bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural Features of the Human Connectome That Facilitate the Switching of Brain Dynamics via Noradrenergic Neuromodulation
Authors: Coronel-Oliveros Carlos , Castro Samy , Cofré Rodrigo , Orio Patricio
Published: July 2021

The structural connectivity of human brain allows the coexistence of segregated and integrated states of activity. Neuromodulatory systems facilitate the transition between these functional states and recent computational studies have shown how an interplay between the noradrenergic and cholinergic systems define these transitions. However, there is still much to be known about the interaction between the structural connectivity and the effect of neuromodulation, and to what extent the connectome facilitates dynamic transitions. In this work, we use a whole brain model, based on the Jasen and Rit equations plus a human structural connectivity matrix, to find out which structural features of the human connectome network define the optimal neuromodulatory effects. We simulated the effect of the noradrenergic system as changes in filter gain, and studied its effects related to the global-, local-, and meso-scale features of the connectome. At the global-scale, we found that the ability of the network of transiting through a variety of dynamical states is disrupted by randomization of the connection weights. By simulating neuromodulation of partial subsets of nodes, we found that transitions between integrated and segregated states are more easily achieved when targeting nodes with greater connection strengths—local feature—or belonging to the rich club—meso-scale feature. Overall, our findings clarify how the network spatial features, at different levels, interact with neuromodulation to facilitate the switching between segregated and integrated brain states and to sustain a richer brain dynamics.
Longitudinal Evaluation of Cerebellar Signs of H-ABC Tubulinopathy in a Patient and in the taiep Model
Authors: Alata Milvia , González-Vega Arturo , Piazza Valeria , Kleinert-Altamirano Anke , Cortes Carmen , Ahumada-Juárez Juan C. , Eguibar Jose R. , López-Juárez Alejandra , Hernandez Victor H.
Published: July 2021

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a central neurodegenerative disease due to mutations in the tubulin beta-4A (TUBB4A) gene, characterized by motor development delay, abnormal movements, ataxia, spasticity, dysarthria, and cognitive deficits. Diagnosis is made by integrating clinical data and radiological signs. Differences in MRIs have been reported in patients that carry the same mutation; however, a quantitative study has not been performed so far. Our study aimed to provide a longitudinal analysis of the changes in the cerebellum (Cb), corpus callosum (CC), ventricular system, and striatum in a patient suffering from H-ABC and in the taiep rat. We correlated the MRI signs of the patient with the results of immunofluorescence, gait analysis, segmentation of cerebellum, CC, and ventricular system, performed in the taiep rat. We found that cerebellar and callosal changes, suggesting a potential hypomyelination, worsened with age, in concomitance with the emergence of ataxic gait. We also observed a progressive lateral ventriculomegaly in both patient and taiep, possibly secondary to the atrophy of the white matter. These white matter changes are progressive and can be involved in the clinical deterioration. Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) gives rise to a spectrum of clinical signs whose pathophysiology still needs to be understood.
Neural Kinesthetic Contribution to Motor Imagery of Body Parts: Tongue, Hands, and Feet
Authors: Giannopulu Irini , Mizutani Haruo
Published: July 2021

Motor imagery (MI) is assimilated to a perception-action process, which is mentally represented. Although several models suggest that MI, and its equivalent motor execution, engage very similar brain areas, the mechanisms underlying MI and their associated components are still under investigation today. Using 22 Ag/AgCl EEG electrodes, 19 healthy participants (nine males and 10 females) with an average age of 25.8 years old (sd = 3.5 years) were required to imagine moving several parts of their body (i.e., first-person perspective) one by one: left and right hand, tongue, and feet. Network connectivity analysis based on graph theory, together with a correlational analysis, were performed on the data. The findings suggest evidence for motor and somesthetic neural synchronization and underline the role of the parietofrontal network for the tongue imagery task only. At both unilateral and bilateral cortical levels, only the tongue imagery task appears to be associated with motor and somatosensory representations, that is, kinesthetic representations, which might contribute to verbal actions. As such, the present findings suggest the idea that imagined tongue movements, involving segmentary kinesthetic actions, could be the prerequisite of language.
NIRS-ICA: A MATLAB Toolbox for Independent Component Analysis Applied in fNIRS Studies
Authors: Zhao Yang , Sun Pei-Pei , Tan Fu-Lun , Hou Xin , Zhu Chao-Zhe
Published: July 2021

Independent component analysis (ICA) is a multivariate approach that has been widely used in analyzing brain imaging data. In the field of functional near-infrared spectroscopy (fNIRS), its promising effectiveness has been shown in both removing noise and extracting neuronal activity-related sources. The application of ICA remains challenging due to its complexity in usage, and an easy-to-use toolbox dedicated to ICA processing is still lacking in the fNIRS community. In this study, we propose NIRS-ICA, an open-source MATLAB toolbox to ease the difficulty of ICA application for fNIRS studies. NIRS-ICA incorporates commonly used ICA algorithms for source separation, user-friendly GUI, and quantitative evaluation metrics assisting source selection, which facilitate both removing noise and extracting neuronal activity-related sources. The options used in the processing can also be reported easily, which promotes using ICA in a more reproducible way. The proposed toolbox is validated and demonstrated based on both simulative and real fNIRS datasets. We expect the release of the toolbox will extent the application for ICA in the fNIRS community.
Synaptic Plasticity in Memristive Artificial Synapses and Their Robustness Against Noisy Inputs
Authors: Du Nan , Zhao Xianyue , Chen Ziang , Choubey Bhaskar , Di Ventra Massimiliano , Skorupa Ilona , Bürger Danilo , Schmidt Heidemarie
Published: July 2021

Emerging brain-inspired neuromorphic computing paradigms require devices that can emulate the complete functionality of biological synapses upon different neuronal activities in order to process big data flows in an efficient and cognitive manner while being robust against any noisy input. The memristive device has been proposed as a promising candidate for emulating artificial synapses due to their complex multilevel and dynamical plastic behaviors. In this work, we exploit ultrastable analog BiFeO3 (BFO)-based memristive devices for experimentally demonstrating that BFO artificial synapses support various long-term plastic functions, i.e., spike timing-dependent plasticity (STDP), cycle number-dependent plasticity (CNDP), and spiking rate-dependent plasticity (SRDP). The study on the impact of electrical stimuli in terms of pulse width and amplitude on STDP behaviors shows that their learning windows possess a wide range of timescale configurability, which can be a function of applied waveform. Moreover, beyond SRDP, the systematical and comparative study on generalized frequency-dependent plasticity (FDP) is carried out, which reveals for the first time that the ratio modulation between pulse width and pulse interval time within one spike cycle can result in both synaptic potentiation and depression effect within the same firing frequency. The impact of intrinsic neuronal noise on the STDP function of a single BFO artificial synapse can be neglected because thermal noise is two orders of magnitude smaller than the writing voltage and because the cycle-to-cycle variation of the current–voltage characteristics of a single BFO artificial synapses is small. However, extrinsic voltage fluctuations, e.g., in neural networks, cause a noisy input into the artificial synapses of the neural network. Here, the impact of extrinsic neuronal noise on the STDP function of a single BFO artificial synapse is analyzed in order to understand the robustness of plastic behavior in memristive artificial synapses against extrinsic noisy input.
Study of Human Tacit Knowledge Based on Electroencephalogram Signal Characteristics
Authors: Zhang Tao , Hua Chengcheng , Chen Jichi , He Enqiu , Wang Hong
Published: July 2021

Tacit knowledge is the kind of knowledge that is difficult to transfer to another person by means of writing it down or verbalizing it. In the mineral grinding process, the proficiency of the operators depends on the tacit knowledge gained from their experience and training rather than on knowledge learned from a handbook. This article proposed a method combining the electroencephalogram (EEG) signals and the industrial process to detect the proficiency of the operators in the mineral grinding process to reveal the effect of tacit knowledge on the functional cortical connection. The functional brain networks of operators were established based on partial direct coherence and directed transfer function of EEG, and the multi-classifiers were used with the graph-theoretic indexes of the FBNs as input to distinguish the trained operators (Hps) from the non-trained operators (Lps). The results showed that the brain networks of Hps had a better connectivity than those of Lps (p < 0.01), and the accuracy of classification was up to 94.2%. Our studies confirm that based on the performance of EEG features and the combination of industrial operational operation and cognitive processes, the proficiency of the operators can be detected.
Altered Topological Properties of Static/Dynamic Functional Networks and Cognitive Function After Radiotherapy for Nasopharyngeal Carcinoma Using Resting-State fMRI
Authors: Leng Xi , Qin Chunhong , Lin Huan , Li Mingrui , Zhao Kui , Wang Hongzhuo , Duan Fuhong , An Jie , Wu Donglin , Liu Qihui , Qiu Shijun
Published: July 2021

Objectives

The purpose of this study was to (1) explore the changes in topological properties of static and dynamic brain functional networks after nasopharyngeal carcinoma (NPC) radiotherapy (RT) using rs-fMRI and graph theoretical analysis, (2) explore the correlation between cognitive function and changes in brain function, and (3) add to the understanding of the pathogenesis of radiation brain injury (RBI).

Methods

Fifty-four patients were divided into 3 groups according to time after RT: PT1 (0–6 months); PT2 (>6 to ≤12 months); and PT3 (>12 months). 29 normal controls (NCs) were included. The subjects’ topological properties were evaluated by graph-theoretic network analysis, the functional connectivity of static functional networks was calculated using network-based statistics, and the dynamic functional network matrix was subjected to cluster analysis. Finally, correlation analyses were conducted to explore the relationship between the altered network parameters and cognitive function.

Results

Assortativity, hierarchy, and network efficiency were significantly abnormal in the PT1 group compared with the NC or PT3 group. The small-world variance in the PT3 group was smaller than that in NCs. The Nodal ClustCoeff of Postcentral_R in the PT2 group was significantly smaller than that in PT3 and NC groups. Functional connectivities were significantly reduced in the patient groups. Most of the functional connectivities of the middle temporal gyrus (MTG) were shown to be significantly reduced in all three patient groups. Most of the functional connectivities of the insula showed significantly reduced in the PT1 and PT3 groups, and most of the functional connectivities in brain regions such as frontal and parietal lobes showed significantly reduced in the PT2 and PT3 groups. These abnormal functional connectivities were correlated with scores on multiple scales that primarily assessed memory, executive ability, and overall cognitive function. The frequency F of occurrence of various states in each subject differed significantly, and the interaction effect of group and state was significant.

Conclusion

The disruption of static and dynamic functional network stability, reduced network efficiency and reduced functional connectivity may be potential biomarkers of RBI. Our findings may provide new insights into the pathogenesis of RBI from the perspective of functional networks.
Mapping Knowledge Structure and Research Frontiers of Ultrasound-Induced Blood-Brain Barrier Opening: A Scientometric Study
Authors: Wu Haiyang , Zhou Yan , Xu Lixia , Tong Linjian , Wang Yulin , Liu Baolong , Yan Hua , Sun Zhiming
Published: July 2021

Background: Among the effective approaches developed for blood-brain barrier (BBB) opening, ultrasound is recognized as a non-invasive technique that can induce localized BBB opening transiently and repeatedly. This technique has aroused broad attention from researchers worldwide, and numerous articles have been published recently. However, no existing study has systematically examined this field from a scientometric perspective. The aim of this study was to summarize the knowledge structure and identify emerging trends and potential hotspots in this field.

Methods: Publications related to ultrasound-induced BBB opening published from 1998 to 2020 were retrieved from Web of Science Core Collection. The search strategies were as follows: topic: (“blood brain barrier” OR “BBB”) AND topic: (ultrasound OR ultrason* OR acoustic* OR sonopora*). The document type was set to articles or reviews with language restriction to English. Three different analysis tools including one online platform, VOS viewer1.6.16, and CiteSpace V5.7.R2 software were used to conduct this scientometric study.

Results: A total of 1,201 valid records were included in the final analysis. The majority of scientific publication was produced by authors from North America, Eastern Asia, and Western Europe. Ultrasound in Medicine and Biology was the most prominent journal. The USA, China, and Canada were the most productive countries. Hynynen K, and Mcdannold N were key researchers with considerable academic influence. According to analysis of keywords, four main research directions were identified: cluster 1 (microbubbles study), cluster 2 (management of intracranial tumors), cluster 3 (ultrasound parameters and mechanisms study), and cluster 4 (treatment of neurodegenerative diseases). The current research hotspot has shifted from the basic research of ultrasound and microbubbles to management of intracranial tumors and neurodegenerative diseases. Burst detection analysis showed that Parkinson's disease, doxorubicin, gold nanoparticle, glioblastoma, gene therapy, and Alzheimer's disease may continue to be the research frontiers.

Conclusion: Ultrasound-induced BBB opening research is in a period of robust development. This study is a starting point, providing a comprehensive overview, development landscape, and future opportunities of this technology, which standout as a useful reference for researchers and decision makers interested in this area.
Prediction Model for Cereblon Expression in Bone Marrow Plasma Cells Based on Blood Markers in Multiple Myeloma Patients
Authors: Lee Byung-Hyun , Kang Ka-Won , Jeon Min Ji , Yu Eun Sang , Kim Dae Sik , Lee Se Ryeon , Sung Hwa Jung , Park Yong , Choi Chul Won , Kim Byung Soo
Published: July 2021

Background

Cereblon (CRBN) is a direct target of immunomodulatory drugs (IMiDs) and is known to be sensitive and responsive to IMiD therapy. We evaluated CRBN expression in bone marrow plasma cells and analyzed whether CRBN expression was associated with multiple myeloma prognosis. Lastly, we developed a nomogram model for predicting high CRBN expression based on clinically significant blood markers.

Methods

We evaluated 143 multiple myeloma patients (internal dataset) who underwent bone marrow examinations. For evaluating the prognostic ability of the nomogram model, two external cohorts (235 patients in external dataset 1 and 156 patients in external dataset 2) were analyzed. The expression of CRBN in bone marrow aspirate samples was evaluated using immunohistochemistry. High CRBN expression was defined as the study-defined H-score ≥6.

Results

In the high CRBN group, the median progression-free survival (PFS) and overall survival (OS) of patients receiving the IMiD-based therapy and non-IMiD therapy were 29 and 10 months for PFS, and NR (not reached) and 54 months for OS, respectively. IMiD-based therapy was significantly associated with better PFS and OS outcomes. High CRBN expression was independently predicted by female sex, high serum free-light chain (FLC) ratio, higher serum M-protein level, and higher β2-microglobulin level. Based on these results, we constructed a new nomogram model to predict high CRBN expression and the effectiveness of IMiD therapy in multiple myeloma.

Conclusion

This nomogram could improve the prognostic evaluation of myeloma patients exhibiting high CRBN expression treated with IMiD therapy and might help provide personalized treatment strategies to clinicians.
The Basic Research of the Combinatorial Therapy of ABT-199 and Homoharringtonine on Acute Myeloid Leukemia
Authors: Shi Yuanfei , Ye Jing , Yang Ying , Zhao Yanchun , Shen Huafei , Ye Xiujin , Xie Wanzhuo
Published: July 2021

Background

Existing research shows that ABT-199, as a first-line drug, have been widely used in hematological malignancies, especially in leukemia, but the clinical efficacy of single drug therapy was limited part of the reason was that BCL-2 inhibitors failure to target other anti-apoptotic BCL-2 family proteins, such as MCL-1. In this case, combination therapy may be a promising way to overcome this obstacle. Here, we investigate the preclinical efficacy of a new strategy combining ABT-199 with homoharringtonine (HHT), a selective inhibitor of MCL-1 may be a promising approach for AML treatment as these two molecules are important in apoptosis.

Methods

A Cell Counting Kit-8 (CCK8) assay and flow cytometry were used to determine the half-maximal inhibitory concentration (IC50) value and cell apoptosis rate, respectively. The flow cytometry results showed that combined treatment with HHT and ABT-199 caused apoptosis in AML patient samples (n=5) but had no effect on normal healthy donor samples (n=11). Furthermore, we used a Western blot assay to explore the mechanism underlying the efficacy of HHT combined with ABT-199. Finally, antileukemic activity was further evaluated in vivo xenograft model.

Results

Our results indicated that ABT-199 combined with HHT significantly inhibited cell growth and promoted apoptosis in both AML cell lines and primary AML tumors in a dose- and time-dependent manner. Moreover, HHT combined with ABT-199 suppressed AML cell growth and progression in vivo xenograft model.

Conclusions

Our research found that HHT combined with ABT-199 exerted its anti-leukemia effect by inducing apoptosis through the treatment of AML in vitro and in vivo.
Radical Versus Non-Radical Resection for Early-Stage Retroperitoneal Sarcoma: A Propensity Score-Matched Analysis
Authors: Weng Chengxin , Wang Jiarong , Zhao Jichun , Yuan Ding , Huang Bin , Wang Tiehao
Published: July 2021

Background

The appropriate surgical procedure for early-stage retroperitoneal sarcoma (RPS) is unclear. Thus, we used a national database to compare the outcomes of radical and non-radical resection in patients with early stage RPS.

Methods

This retrospective study included 886 stage I RPS patients from 2004 to 2015 in the SEER database. Outcomes were compared using the multivariate Cox proportional hazards models and the results were presented as adjusted hazards ratio (AHR) with corresponding 95% confidence intervals (95%CIs). Propensity score-matched analyses were also performed for sensitive analyses.

Results

For the 886 stage I RPS patients, 316 underwent radical resection, and 570 underwent non-radical resection, with a median follow-up of 4.58 (2.73-8.35) years. No difference was observed in overall mortality (AHR 0.84, 95%CI 0.62-1.15; P = 0.28) or RPS-specific mortality (AHR 0.88, 95%CI 0.57-1.36; P = 0.56) between groups. The results were similar in propensity score-matching analyses. However, subgroup analysis revealed that radical resection was associated with significantly decreased risks of overall mortality in male (AHR 0.61, 95%CI 0.38-0.98; P = 0.04) and in patients with radiotherapy (AHR 0.56, 95%CI 0.32-0.98; P = 0.04).

Conclusion

Radical resection did not improve midterm survival outcomes compared with non-radical resection in overall patients with early stage RPS. However, male patients or patients who received radiotherapy might benefit from radical resection with improved overall survival.
Effectiveness of Carbon Ion Radiation in Locally Advanced Pancreatic Cancer
Authors: Liermann Jakob , Naumann Patrick , Weykamp Fabian , Hoegen Philipp , Debus Juergen , Herfarth Klaus
Published: July 2021

Purpose

Effective treatment strategies for unresectable locally advanced pancreatic cancer (LAPC) patients are eagerly warranted. Recently, convincing oncological outcomes were demonstrated by carbon ion radiotherapy. Nevertheless, there is a lack of evidence for this modern radiation technique due to the limited number of carbon ion facilities worldwide. Here, we analyze feasibility and efficacy of carbon ion radiotherapy in the management of LAPC at Heidelberg Ion Beam Therapy Center (HIT).

Methods

Between 2015 and 2020, 21 LAPC patients were irradiated with carbon ions with a total dose of 48 Gy (RBE) in single doses of 4 Gy (RBE). Three patients (14%) were treated with concomitant chemotherapy with gemcitabine 300 mg/m2 body surface weekly. Toxicity rates were extracted from the charts. Overall survival, progression free survival, local control, and locoregional control were evaluated using Kaplan–Meier estimates.

Results

One patient developed ascites CTCAE grade III during radiotherapy, which was related to a later histologically confirmed metachronous peritoneal carcinomatosis. No further higher-graded toxicity could be observed. The most common symptoms were nausea and abdominal pain. After a median estimated follow-up time of 19.1 months, the median progression free survival was 3.7 months, and the median overall survival was 11.9 months. The estimated 1-year local control and locoregional control rates were 89 and 84%, respectively.

Conclusion

Carbon ion radiotherapy of LAPC patients is safely feasible. Local tumor control rates were high. Nevertheless, compared to historical data, an overall survival improvement could not be observed. This could be explained by the poor prognosis of the selected underlying patients that mostly did not respond to prior chemotherapy as well as the early and frequent emergence of distant metastases that demonstrate the necessity of additional chemotherapy in further studies.
Acupuncture Treatment for Nocturnal Crying in Pediatric Patients: A Systematic Review of Clinical Studies
Authors: Ang Lin , Song Eunhye , Lee Hye Won , Kim Jung Tae , Kim Eunseop , Lee Myeong Soo
Published: July 2021

Background:Nocturnal crying is a common condition in which children intermittently or continuously cry and fuss during the night, at certain times or throughout the night. It is a common pediatric sleep disturbance for which medical assistance is highly sought by parents, and one of the non-pharmacologic treatments for nocturnal crying is pediatric acupuncture. This review aimed to review the literature about the effectiveness and safety of pediatric acupuncture for nocturnal crying.

Methods:Literature searches were performed on PubMed, the Cochrane Controlled Register of Trials (CENTRAL), Allied and Complementary Medicine Database (AMED), Chinese National Knowledge Infrastructure Database (CNKI), Wanfang Database, and Chinese Science and Technique Journals Database (VIP), OASIS, the Research Information Service System (RISS), and National Digital Science Library (NDSL) from the available date of inception until December 28, 2020. Two review authors independently screened the titles and abstracts of all relevant articles from the search to select eligible articles. All variants of clinical studies on acupuncture treatment for nocturnal crying, including case reports and case studies, were eligible. Data were independently extracted by two review authors using a standard data extraction form. Retrieved data are presented in a tabular form and narratively discussed.

Results:We included 12 studies (10 case series and two case reports) with a total sample size of 2,324 children recruited from the hospital outpatient department. All of the included studies were conducted in mainland China and administered acupuncture as the sole intervention. For the primary outcome, the total efficacy rate of acupuncture treatment for nocturnal crying was reported as 100% in 9 studies, 95% in one study, 94% in another study, and 86% in the remaining study. For the secondary outcome, one study reported a 14% recurrence rate, whereas another study reported an 11% recurrence rate after treatment. There were no follow-ups in most of the studies. None of the studies reported possible adverse events. Most children recovered after one treatment. Generally, the acupoints that were most frequently selected were acupoints EM30 and PC9.

Conclusions:This comprehensive review suggested that pediatric acupuncture may be an effective treatment for nocturnal crying, which could be worth investigating further.
Capacity Building for a New Multicenter Network Within the ECHO IDeA States Pediatric Clinical Trials Network
Authors: Annett Robert D. , Bickel Scott , Carlson John C. , Cowan Kelly , Cox Sara , Fisher Mark J. , Jarvis J. Dean , Kong Alberta S. , Kosut Jessica S. , Kulbeth Kurtis R. , Laptook Abbot , McElfish Pearl A. , McNally Mary M. , Pachter Lee M. , Pahud Barbara A. , Pyles Lee A. , Shaw Jennifer , Simonsen Kari , Snowden Jessica , Turley Christine B. , Atz Andrew M.
Published: July 2021

Introduction: Research capacity building is a critical component of professional development for pediatrician scientists, yet this process has been elusive in the literature. The ECHO IDeA States Pediatric Clinical Trials Network (ISPCTN) seeks to implement pediatric trials across medically underserved and rural populations. A key component of achieving this objective is building pediatric research capacity, including enhancement of infrastructure and faculty development. This article presents findings from a site assessment inventory completed during the initial year of the ISPCTN.

Methods: An assessment inventory was developed for surveying ISPCTN sites. The inventory captured site-level activities designed to increase clinical trial research capacity for pediatrician scientists and team members. The inventory findings were utilized by the ISPCTN Data Coordinating and Operations Center to construct training modules covering 3 broad domains: Faculty/coordinator development; Infrastructure; Trials/Research concept development.

Results: Key lessons learned reveal substantial participation in the training modules, the importance of an inventory to guide the development of trainings, and recognizing local barriers to clinical trials research.

Conclusions: Research networks that seek to implement successfully completed trials need to build capacity across and within the sites engaged. Our findings indicate that building research capacity is a multi-faceted endeavor, but likely necessary for sustainability of a unique network addressing high impact pediatric health problems. The ISPCTN emphasis on building and enhancing site capacity, including pediatrician scientists and team members, is critical to successful trial implementation/completion and the production of findings that enhance the lives of children and families.
Function of Uric Acid Transporters and Their Inhibitors in Hyperuricaemia
Authors: Sun Hao-lu , Wu Yi-wan , Bian He-ge , Yang Hui , Wang Heng , Meng Xiao-ming , Jin Juan
Published: July 2021

Disorders of uric acid metabolism may be associated with pathological processes in many diseases, including diabetes mellitus, cardiovascular disease, and kidney disease. These diseases can further promote uric acid accumulation in the body, leading to a vicious cycle. Preliminary studies have proven many mechanisms such as oxidative stress, lipid metabolism disorders, and rennin angiotensin axis involving in the progression of hyperuricaemia-related diseases. However, there is still lack of effective clinical treatment for hyperuricaemia. According to previous research results, NPT1, NPT4, OAT1, OAT2, OAT3, OAT4, URAT1, GLUT9, ABCG2, PDZK1, these urate transports are closely related to serum uric acid level. Targeting at urate transporters and urate-lowering drugs can enhance our understanding of hyperuricaemia and hyperuricaemia-related diseases. This review may put forward essential references or cross references to be contributed to further elucidate traditional and novel urate-lowering drugs benefits as well as provides theoretical support for the scientific research on hyperuricemia and related diseases.
Perampanel Reduces Hyperthermia-Induced Seizures in Dravet Syndrome Mouse Model
Authors: Ho Shih-Yin , Lin Li , Chen I-Chun , Tsai Che-Wen , Chang Fang-Chia , Liou Horng-Huei
Published: July 2021

Treatment options for Dravet syndrome are limited. The aim of this study was to evaluate the antiepileptic effect of the AMPA receptor antagonist perampanel (PER) on a mouse model of Dravet syndrome (Scn1aE1099X/+). We report here that the PER (2 mg/kg) treatment inhibited the spontaneous recurrent seizures and attenuated epileptic activity in Scn1aE1099X/+ mice. In the hyperthermia-induced seizure experiment, PER clearly increased temperature tolerance and significantly ameliorated seizure frequency and discharge duration. PER also demonstrated antiepileptic effects in a cross-over study and a synergistic effect for attenuating heat-induced seizure when given in combination with stiripentol or valproic acid. The results showed that PER effectively decreased the occurrence of spontaneous recurrent seizures and showed significant therapeutic potential for hyperthermia-induced seizures with regard to both susceptibility and severity in a Dravet syndrome mouse model. Potential therapeutic effects of PER for treatment of Dravet syndrome were demonstrated.
Properties, Pharmacology, and Pharmacokinetics of Active Indole and Oxindole Alkaloids in Uncaria Hook
Authors: Kushida Hirotaka , Matsumoto Takashi , Ikarashi Yasushi
Published: July 2021

Uncaria Hook (UH) is a dry stem with hook of Ucaria plant and is contained in Traditional Japanese and Chinese medicine such as yokukansan, yokukansankachimpihange, chotosan, Gouteng-Baitouweng, and Tianma-Gouteng Yin. UH contains active indole and oxindole alkaloids and has the therapeutic effects on ailments of the cardiovascular and central nervous systems. The recent advances of analytical technology led to reports of detailed pharmacokinetics of UH alkaloids. These observations of pharmacokinetics are extremely important for understanding the treatment’s pharmacological activity, efficacy, and safety. This review describes properties, pharmacology, and the recently accumulated pharmacokinetic findings of UH alkaloids, and discusses challenges and future prospects. UH contains major indole and oxindole alkaloids such as corynoxeine, isocorynoxeine, rhynchophylline, isorhynchophylline, hirsuteine, hirsutine, and geissoschizine methyl ether (GM). These alkaloids exert neuroprotective effects against Alzheimer’s disease, Parkinson’s disease, and depression, and the mechanisms of these effects include anti-oxidant, anti-inflammatory, and neuromodulatory activities. Among the UH alkaloids, GM exhibits comparatively potent pharmacological activity (e.g., agonist activity at 5-HT1A receptors). UH alkaloids are absorbed into the blood circulation and rapidly eliminated when orally administered. UH alkaloids are predominantly metabolized by Cytochrome P450 (CYP) and converted into various metabolites, including oxidized and demethylated forms. Regarding GM metabolism by CYPs, a gender-dependent difference is observed in rats but not in humans. Several alkaloids are detected in the brain after passing through the blood–brain barrier in rats upon orally administered. GM is uniformly distributed in the brain and binds to various channels and receptors such as the 5-HT receptor. By reviewing the pharmacokinetics of UH alkaloids, challenges were found, such as differences in pharmacokinetics between pure drug and crude drug products administration, food-influenced absorption, metabolite excretion profile, and intestinal tissue metabolism of UH alkaloids. This review will provide readers with a better understanding of the pharmacokinetics of UH alkaloids and their future challenges, and will be helpful for further research on UH alkaloids and crude drug products containing UH.
Toxicological Assessment of Bromochlorophene: Single and Repeated-Dose 28-Day Oral Toxicity, Genotoxicity, and Dermal Application in Sprague–Dawley Rats
Authors: Won Hansol , Jeong Da Hye , Shin Hyo-Sook , Lee Jin Hee , Lee Jeong Pyo , Yang Jun-Young , Jung Kikyung , Jeong Jayoung , Oh Jae Ho
Published: July 2021

Bromochlorophene (BCP) has shown good properties in sterilization and antibacterial activity and is widely used as a household chemical. We evaluated the genotoxicity, single and repeated-dose 28-day oral toxicity, and dermal application of a BCP suspension in Sprague–Dawley (SD) rats. For the single-dose toxicity study, a dose of 25–1,000 mg per kg of bodyweight (mg/kg b.w.) of BCP was given once orally to SD rats. Mortality and clinical signs were observed and recorded for the first 30 min after treatment, at 4 h post-administration, and then at least once daily for 14 days after administration. For the repeated-dose 28-day toxicity study, the high dose was set at 1,000 mg/kg b.w. and the middle, middle-low, and low dose were set to 500, 250, and 125 mg/kg, respectively. Hematology and biochemistry parameters were examined. Gross pathologic and histopathologic examinations were performed on selected tissues from all animals. A bacterial reverse mutation assay, in vitro chromosomal aberration assay, and in vivo micronucleus assay were performed to assess genotoxicity-dermal application exposure assessment of BCP in rats. A high oral approximate lethal dose (ALD) of 1,000 mg/kg was observed in the single-dose toxicity test. During the repeated-dose 28-day time period, most animal deaths after administration occurred during the first 3 weeks. The 1,000 mg/kg b.w. oral dose caused the death of six male rats (6/7) and four female rats (4/7). At 500 mg/kg b.w., the female rats showed mortality (1/7). For the biochemistry assays, cholesterol was increased significantly compared to vehicle in both sexes in the 250 and 500 mg/kg groups. Histopathological changes with treatment-related findings were observed in the pancreas in female rats treated with a high dose of BCP compared with the vehicle group. BCP showed no genotoxic effect. These data suggested that the ALD of BCP, estimated as a non-genotoxic substance, was over 1,000 mg/kg b.w. in the single-dose toxicity study, and the NOAEL of BCP was considered to be 250 mg/kg b.w. for male and female rats after repeated oral administration for 28 days under the present study conditions.
The Adverse Effects of Prenatal METH Exposure on the Offspring: A Review
Authors: Li Jia-Hao , Liu Jia-Li , Zhang Kai-Kai , Chen Li-Jian , Xu Jing-Tao , Xie Xiao-Li
Published: July 2021

Abuse of methamphetamine (METH), an illicit psychostimulant, is a growing public health issue. METH abuse during pregnancy is on the rise due to its stimulant, anorectic, and hallucinogenic properties. METH can lead to multiple organ toxicity in adults, including neurotoxicity, cardiovascular toxicity, and hepatotoxicity. It can also cross the placental barrier and have long-lasting effects on the fetus. This review summarizes neurotoxicity, cardiovascular toxicity, hepatotoxicity, toxicity in other organs, and biomonitoring of prenatal METH exposure, as well as the possible emergence of sensitization associated with METH. We proposed the importance of gut microbiota in studying prenatal METH exposure. There is rising evidence of the adverse effects of METH exposure during pregnancy, which are of significant concern.
Characterization of the Electrophysiologic Remodeling of Patients With Ischemic Cardiomyopathy by Clinical Measurements and Computer Simulations Coupled With Machine Learning
Authors: Aronis Konstantinos N. , Prakosa Adityo , Bergamaschi Teya , Berger Ronald D. , Boyle Patrick M. , Chrispin Jonathan , Ju Suyeon , Marine Joseph E. , Sinha Sunil , Tandri Harikrishna , Ashikaga Hiroshi , Trayanova Natalia A.
Published: July 2021

Rationale

Patients with ischemic cardiomyopathy (ICMP) are at high risk for malignant arrhythmias, largely due to electrophysiological remodeling of the non-infarcted myocardium. The electrophysiological properties of the non-infarcted myocardium of patients with ICMP remain largely unknown.

Objectives

To assess the pro-arrhythmic behavior of non-infarcted myocardium in ICMP patients and couple computational simulations with machine learning to establish a methodology for the development of disease-specific action potential models based on clinically measured action potential duration restitution (APDR) data.

Methods and Results

We enrolled 22 patients undergoing left-sided ablation (10 ICMP) and compared APDRs between ICMP and structurally normal left ventricles (SNLVs). APDRs were clinically assessed with a decremental pacing protocol. Using genetic algorithms (GAs), we constructed populations of action potential models that incorporate the cohort-specific APDRs. The variability in the populations of ICMP and SNLV models was captured by clustering models based on their similarity using unsupervised machine learning. The pro-arrhythmic potential of ICMP and SNLV models was assessed in cell- and tissue-level simulations. Clinical measurements established that ICMP patients have a steeper APDR slope compared to SNLV (by 38%, p < 0.01). In cell-level simulations, APD alternans were induced in ICMP models at a longer cycle length compared to SNLV models (385–400 vs 355 ms). In tissue-level simulations, ICMP models were more susceptible for sustained functional re-entry compared to SNLV models.

Conclusion

Myocardial remodeling in ICMP patients is manifested as a steeper APDR compared to SNLV, which underlies the greater arrhythmogenic propensity in these patients, as demonstrated by cell- and tissue-level simulations using action potential models developed by GAs from clinical measurements. The methodology presented here captures the uncertainty inherent to GAs model development and provides a blueprint for use in future studies aimed at evaluating electrophysiological remodeling resulting from other cardiac diseases.
Comparison Between 5- and 1-Year Outcomes Using Cutoff Values of Pressure Drop Coefficient and Fractional Flow Reserve for Diagnosing Coronary Artery Diseases
Authors: Banerjee Rupak K. , Ramadurai Sruthi , Manegaonkar Shreyash M. , Rao Marepalli B. , Rakkimuthu Sathyaprabha , Effat Mohamed A.
Published: July 2021

Background

The current pressure-based coronary diagnostic index, fractional flow reserve (FFR), has a limited efficacy in the presence of microvascular disease (MVD). To overcome the limitations of FFR, the objective is to assess the recently introduced pressure drop coefficient (CDP), a fundamental fluid dynamics-based combined pressure–flow index.

Methods

We hypothesize that CDP will result in improved clinical outcomes in comparison to FFR. To test the hypothesis, chi-square test was performed to compare the percent major adverse cardiac events (%MACE) at 5 years between (a) FFR < 0.75 and CDP > 27.9 and (b) FFR < 0.80 and CDP > 25.4 groups using a prospective cohort study. Furthermore, Kaplan–Meier survival curves were compared between the FFR and CDP groups. The results were considered statistically significant for p < 0.05. The outcomes of the CDP arm were presumptive as clinical decision was solely based on the FFR.

Results

For the complete patient group, the %MACE in the CDP > 27.9 group (10 out of 35, 29%) was lower in comparison to the FFR < 0.75 group (11 out of 20, 55%), and the difference was near significant (p = 0.05). The survival analysis showed a significantly higher survival rate (p = 0.01) in the CDP > 27.9 group (n = 35) when compared to the FFR < 0.75 group (n = 20). The results remained similar for the FFR = 0.80 cutoff. The comparison of the 5-year MACE outcomes with the 1-year outcomes for the complete patient group showed similar trends, with a higher statistical significance for a longer follow-up period of 5 years.

Conclusion

Based on the MACE and survival analysis outcomes, CDP could possibly be an alternate diagnostic index for decision-making in the cardiac catheterization laboratory.

Clinical Trial Registration

www.ClinicalTrials.gov, identifier NCT01719016.
Amadis: A Comprehensive Database for Association Between Microbiota and Disease
Authors: Li Long , Jing Qingxu , Yan Sen , Liu Xuxu , Sun Yuanyuan , Zhu Defu , Wang Dawei , Hao Chenjun , Xue Dongbo
Published: July 2021

The human gastrointestinal tract represents a symbiotic bioreactor that can mediate the interaction of the human host. The deployment and integration of multi-omics technologies have depicted a more complete image of the functions performed by microbial organisms. In addition, a large amount of data has been generated in a short time. However, researchers struggling to keep track of these mountains of information need a way to conveniently gain a comprehensive understanding of the relationship between microbiota and human diseases. To tackle this issue, we developed Amadis (http://gift2disease.net/GIFTED), a manually curated database that provides experimentally supported microbiota-disease associations and a dynamic network construction method. The current version of the Amadis database documents 20167 associations between 221 human diseases and 774 gut microbes across 17 species, curated from more than 1000 articles. By using the curated data, users can freely select and combine modules to obtain a specific microbe-based human disease network. Additionally, Amadis provides a user-friendly interface for browsing, searching and downloading. We hope it can serve as a useful and valuable resource for researchers exploring the associations between gastrointestinal microbiota and human diseases.
Regulation of the Autonomic Nervous System on Intestine
Authors: Duan Hongyi , Cai Xueqin , Luan Yingying , Yang Shuo , Yang Juan , Dong Hui , Zeng Huihong , Shao Lijian
Published: July 2021

Intestine is composed of various types of cells including absorptive epithelial cells, goblet cells, endocrine cells, Paneth cells, immunological cells, and so on, which play digestion, absorption, neuroendocrine, immunological function. Intestine is innervated with extrinsic autonomic nerves and intrinsic enteric nerves. The neurotransmitters and counterpart receptors are widely distributed in the different intestinal cells. Intestinal autonomic nerve system includes sympathetic and parasympathetic nervous systems, which regulate cellular proliferation and function in intestine under physiological and pathophysiological conditions. Presently, distribution and functional characteristics of autonomic nervous system in intestine were reviewed. How autonomic nervous system regulates intestinal cell proliferation was discussed. Function of autonomic nervous system on intestinal diseases was extensively reviewed. It might be helpful to properly manipulate autonomic nervous system during treating different intestinal diseases.
Terpene Synthase-b and Terpene Synthase-e/f Genes Produce Monoterpenes for Phalaenopsis bellina Floral Scent
Authors: Huang Hsin , Kuo Yi-Wei , Chuang Yu-Chen , Yang Ya-Ping , Huang Li-Min , Jeng Mei-Fen , Chen Wen-Huei , Chen Hong-Hwa
Published: July 2021

Orchids are the most species-rich plants and highly interactive with pollinators via visual or olfactory cues. Biosynthesis and emission of volatile organic compounds (VOCs) to the atmosphere facilitate the olfactory cues and ensure successful pollination. Phalaenopsis bellina is a scented orchid with monoterpenes as major VOCs, comprising linalool, geraniol, and their derivatives. Comparative transcriptomics analysis identified four terpene synthase-b (TPS-b) genes and two TPS-e/f genes with differential gene expression between scented and scentless Phalaenopsis species. Here, we confirmed their differential expression between scented and scentless Phalaenopsis orchids and excluded one TPS-b candidate. We analyzed the temporal and spatial expression and functionally characterized these TPSs. Both TPS-b and TPS-e/f genes showed an increased expression on blooming day or 3 days post-anthesis (D + 3) before the optimal emission of floral scent on D + 5, with especially high expression of PbTPS5 and PbTPS10. The TPS-b genes are expressed exclusively in reproductive organs, whereas the TPS-e/f genes are expressed in both reproductive and vegetative organs. In planta functional characterization of both PbTPS5 and PbTPS10 in tobacco and scentless Phalaenopsis plants did not produce terpenoids. Further ectopic expression in scented Phalaenopsis cultivar P. I-Hsin Venus showed that linalool was the main product, with PbTPS10 displaying 3-fold higher activity than PbTPS5. On in vitro enzyme assay with purified recombinant TPS-b proteins ectopically expressed in Escherichia coli, geraniol was the product catalyzed by PbTPS5 and PbTPS9. PbTPS3 was a linalool/(β)-cis-ocimene synthase and PbTPS4 a linalool synthase. In conclusion, both TPS-b and TPS-e/f enzymes orchestrated floral monoterpene biosynthesis in P. bellina.