Logan Ryan W.
Published: June 2022

Opioid use disorder (OUD) and deaths from drug overdoses have reached unprecedented levels. Given the enormous impact of the opioid crisis on public health, a more thorough, in-depth understanding of the consequences of opioids on the brain is required to develop novel interventions and pharmacological therapeutics. In the brain, the effects of opioids are far reaching, from genes to cells, synapses, circuits, and ultimately behavior. Accumulating evidence implicates a primary role for the extracellular matrix (ECM) in opioid-induced plasticity of synapses and circuits, and the development of dependence and addiction to opioids. As a network of proteins and polysaccharides, including cell adhesion molecules, proteases, and perineuronal nets, the ECM is intimately involved in both the formation and structural support of synapses. In the human brain, recent findings support an association between altered ECM signaling and OUD, particularly within the cortical and striatal circuits involved in cognition, reward, and craving. Furthermore, the ECM signaling proteins, including matrix metalloproteinases and proteoglycans, are directly involved in opioid seeking, craving, and relapse behaviors in rodent opioid models. Both the impact of opioids on the ECM and the role of ECM signaling proteins in opioid use disorder, may, in part, depend on biological sex. Here, we highlight the current evidence supporting sex-specific roles for ECM signaling proteins in the brain and their associations with OUD. We emphasize knowledge gaps and future directions to further investigate the potential of the ECM as a therapeutic target for the treatment of OUD.
Recent Advances on the Function and Purification of Milk Exosomes: A Review
Authors: Li Xiaoping , Su Lan , Zhang Xinling , Chen Qi , Wang Ying , Shen Zhenwei , Zhong Tian , Wang Ling , Xiao Ying , Feng Xiao , Yu Xi
Published: June 2022

Exosomes are nano-scale extracellular vesicles, which can be used as drug carriers, tumor treatment, intestinal development and immune regulator. That is why it has great potential in pharmacy, functional foods, nutritional supplements, especially those for infants, postoperative patients, chemotherapy patients and the elderly. In addition, abnormal exosome level is also related to diseases such as cardiovascular diseases, tumor, diabetes, neurodegenerative and autoimmune diseases, as well as infectious diseases. Despite its high biological significance, pharmaceutical and nutritional value, the low abundancy of exosomes in milk is one of the bottlenecks restricting its in-depth research and real-life application. At present, there is no unified standard for the extraction of breast milk exosomes. Therefore, choosing the proper extraction method is very critical for its subsequent research and development. Based on this, this paper reviewed the purification techniques, the function and the possible applications of milk exosomes based on 47 latest references. Humble advices on future directions, prospects on new ideas and methods which are useful for the study of exosomes are proposed at the end of the paper as well.
Regulatory Effect of Mung Bean Peptide on Prediabetic Mice Induced by High-Fat Diet
Authors: Li Lina , Tian Yu , Zhang Shu , Feng Yuchao , Wang Haoyu , Cheng Xiaoyu , Ma Yantao , Zhang Rui , Wang Changyuan
Published: June 2022

Dietary supplementation with mung bean peptides (MBPs) has several health benefits. However, the effect of MBPs on prediabetes and gut microbiota imbalance caused by a high-fat diet (HFD) has not been thoroughly studied. In this study, dietary supplementation with MBPs for 5 weeks significantly reduced HFD-induced body weight gain, hyperglycaemia, hyperlipidaemia, insulin resistance, inflammation, and oxidative stress and alleviated liver and kidney damage in mice. In addition, it significantly reversed the HFD-induced gut microbiota imbalance, increased the gut microbial diversity, and decreased the abundance of Firmicutes and Bacteroidetes in prediabetic mice. Furthermore, we identified Lachnospiraceae_NK4A136 and Lactobacillus as important eubacteria with the potential to alleviate the clinical symptoms of prediabetes. According to PICRUSt2 analysis, the changes in intestinal microflora induced by MBPs diet intervention may be related to the downregulation of expression of genes such as rocR, lysX1, and grdA and regulation of seven pathways, including pyruvate, succinic acid, and butyric acid. Moreover, 17 genera with significantly altered levels in the intestine of HFD-fed mice, including Akkermansia, Roseburia, and Ruminiclostridium, were significantly correlated with 26 important differential metabolites, such as D-glutathione, anti-oleic acid, and cucurbitacin. Overall, these results show that MBPs diet intervention plays a key role in the management of HFD-induced prediabetes.
Plasma Circulating Tumor Epstein–Barr Virus for the Surveillance of Cancer Progression in Bone-Only Metastatic Nasopharyngeal Carcinoma
Authors: Liu Guo-Ying , Xia Wei-Xiong , Bi Zhuo-Fei , Lu Nian , Li Wang-Zhong , Bei Wei-Xin , Liang Hu , Xie Jun-Zhi , Liu Yi-Min , Yao He-Rui , Xiang Yan-Qun
Published: June 2022

Background

Plasma Epstein–Barr virus DNA (EBV-DNA) is a sensitive and specific biomarker for nasopharyngeal carcinoma (NPC). We investigated whether longitudinal monitoring of EBV-DNA could accurately detect clinical disease progression in NPC patients with bone-only metastases.

Methods

In this retrospective study, a total of 105 patients with bone-only metastatic NPC who were treated with platinum-based first-line chemotherapy were enrolled. Undetectable EBV-DNA after first-line chemotherapy was defined as a biochemical complete response (BCR). The correlation of the EBV-DNA dynamic status with overall survival (OS) and progression-free survival (PFS) was determined by Cox regression. The correlation between non-normalized EBV-DNA period and PFS period was determined.

Results

After a median follow-up time of 53.4 months [Interquartile range (IQR): 42.8–80.6], 64 patients had disease progression. Thirty-nine of 105 patients (37.1%) had a BCR at all follow-up time points, and none of these 39 patients had disease progression, corresponding to a negative predictive value (NPV) of 100%. Sixty-six patients had a detectable EBV-DNA during surveillance, with 64 diagnosed as disease progression at the last follow-up, for a positive predictive value (PPV) of 97.0%. Actuarial 3-year OS rates were 45.0% for patients with detectable EBV-DNA during posttreatment surveillance and 100% for patients with undetectable EBV-DNA. Lastly, median lead time between non-normalized EBV-DNA and clinically proven progression was 5.87 ± 0.67 months.

Conclusions

Taken together, EBV-DNA provided predictive value for the bone-only metastatic NPC patients. The results should be validated in prospective randomized studies.
Construction of ceRNA Networks Associated With CD8 T Cells in Breast Cancer
Authors: Chen Zhilin , Feng Ruifa , Kahlert Ulf Dietrich , Chen Zhitong , Torres-dela Roche Luz Angela , Soliman Amr , Miao Chen , De Wilde Rudy Leon , Shi Wenjie
Published: June 2022

Background

The infiltration of CD8 T cells is usually linked to a favorable prognosis and may predict the therapeutic response of breast cancer patients to immunotherapy. The purpose of this research is to investigate the competing endogenous RNA (ceRNA) network correlated with the infiltration of CD8 T cells.

Methods

Based on expression profiles, CD8 T cell abundances for each breast cancer (BC) patient were inferred using the bioinformatic method by immune markers and expression profiles. We were able to extract the differentially expressed RNAs (DEmRNAs, DEmiRNAs, and DElncRNAs) between low and high CD8 T-cell samples. The ceRNA network was constructed using Cytoscape. Machine learning models were built by lncRNAs to predict CD8 T-cell abundances. The lncRNAs were used to develop a prognostic model that could predict the survival rates of BC patients. The expression of selected lncRNA (XIST) was validated by quantitative real-time PCR (qRT-PCR).

Results

A total of 1,599 DElncRNAs, 89 DEmiRNAs, and 1,794 DEmRNAs between high and low CD8 T-cell groups were obtained. Two ceRNA networks that have positive or negative correlations with CD8 T cells were built. Among the two ceRNA networks, nine lncRNAs (MIR29B2CHG, NEAT1, MALAT1, LINC00943, LINC01146, AC092718.4, AC005332.4, NORAD, and XIST) were selected for model construction. Among six prevalent machine learning models, artificial neural networks performed best, with an area under the curve (AUC) of 0.855. Patients from the high-risk category with BC had a lower survival rate compared to those from the low-risk group. The qRT-PCR results revealed significantly reduced XIST expression in normal breast samples, which was consistent with our integrated analysis.

Conclusion

These results potentially provide insights into the ceRNA networks linked with T-cell infiltration and provide accurate models for T-cell prediction.
Introducing the New Surgical Robot HUGO™ RAS: System Description and Docking Settings for Gynecological Surgery
Authors: Gueli Alletti Salvatore , Chiantera Vito , Arcuri Giovanni , Gioè Alessandro , Oliva Riccardo , Monterossi Giorgia , Fanfani Francesco , Fagotti Anna , Scambia Giovanni
Published: June 2022

This study provides a detailed description of the new HUGO™ RAS System and suggests docking settings for gynecological surgery. The system is composed of an “open” surgical console with an HD–3D passive display, a system tower, and four arm carts. Each arm has an extremely wide range of adaptability resulting from the numerous joints. The human cadaver labs were performed at the ORSI Academy between August and December 2021. All procedures were performed by two surgical teams, each composed of a high-volume surgeon experienced in robotic surgery, gynecologic oncology, and pelvic sidewall surgery, and one bedside assistant. Three main gynecological surgical scenarios were identified: standard pelvic surgery, pelvic sidewall surgery, and para-aortic/upper abdominal surgery. Concerning the port placement, the chosen options were called “straight” and “bridge”; instead, the so-called “compact” and “butterfly” configurations were identified for the arm cart positioning. Four cadavers were used to perform total hysterectomy, radical hysterectomy, pelvic exenteration, pelvic and para-aortic lymphadenectomy, and omentectomy. We performed several tests, identifying the best system configurations to draw the proper efficiency from the flexibility of the system in all gynecological surgical scenarios. The straight port placement seems to be adequate for standard pelvic surgery. The bridge trocar position is best to reach the deeper and lateral anatomical regions of the female pelvis. The compact and butterfly arm cart allocations are adequate for both straight and bridge port placement. When deep pelvic surgery was performed, the bedside assistant became more proficient by working with a standard laparoscopic instrument from an ancillary port placed in the left iliac fossa. The arm carts needed to be moved in an open manner, like for the proposed butterfly configuration. On the contrary, the compact disposition left enough space to assist from Palmer’s point port. Several basic and advanced gynecological surgical procedures were performed and completed successfully without encountering any technical or surgical issue, the results obtained were judged sufficient to proceed with the clinical experience in daily practice. The HUGO™ RAS system is flexible and highly performative in various surgical scenarios.
The Influence of Adverse Childhood Experiences in Pain Management: Mechanisms, Processes, and Trauma-Informed Care
Authors: Tidmarsh Lydia V. , Harrison Richard , Ravindran Deepak , Matthews Samantha L. , Finlay Katherine A.
Published: June 2022

Adverse childhood experiences (ACEs) increase the likelihood of reduced physical and psychological health in adulthood. Though understanding and psychological management of traumatic experiences is growing, the empirical exploration of ACEs and physical clinical outcomes remains under-represented and under-explored. This topical review aimed to highlight the role of ACEs in the experience of chronic pain, pain management services and clinical decision making by: (1) providing an overview of the relationship between ACEs and chronic pain; (2) identifying biopsychosocial mechanisms through which ACEs may increase risk of persistent pain; (3) highlighting the impact of ACEs on patient adherence and completion of pain management treatment; and (4) providing practical clinical implications for pain management. Review findings demonstrated that in chronic pain, ACEs are associated with increased pain complications, pain catastrophizing and depression and the combination of these factors further heightens the risk of early treatment attrition. The pervasive detrimental impacts of the COVID-19 pandemic on ACEs and their cyclical effects on pain are discussed in the context of psychological decline during long treatment waitlists. The review highlights how people with pain can be further supported in pain services by maintaining trauma-informed practices and acknowledging the impact of ACEs on chronic pain and detrimental health outcomes. Clinicians who are ACE-informed have the potential to minimize the negative influence of ACEs on treatment outcomes, ultimately optimizing the impact of pain management services.
Molecular Spectrum, Ethnic and Geographical Distribution of Thalassemia in the Southern Area of Hainan, China
Authors: Yu Ying , Lu Chunjiao , Gao Ying , Li Cuiyun , Li Dongxue , Wang Jie , Wei Hui , Lu Zhaohui , You Guoling
Published: June 2022

Background

Thalassemia is one of the most common genetic diseases in southern China. Accurate population frequency data regarding the occurrence and distribution of thalassemia are important for designing appropriate prevention strategies for thalassemia. This study aims to reveal the molecular spectrum, ethnic and geographical distribution of thalassemia in the southern area of Hainan Province, China.

Methods

A total of 9813 suspected carriers of thalassemia were screened for genetic analysis by using the PCR-reverse dot blot hybridization method targeting three known deletions of α-thalassemias (--SEA, -α3.7, and -α4.2), three nondeletional mutations of α-thalassaemias (αCS, αQS, and αWS) and the 17 most common mutations of β-thalassaemias in the Chinese population.

Results

Approximately 6,924 subjects were genetically diagnosed as thalassemia carriers or patients, including 5812 cases of α-thalassemia (83.9%), 369 cases of β-thalassemia (5.3%), and 743 cases of α-composite β-thalassemia (10.7%). A total of 21 distinct genotypes were identified among the 5,812 α-thalassemia carriers, -α4.2/αα, -α3.7/αα, and -α3.7/-α4.2 were the most common α-thalassemia genotypes. The most frequent β-thalassemia genotype was βCD41−42/βN, with a notable proportion of 69.6%, followed by the β−28M/βN, βIVS−II−654/βN, βCD71−72/βN, βE/βN, and βCD17/βN genotypes. In addition, 37 genotypes were detected among the 743 cases of both α- and β-thalassemia mutations. The α-thalassemia genotypes were most commonly found in the Li people, who accounted for 73.5% of α-thalassemia carriers. The β-thalassemia genotypes were most commonly identified in the Han people, who accounted for 59.4% of β-thalassemia carriers. Among the subjects carrying both α- and β-thalassemia variations, only three ethnic minorities were identified, including the Li, Han, and Miao people, accounting for 82.0, 17.4, and 0.7%, respectively.

Conclusions

Our study indicates that there is high genetic heterogeneity, geographical and ethnic differences in thalassemia in populations in the southern area of Hainan Province. These findings will be helpful in guiding genetic counseling and prenatal diagnosis of thalassemia in Hainan Province.
BI 1015550 is a PDE4B Inhibitor and a Clinical Drug Candidate for the Oral Treatment of Idiopathic Pulmonary Fibrosis
Authors: Herrmann Franziska Elena , Hesslinger Christian , Wollin Lutz , Nickolaus Peter
Published: June 2022

The anti-inflammatory and immunomodulatory abilities of oral selective phosphodiesterase 4 (PDE4) inhibitors enabled the approval of roflumilast and apremilast for use in chronic obstructive pulmonary disease and psoriasis/psoriatic arthritis, respectively. However, the antifibrotic potential of PDE4 inhibitors has not yet been explored clinically. BI 1015550 is a novel PDE4 inhibitor showing a preferential enzymatic inhibition of PDE4B. In vitro, BI 1015550 inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) and phytohemagglutinin-induced interleukin-2 synthesis in human peripheral blood mononuclear cells, as well as LPS-induced TNF-α synthesis in human and rat whole blood. In vivo, oral BI 1015550 shows potent anti-inflammatory activity in mice by inhibiting LPS-induced TNF-α synthesis ex vivo and in Suncus murinus by inhibiting neutrophil influx into bronchoalveolar lavage fluid stimulated by nebulized LPS. In Suncus murinus, PDE4 inhibitors induce emesis, a well-known gastrointestinal side effect limiting the use of PDE4 inhibitors in humans, and the therapeutic ratio of BI 1015550 appeared to be substantially improved compared with roflumilast. Oral BI 1015550 was also tested in two well-known mouse models of lung fibrosis (induced by either bleomycin or silica) under therapeutic conditions, and appeared to be effective by modulating various model-specific parameters. To better understand the antifibrotic potential of BI 1015550 in vivo, its direct effect on human fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) was investigated in vitro. BI 1015550 inhibited transforming growth factor-β-stimulated myofibroblast transformation and the mRNA expression of various extracellular matrix proteins, as well as basic fibroblast growth factor plus interleukin-1β-induced cell proliferation. Nintedanib overall was unremarkable in these assays, but interestingly, the inhibition of proliferation was synergistic when it was combined with BI 1015550, leading to a roughly 10-fold shift of the concentration–response curve to the left. In summary, the unique preferential inhibition of PDE4B by BI 1015550 and its anticipated improved tolerability in humans, plus its anti-inflammatory and antifibrotic potential, suggest BI 1015550 to be a promising oral clinical candidate for the treatment of IPF and other fibro-proliferative diseases.
Role of N6-Methyladenosine Methylation Regulators in the Drug Therapy of Digestive System Tumours
Authors: Xia Zhelin , Kong Fanhua , Wang Kunpeng , Zhang Xin
Published: June 2022

Digestive system tumours, including stomach, colon, esophagus, liver and pancreatic tumours, are serious diseases affecting human health. Although surgical treatment and postoperative chemoradiotherapy effectively improve patient survival, current diagnostic and therapeutic strategies for digestive system tumours lack sensitivity and specificity. Moreover, the tumour’s tolerance to drug therapy is enhanced owing to tumour cell heterogeneity. Thus, primary or acquired treatment resistance is currently the main hindrance to chemotherapy efficiency. N6-methyladenosine (m6A) has various biological functions in RNA modification. m6A modification, a key regulator of transcription expression, regulates RNA metabolism and biological processes through the interaction of m6A methyltransferase (“writers”) and demethylase (“erasers”) with the binding protein decoding m6A methylation (“readers”). Additionally, m6A modification regulates the occurrence and development of tumours and is a potential driving factor of tumour drug resistance. This review systematically summarises the regulatory mechanisms of m6A modification in the drug therapy of digestive system malignancies. Furthermore, it clarifies the related mechanisms and therapeutic prospects of m6A modification in the resistence of digestive system malignancies to drug therapy.
Differences in Multicomponent Pharmacokinetics, Tissue Distribution, and Excretion of Tripterygium Glycosides Tablets in Normal and Adriamycin–Induced Nephrotic Syndrome Rat Models and Correlations With Efficacy and Hepatotoxicity
Authors: Wu Wei , Cheng Rui , Boucetta Hamza , Xu Lei , Pan Jing–ru , Song Min , Lu Yu–ting , Hang Tai–jun
Published: June 2022

Tripterygium glycosides tablets (TGT) are widely used for treating nephrotic syndrome (NS), but hepatotoxicity is frequently reported. The presence of underlying disease(s) can alter the disposition of drugs and affect their efficacy and toxicity. However, no studies have reported the impact of NS on the ADME profiles of TGT or its subsequent impact on the efficacy and toxicity. Thus, the efficacy and hepatotoxicity of TGT were evaluated in normal and NS rats after oral administration of TGT (10 mg/kg/day) for 4 weeks. The corresponding ADME profiles of the six key TGT components (triptolide (TPL), wilforlide A (WA), wilforgine (WFG), wilfortrine (WFT), wilfordine (WFD), and wilforine (WFR)) were also measured and compared in normal and NS rats after a single oral gavage of 10 mg/kg TGT. Canonical correlation analysis (CCA) of the severity of NS and the in vivo exposure of the six key TGT components was performed to screen the anti–NS and hepatotoxic material bases of TGT. Finally, the efficacy and hepatotoxicity of the target compounds were evaluated in vitro. The results showed that TGT decreased the NS symptoms in rats, but caused worse hepatotoxicity under the NS state. Significant differences in the ADME profiles of the six key TGT components between the normal and NS rats were as follows: higher plasma and tissue exposure, lower urinary and biliary excretion, and higher fecal excretion for NS rats. Based on CCA and in vitro verification, TPL, WA, WFG, WFT, WFD, and WFR were identified as the anti–NS material bases of TGT, whereas TPL, WFG, WFT, and WFD were recognized as the hepatotoxic material bases. In conclusion, NS significantly altered the ADME profiles of the six key TGT components detected in rats, which were related to the anti–NS and hepatotoxic effects of TGT. These results are useful for the rational clinical applications of TGT.