bluuebunny/crossref_metadata_2025 huggingface dataset:
A Temporal Activity of CA1 Neurons Underlying Short-Term Memory for Social Recognition Altered in PTEN Mouse Models of Autism Spectrum Disorder
Authors: Chai An-Ping , Chen Xue-Feng , Xu Xiao-Shan , Zhang Na , Li Meng , Li Jin-Nan , Zhang Lei , Zhang Dai , Zhang Xia , Mao Rong-Rong , Ding Yu-Qiang , Xu Lin , Zhou Qi-Xin
Published: July 2021

Memory-guided social recognition identifies someone from previous encounters or experiences, but the mechanisms of social memory remain unclear. Here, we find that a short-term memory from experiencing a stranger mouse lasting under 30 min interval is essential for subsequent social recognition in mice, but that interval prolonged to hours by replacing the stranger mouse with a familiar littermate. Optogenetic silencing of dorsal CA1 neuronal activity during trials or inter-trial intervals disrupted short-term memory-guided social recognition, without affecting the ability of being sociable or long-term memory-guided social recognition. Postnatal knockdown or knockout of autism spectrum disorder (ASD)-associated phosphatase and tensin homolog (PTEN) gene in dorsal hippocampal CA1 similarly impaired neuronal firing rate in vitro and altered firing pattern during social recognition. These PTEN mice showed deficits in social recognition with stranger mouse rather than littermate and exhibited impairment in T-maze spontaneous alternation task for testing short-term spatial memory. Thus, we suggest that a temporal activity of dorsal CA1 neurons may underlie formation of short-term memory to be critical for organizing subsequent social recognition but that is possibly disrupted in ASD.
Single Cell Transcriptomics of Ependymal Cells Across Age, Region and Species Reveals Cilia-Related and Metal Ion Regulatory Roles as Major Conserved Ependymal Cell Functions
Authors: MacDonald Adam , Lu Brianna , Caron Maxime , Caporicci-Dinucci Nina , Hatrock Dale , Petrecca Kevin , Bourque Guillaume , Stratton Jo Anne
Published: July 2021

Ependymal cells are ciliated-epithelial glial cells that develop from radial glia along the surface of the ventricles of the brain and the spinal canal. They play a critical role in cerebrospinal fluid (CSF) homeostasis, brain metabolism, and the clearance of waste from the brain. These cells have been implicated in disease across the lifespan including developmental disorders, cancer, and neurodegenerative disease. Despite this, ependymal cells remain largely understudied. Using single-cell RNA sequencing data extracted from publicly available datasets, we make key findings regarding the remarkable conservation of ependymal cell gene signatures across age, region, and species. Through this unbiased analysis, we have discovered that one of the most overrepresented ependymal cell functions that we observed relates to a critically understudied role in metal ion homeostasis. Our analysis also revealed distinct subtypes and states of ependymal cells across regions and ages of the nervous system. For example, neonatal ependymal cells maintained a gene signature consistent with developmental processes such as determination of left/right symmetry; while adult ventricular ependymal cells, not spinal canal ependymal cells, appeared to express genes involved in regulating cellular transport and inflammation. Together, these findings highlight underappreciated functions of ependymal cells, which will be important to investigate in order to better understand these cells in health and disease.
Multiple Sources of Cholinergic Input to the Superior Olivary Complex
Authors: Beebe Nichole L. , Zhang Chao , Burger R. Michael , Schofield Brett R.
Published: July 2021

The superior olivary complex (SOC) is a major computation center in the brainstem auditory system. Despite previous reports of high expression levels of cholinergic receptors in the SOC, few studies have addressed the functional role of acetylcholine in the region. The source of the cholinergic innervation is unknown for all but one of the nuclei of the SOC, limiting our understanding of cholinergic modulation. The medial nucleus of the trapezoid body, a key inhibitory link in monaural and binaural circuits, receives cholinergic input from other SOC nuclei and also from the pontomesencephalic tegmentum. Here, we investigate whether these same regions are sources of cholinergic input to other SOC nuclei. We also investigate whether individual cholinergic cells can send collateral projections bilaterally (i.e., into both SOCs), as has been shown at other levels of the subcortical auditory system. We injected retrograde tract tracers into the SOC in gerbils, then identified retrogradely-labeled cells that were also immunolabeled for choline acetyltransferase, a marker for cholinergic cells. We found that both the SOC and the pontomesencephalic tegmentum (PMT) send cholinergic projections into the SOC, and these projections appear to innervate all major SOC nuclei. We also observed a small cholinergic projection into the SOC from the lateral paragigantocellular nucleus of the reticular formation. These various sources likely serve different functions; e.g., the PMT has been associated with things such as arousal and sensory gating whereas the SOC may provide feedback more closely tuned to specific auditory stimuli. Further, individual cholinergic neurons in each of these regions can send branching projections into both SOCs. Such projections present an opportunity for cholinergic modulation to be coordinated across the auditory brainstem.
Factors Associated With Response to Pilot Home-Based Light Therapy for Fatigue Following Traumatic Brain Injury and Stroke
Authors: Connolly Laura J. , Rajaratnam Shantha M. W. , Spitz Gershon , Lockley Steven W. , Ponsford Jennie L.
Published: July 2021

Background:Fatigue and sleep disturbance are common and debilitating problems after brain injury. Light therapy shows promise as a potential treatment. We conducted a trial of in-home light therapy to alleviate fatigue and sleep disturbance. The aim of the current study was to identify factors moderating treatment response.

Methods:Participants were 24 individuals with traumatic brain injury (TBI) (n= 19) or stroke (n= 5) reporting clinically significant fatigue. Outcomes included fatigue on Brief Fatigue Inventory (primary outcome), sleep disturbance on Pittsburgh Sleep Quality Index, reaction time (RT) on Psychomotor Vigilance Task and time spent in productive activity. Interactions of demographic and clinical variables with these outcomes were examined in linear mixed-model analyses.

Results:Whilst there were no variables found to be significantly associated with change in our primary outcome of fatigue, some variables revealed medium or large effect sizes, including chronotype, eye color, injury severity as measured by PTA, and baseline depressive symptoms. Chronotype significantly moderated sleep quality, with evening chronotype being associated with greater improvement during treatment. Injury type significantly predicted mean RT, with stroke participants exhibiting greater post-treatment reduction than TBI. Age significantly predicted productive activity during Treatment, with younger participants showing stronger Treatment effect.

Conclusion:Light therapy may have a greater impact on sleep in younger individuals and those with an evening chronotype. Older individuals may need higher treatment dose to achieve benefit.

Clinical Trial Registration:www.anzctr.org.au, identifier: ACTRN12617000866303.
Computerized Dual-Task Testing of Gait Visuomotor and Cognitive Functions in Parkinson’s Disease: Test-Retest Reliability and Validity
Authors: Bhatt Mayank , Mahana Bhuvan , Ko Ji Hyun , Kolesar Tiffany A. , Kanitkar Anuprita , Szturm Tony
Published: July 2021

Background

Mobility and cognitive impairments in Parkinson’s disease (PD) often coexist and are prognostic of adverse health events. Consequently, assessment and training that simultaneously address both gait function and cognition are important to consider in rehabilitation and promotion of healthy aging. For this purpose, a computer game-based rehabilitation treadmill platform (GRP) was developed for dual-task (DT) assessment and training.

Objective

The first objective was to establish the test-retest reliability of the GRP assessment protocol for DT gait, visuomotor and executive cognitive function in PD patients. The second objective was to examine the effect of task condition [single task (ST) vs. DT] and disease severity (stage 2 vs. stage 3) on gait, visuomotor and cognitive function.

Methods

Thirty individuals aged 55 to 70 years, diagnosed with PD; 15 each at Hoehn and Yahr scale stage 2 (PD-2) and 3 (PD-3) performed a series of computerized visuomotor and cognitive game tasks while sitting (ST) and during treadmill walking (DT). A treadmill instrumented with a pressure mat was used to record center of foot pressure and compute the average and coefficient of variation (COV) of step time, step length, and drift during 1-min, speed-controlled intervals. Visuomotor and cognitive game performance measures were quantified using custom software. Testing was conducted on two occasions, 1 week apart.

Results

With few exceptions, the assessment protocol showed moderate to high intraclass correlation coefficient (ICC) values under both ST and DT conditions for the spatio-temporal gait measures (average and COV), as well as the visuomotor tracking and cognitive game performance measures. A significant decline in gait, visuomotor, and cognitive game performance measures was observed during DT compared to ST conditions, and in the PD-3 compared to PD-2 groups.

Conclusion

The high to moderate ICC values along with the lack of systematic errors in the measures indicate that this tool has the ability to repeatedly record reliable DT interference (DTI) effects over time. The use of interactive digital media provides a flexible method to produce and evaluate DTI for a wide range of executive cognitive activities. This also proves to be a sensitive tool for tracking disease progression.

Clinical Trial Registration

www.ClinicalTrials.gov, identifier NCT03232996.
How to Arrange Follow-Up Time-Intervals for Longitudinal Brain MRI Studies in Neurodegenerative Diseases
Authors: Müller Hans-Peter , Behler Anna , Landwehrmeyer G. Bernhard , Huppertz Hans-Jürgen , Kassubek Jan
Published: July 2021

Background

Longitudinal brain MRI monitoring in neurodegeneration potentially provides substantial insights into the temporal dynamics of the underlying biological process, but is time- and cost-intensive and may be a burden to patients with disabling neurological diseases. Thus, the conceptualization of follow-up time-intervals in longitudinal MRI studies is an essential challenge and substantial for the results. The objective of this work is to discuss the association of time-intervals and the results of longitudinal trends in the frequently used design of one baseline and two follow-up scans.

Methods

Different analytical approaches for calculating the linear trend of longitudinal parameters were studied in simulations including their performance of dealing with outliers; these simulations were based on the longitudinal striatum atrophy in MRI data of Huntington’s disease patients, detected by atlas-based volumetry (ABV).

Results

For the design of one baseline and two follow-up visits, the simulations with outliers revealed optimum results for identical time-intervals between baseline and follow-up scans. However, identical time-intervals between the three acquisitions lead to the paradox that, depending on the fit method, the first follow-up scan results do not influence the final results of a linear trend analysis.

Conclusions

This theoretical study analyses how the design of longitudinal imaging studies with one baseline and two follow-up visits influences the results. Suggestions for the analysis of longitudinal trends are provided.
Electroacupuncture and Moxibustion-Like Stimulation Relieves Inflammatory Muscle Pain by Activating Local Distinct Layer Somatosensory Afferent Fibers
Authors: Chen Lizhen , Wang Xiaoyu , Zhang Xiaoning , Wan Hongye , Su Yangshuai , He Wei , Xie Yikuan , Jing Xianghong
Published: July 2021

Recent studies have shown that both superficial and deep acupuncture produced clinically relevant and persistent effect on chronic pain, and several subtypes of somatic primary afferents played critical roles in acupuncture and moxibustion analgesia. However, which kind of primary afferents in the superficial and deep tissue of the acupoint is activated by acupuncture or moxibustion to relieve pain persistently remains unclear. The aim of this study is to investigate the roles of distinct peripheral afferents in different layers of the tissue (muscle or skin) in the acupoint for pain relief. Muscular A-fibers activated by deep electroacupuncture (dEA) with lower intensity (approximately 1 mA) persistently alleviated inflammatory muscle pain. Meanwhile, cutaneous C-nociceptors excited by noxious moxibustion-like stimulation (MS) and topical application of capsaicin (CAP) on local acupoint area produced durable analgesic effect. Additionally, spontaneous activity of C-fibers caused by muscular inflammation was also inhibited by dEA and CAP. Furthermore, decreases in pain behavior induced by dEA disappeared after deep A-fibers were demyelinated by cobra venom, whereas CAP failed to relieve pain following cutaneous denervation. Collectively, these results indicate that dEA and MS ameliorate inflammatory muscle pain through distinct primary afferents in different layers of somatic tissue; the former is achieved by activating muscular A-fibers, while the latter is mediated by activating cutaneous C-fibers.
Nerve Growth Factor Biodelivery: A Limiting Step in Moving Toward Extensive Clinical Application?
Authors: Alastra Giuseppe , Aloe Luigi , Baldassarro Vito Antonio , Calzà Laura , Cescatti Maura , Duskey Jason Thomas , Focarete Maria Letizia , Giacomini Daria , Giardino Luciana , Giraldi Valentina , Lorenzini Luca , Moretti Marzia , Parmeggiani Irene , Sannia Michele , Tosi Giovanni
Published: July 2021

Nerve growth factor (NGF) was the first-discovered member of the neurotrophin family, a class of bioactive molecules which exerts powerful biological effects on the CNS and other peripheral tissues, not only during development, but also during adulthood. While these molecules have long been regarded as potential drugs to combat acute and chronic neurodegenerative processes, as evidenced by the extensive data on their neuroprotective properties, their clinical application has been hindered by their unexpected side effects, as well as by difficulties in defining appropriate dosing and administration strategies. This paper reviews aspects related to the endogenous production of NGF in healthy and pathological conditions, along with conventional and biomaterial-assisted delivery strategies, in an attempt to clarify the impediments to the clinical application of this powerful molecule.
Neuromodulation and Behavioral Flexibility in Larval Zebrafish: From Neurotransmitters to Circuits
Authors: Corradi Laura , Filosa Alessandro
Published: July 2021

Animals adapt their behaviors to their ever-changing needs. Internal states, such as hunger, fear, stress, and arousal are important behavioral modulators controlling the way an organism perceives sensory stimuli and reacts to them. The translucent zebrafish larva is an ideal model organism for studying neuronal circuits regulating brain states, owning to the possibility of easy imaging and manipulating activity of genetically identified neurons while the animal performs stereotyped and well-characterized behaviors. The main neuromodulatory circuits present in mammals can also be found in the larval zebrafish brain, with the advantage that they contain small numbers of neurons. Importantly, imaging and behavioral techniques can be combined with methods for generating targeted genetic modifications to reveal the molecular underpinnings mediating the functions of such circuits. In this review we discuss how studying the larval zebrafish brain has contributed to advance our understanding of circuits and molecular mechanisms regulating neuromodulation and behavioral flexibility.
Progesterone Receptor Expression in Meningiomas: Pathological and Prognostic Implications
Authors: Maiuri Francesco , Mariniello Giuseppe , de Divitiis Oreste , Esposito Felice , Guadagno Elia , Teodonno Giuseppe , Barbato Marcello , Del Basso De Caro Marialaura
Published: July 2021

Background

The progesterone receptor (PR) is variably expressed in most meningiomas and was found to have prognostic significance. However, the correlation with patient age, tumor location, time to recurrence, and pattern of regrowth has scarcely been discussed.

Methods

A surgical series of 300 patients with meningiomas is reviewed. The PR expression was classified as: 0. absent; 1. low (<15%); 2. moderately low (16–50%); 3. moderately high (51–79%); 4. high (≥80%). The PR values were correlated with the patient age and sex, meningioma location, WHO grade, Ki-67 MIB1, recurrence rate, pattern of recurrence (local-peripheral versus multicentric diffuse), and time to recurrence.

Results

The PR expression has shown lower rate of high expression in the elderly group (p = 0.032) and no sex difference (including premenopausal versus postmenopausal women), higher expression in medial skull base and spinal versus other locations (p = 0.0036), inverse correlation with WHO grade and Ki67-MIB1 (p < 0.0001). Meningiomas which recurred showed at initial surgery higher rates of low or moderately low PR expression than the non-recurrent ones (p = 0.0004), whereas the pattern of regrowth was not significant. Higher rates of PR values ≥80% were found in cases with time to recurrence >5 years (p = 0.036).

Conclusion

The higher PR expression in medial skull base meningiomas, the significant correlation with the time to recurrence, the lack of difference of PR expression between premenopausal and postmenopausal women and between local-peripheral versus multicentric-diffuse recurrences are the most relevant unreported findings of this study. The rate of PR expression must be included in the routine pathological diagnosis of meningiomas because of its prognostic significance.
Support Vector Machine Model Predicts Dose for Organs at Risk in High-Dose Rate Brachytherapy of Cervical Cancer
Authors: Zhou Ping , Li Xiaojie , Zhou Hao , Fu Xiao , Liu Bo , Zhang Yu , Lin Sheng , Pang Haowen
Published: July 2021

Introduction

This study aimed to establish a support vector machine (SVM) model to predict the dose for organs at risk (OARs) in intracavitary brachytherapy planning for cervical cancer with tandem and ovoid treatments.

Methods

Fifty patients with loco-regionally advanced cervical cancer treated with 200 CT-based tandem and ovoid brachytherapy plans were included. The brachytherapy plans were randomly divided into the training (N = 160) and verification groups (N = 40). The bladder, rectum, sigmoid colon, and small intestine were divided into sub-OARs. The SVM model was established using MATLAB software based on the sub-OAR volume to predict the bladder, rectum, sigmoid colon, and small intestine D2cm3. Model performance was quantified by mean squared error (MSE) and δ (δ=|D2cm3/Dprescription(actual)−D2cm3/Dprescription(predicted)|). The goodness of fit of the model was quantified by the coefficient of determination (R2). The accuracy and validity of the SVM model were verified using the validation group.

Results

The D2cm3 value of the bladder, rectum, sigmoid colon, and small intestine correlated with the volume of the corresponding sub-OARs in the training group. The mean squared error (MSE) in the SVM model training group was <0.05; the R2 of each OAR was >0.9. There was no significant difference between the D2cm3 -predicted and actual values in the validation group (all P > 0.05): bladder δ = 0.024 ± 0.022, rectum δ = 0.026 ± 0.014, sigmoid colon δ = 0.035 ± 0.023, and small intestine δ = 0.032 ± 0.025.

Conclusion

The SVM model established in this study can effectively predict the D2cm3 for the bladder, rectum, sigmoid colon, and small intestine in cervical cancer brachytherapy.
Advanced Deep Learning Approach to Automatically Segment Malignant Tumors and Ablation Zone in the Liver With Contrast-Enhanced CT
Authors: He Kan , Liu Xiaoming , Shahzad Rahil , Reimer Robert , Thiele Frank , Niehoff Julius , Wybranski Christian , Bunck Alexander C. , Zhang Huimao , Perkuhn Michael
Published: July 2021

Objective

Liver cancer is one of the most commonly diagnosed cancer, and energy-based tumor ablation is a widely accepted treatment. Automatic and robust segmentation of liver tumors and ablation zones would facilitate the evaluation of treatment success. The purpose of this study was to develop and evaluate an automatic deep learning based method for (1) segmentation of liver and liver tumors in both arterial and portal venous phase for pre-treatment CT, and (2) segmentation of liver and ablation zones in both arterial and portal venous phase for after ablation treatment.

Materials and Methods

252 CT images from 63 patients undergoing liver tumor ablation at a large University Hospital were retrospectively included; each patient had pre-treatment and post-treatment multi-phase CT images. 3D voxel-wise manual segmentation of the liver, tumors and ablation region by the radiologist provided reference standard. Deep learning models for liver and lesion segmentation were initially trained on the public Liver Tumor Segmentation Challenge (LiTS) dataset to obtain base models. Then, transfer learning was applied to adapt the base models on the clinical training-set, to obtain tumor and ablation segmentation models both for arterial and portal venous phase images. For modeling, 2D residual-attention Unet (RA-Unet) was employed for liver segmentation and a multi-scale patch-based 3D RA-Unet for tumor and ablation segmentation.

Results

On the independent test-set, the proposed method achieved a dice similarity coefficient (DSC) of 0.96 and 0.95 for liver segmentation on arterial and portal venous phase, respectively. For liver tumors, the model on arterial phase achieved detection sensitivity of 71%, DSC of 0.64, and on portal venous phase sensitivity of 82%, DSC of 0.73. For liver tumors >0.5cm3 performance improved to sensitivity 79%, DSC 0.65 on arterial phase and, sensitivity 86%, DSC 0.72 on portal venous phase. For ablation zone, the model on arterial phase achieved detection sensitivity of 90%, DSC of 0.83, and on portal venous phase sensitivity of 90%, DSC of 0.89.

Conclusion

The proposed deep learning approach can provide automated segmentation of liver tumors and ablation zones on multi-phase (arterial and portal venous) and multi-time-point (before and after treatment) CT enabling quantitative evaluation of treatment success.
Targeted Sequencing of Ascites and Peritoneal Washing Fluid of Patients With Gastrointestinal Cancers and Their Clinical Applications and Limitations
Authors: Bae Go Eun , Kim Seok-Hwan , Choi Min Kyung , Kim Jin-Man , Yeo Min-Kyung
Published: July 2021

Cytology from gastrointestinal (GI) cancers is frequently obtained from ascites and peritoneal washing fluids. Examination of ascites and peritoneal washing fluids from patients with GI cancers can help in the tumor staging and prognosis. Tumor-derived DNA in these cytology samples can be a target for next generation sequencing (NGS). Targeted NGS was evaluated in ascites and peritoneal washing samples obtained from 33 patients with GI cancers. These sequences were compared with those from tumor tissue samples, and correlated with cytopathologic findings of the ascites and peritoneal fluid samples. The correlation between fluid and tissue genotyping results was 25%, with a sensitivity of 21.43%. The volume of tumor contained within the fluid samples was low, ranging from ~0 to 10%. Importantly, the sensitivity of detection of somatic mutations in the fluid samples could be increased to 69.2% by assessing samples containing >2% tumor volume. Evaluation of cells from ascitic fluid showed the presence of KRAS, TP53, and CDH1 mutations in 33, 13, and 7%, respectively, of patients with pancreatic cancer, and the presence of KRAS, TP53, and APC mutations in 25, 12, and 13%, respectively, of patients with gastric cancer. Ascites of one of the latter patients acquired KRAS mutation, which was a novel mutation during metastasis. Targeted NGS of ascites and peritoneal washing fluid have clinical implications, as well as limitations, in patients with GI cancers. NGS-based cytology examination may expand cytomolecular practices in GI cancer patients.
Reversing Epigenetic Gene Silencing to Overcome Immune Evasion in CNS Malignancies
Authors: Ratnam Nivedita M. , Sonnemann Heather M. , Frederico Stephen C. , Chen Huanwen , Hutchinson Marsha-Kay N. D. , Dowdy Tyrone , Reid Caitlin M. , Jung Jinkyu , Zhang Wei , Song Hua , Zhang Meili , Davis Dionne , Larion Mioara , Giles Amber J. , Gilbert Mark R.
Published: July 2021

Glioblastoma (GBM) is an aggressive brain malignancy with a dismal prognosis. With emerging evidence to disprove brain-immune privilege, there has been much interest in examining immunotherapy strategies to treat central nervous system (CNS) cancers. Unfortunately, the limited success of clinical studies investigating immunotherapy regimens, has led to questions about the suitability of immunotherapy for these cancers. Inadequate inherent populations of tumor infiltrating lymphocytes (TILs) and limited trafficking of systemic, circulating T cells into the CNS likely contribute to the poor response to immunotherapy. This paucity of TILs is in concert with the finding of epigenetic silencing of genes that promote immune cell movement (chemotaxis) to the tumor. In this study we evaluated the ability of GSK126, a blood-brain barrier (BBB) permeable small molecule inhibitor of EZH2, to reverse GBM immune evasion by epigenetic suppression of T cell chemotaxis. We also evaluated the in vivo efficacy of this drug in combination with anti-PD-1 treatment on tumor growth, survival and T cell infiltration in syngeneic mouse models. GSK126 reversed H3K27me3 in murine and human GBM cell lines. When combined with anti-PD-1 treatment, a significant increase in activated T cell infiltration into the tumor was observed. This resulted in decreased tumor growth and enhanced survival both in sub-cutaneous and intracranial tumors of immunocompetent, syngeneic murine models of GBM. Additionally, a significant increase in CXCR3+ T cells was also seen in the draining lymph nodes, suggesting their readiness to migrate to the tumor. Closer examination of the mechanism of action of GSK126 revealed its ability to promote the expression of IFN-γ driven chemokines CXCL9 and CXCL10 from the tumor cells, that work to traffic T cells without directly affecting T maturation and/or proliferation. The loss of survival benefit either with single agent or combination in immunocompromised SCID mice, suggest that the therapeutic efficacy of GSK126 in GBM is primarily driven by lymphocytes. Taken together, our data suggests that in glioblastoma, epigenetic modulation using GSK126 could improve current immunotherapy strategies by reversing the epigenetic changes that enable immune cell evasion leading to enhanced immune cell trafficking to the tumor.
Super-Enhancer Induced IL-20RA Promotes Proliferation/Metastasis and Immune Evasion in Colorectal Cancer
Authors: Yu Dingye , Yang Xiao , Lin Jianwei , Cao Zichao , Lu Chenghao , Yang Zheyu , Zheng Minhua , Pan Ruijun , Cai Wei
Published: July 2021

Unveiling key oncogenic events in malignancies is the key to improving the prognosis and therapeutic outcome of malignancies. Lines of evidence have shown that super-enhancers control the expression of genes that determine the cell fate, but the oncogenic super-enhancers in colorectal cancer (CRC) and their impact on carcinogens remain largely unexplored. Here, we identified a new oncogenic super-enhancer-regulated gene, IL-20RA, in CRC. Using the integrative analysis of H3K27ac ChIP-seq and RNA-seq in CRC tumors and normal colon tissues, we obtained a series of oncogenic super-enhancers in CRC. We found that super-enhancer inhibition by JQ-1 or iBET-151 suppressed the growth of tumor cells and inhibited the expression of IL-20RA. We found that IL-20RA was highly expressed in the tumor tissue of CRC and related to the advanced stage. Further functional studies showed that knockdown of IL-20RA inhibited the growth and metastasis of CRC. In addition, we found that IL-20RA was involved in regulating oncogenic and immune pathways and affecting the expression of genes related to cell proliferation and immune evasion in CRC. Together, our study demonstrated a novel oncogene in CRC and shed new light on oncogenic super-enhancer contributions to cell proliferation and immune escape.
Case Report: Rare Iliac Vein Compression (May–Thurner) Syndrome in a Pediatric Patient
Authors: Ji Lianfu , Yang Fan , Chen Xuan , Chen Jinlong , Cheng Xueying , Yin Jie , Qin Yuming , Yang Shiwei
Published: July 2021

Iliac vein compression syndrome (IVCS) or May–Thurner syndrome occurs predominantly in young to middle-aged women. Here we reported a case of IVCS in a 5-year-old boy. The child was admitted to our vasculocardiology department with left lower extremity that had been swollen for 1 month. Blood tests revealed coagulation routine and platelets in the normal ranges. Computer tomography angiography (CTA) and magnetic resonance imaging (MRI) showed the left common iliac vein had become narrow before it entered the right common iliac vein. To further clarify, we performed angiography, which clearly showed the stenosis and the blood return of the left common iliac vein. So IVCS was diagnosed. What is more, we found the aorta descended to the right of the spine, and this may be the reason for the apparent compression of the left common iliac vein. Given the young age and mild symptoms of the child, the treatment was conservative mainly including elevation of the affected limb, wearing medical elastic socks, and short-term oral aspirin for anticoagulation. Meanwhile, the boy is being followed up closely. If the swelling of the left lower extremity significantly increases, stent placement may need to be considered in the future.
Case Report: A Case of Congenital Nephrogenic Diabetes Insipidus Caused by Thr273Met Mutation in Arginine Vasopressin Receptor 2
Authors: Huang Li , Ma Lina , Li Linjing , Luo Jiajia , Sun Tianhong
Published: July 2021

Congenital nephrogenic diabetes insipidus (CNDI) is a rare hereditary tubular dysfunction caused mainly by X-linked recessive inheritance ofAVPR2gene mutations. Pathogenic genes are a result of mutations inAVPR2on chromosome Xq28 and inAQP2on chromosome 12q13. The clinical manifestations of CNDI include polyuria, compensatory polydipsia, thirst, irritability, constipation, developmental delay, mental retardation, persistent decrease in the specific gravity of urine, dehydration, and electrolyte disorders (hypernatremia and hyperchloremia). Herein, we report a rare case of CNDI caused by anAVPR2mutation in a 2-year-old Chinese boy who had sustained polyuria, polydipsia, and irritability for more than 20 months. Laboratory examinations showed no obvious abnormality in blood sodium and chloride levels but decreased urine osmolality and specific gravity. Imaging findings were also normal. However, genetic analysis revealed a C > T transition leading to T273M missense mutations in AVPR2. We provided the boy a low-sodium diet and administered oral hydrochlorothiazide and indomethacin for 1 month, after which his clinical symptoms significantly improved. This case report suggests that CNDI is characterized by pathogenic T273M missense mutations alone and expands our understanding of the pathogenesis of CNDI.
Total Flavones of Abelmoschus manihot Ameliorates Podocyte Pyroptosis and Injury in High Glucose Conditions by Targeting METTL3-Dependent m6A Modification-Mediated NLRP3-Inflammasome Activation and PTEN/PI3K/Akt Signaling
Authors: Liu Bu-Hui , Tu Yue , Ni Guang-Xia , Yan Jin , Yue Liang , Li Zi-Lin , Wu Jing-Jing , Cao Yu-Ting , Wan Zi-Yue , Sun Wei , Wan Yi-Gang
Published: July 2021

Background: The total flavones of Abelmoschus manihot (TFA), a compound that is extracted from Abelmoschus manihot, has been widely used in China to reduce podocyte injury in diabetic kidney disease (DKD). However, the mechanisms underlying the therapeutic action of this compound have yet to be elucidated. Podocyte pyroptosis is characterized by activation of the NLRP3 inflammasome and plays an important role in inflammation-mediated diabetic kidneys. Regulation of the PTEN/PI3K/Akt pathway is an effective strategy for improving podocyte damage in DKD. Previous research has also shown that N6-methyladenosine (m6A) modification is involved in DKD and that m6A-modified PTEN regulates the PI3K/Akt pathway. In this study, we investigated whether TFA alleviates podocyte pyroptosis and injury by targeting m6A modification-mediated NLRP3-inflammasome activation and PTEN/PI3K/Akt signaling.

Methods: We used MPC-5 cells under high glucose (HG) conditions to investigate the key molecules that are involved in podocyte pyroptosis and injury, including activation of the NLRP3 inflammasome and the PTEN/PI3K/Akt pathway. We detected alterations in the levels of three methyltransferases that are involved in m6A modification. We also investigated changes in the levels of these key molecules in podocytes with the overexpression or knockdown of methyltransferase-like (METTL)3.

Results: Analysis showed that TFA and MCC950 protected podocytes against HG-induced pyroptosis and injury by reducing the protein expression levels of gasdermin D, interleukin-1β, and interleukin-18, and by increasing the protein expression levels of nephrin, ZO-1, WT1 and podocalyxin. TFA and 740Y-P inhibited activation of the NLRP3 inflammasome via the PI3K/Akt pathway by inhibiting the protein levels of NIMA-related kinase7, NLRP3, ASC, and caspase-1, and by increasing the protein expression levels of p-PI3K and p-Akt. TFA improved pyroptosis and injury in HG-stimulated podocytes by regulating METTL3-dependent m6A modification.

Conclusion: Collectively, our data indicated that TFA could ameliorate pyroptosis and injury in podocytes under HG conditions by adjusting METTL3-dependent m6A modification and regulating NLRP3-inflammasome activation and PTEN/PI3K/Akt signaling. This study provides a better understanding of how TFA can protect podocytes in DKD.
Atractylenolide I Inhibits NLRP3 Inflammasome Activation in Colitis-Associated Colorectal Cancer via Suppressing Drp1-Mediated Mitochondrial Fission
Authors: Qin Yao , Yu Yanwei , Yang Chendong , Wang Zhuien , Yang Yi , Wang Chongxu , Zheng Qiusheng , Li Defang , Xu Wenjuan
Published: July 2021

Inflammatory bowel disease (IBD) is an important high-risk factor that promotes the occurrence and development of colon cancer. Research on the mechanism of regulating NLRP3 can provide potential targets for treating NLRP3 inflammasome–related diseases and changing the inflammatory potential of immune cells. In this study, the effects of atractylenolide I on colitis-associated CRC (caCRC) and inflammasome activation were investigated both in vivo and in vitro. Furthermore, the role of atractylenolide I on Drp1-mediated mitochondrial fission was analyzed via Western blotting and transmission electron microscopy (TEM). Moreover, the Drp1 overexpression lentiviral vector was used to study the role of Drp1 on the signaling mechanisms of atractylenolide I. Atractylenolide I treatment significantly reduced the cell viability of human HCT116 and SW480 cells and induced apoptosis, and effectively inhibited colon tumors in the AOM/DSS mouse model. The reduction of NLRP3 inflammasome activation and excessive fission of mitochondria mediated by Drp1 were associated with the administration of atractylenolide I. Upregulation of Drp1 reversed the inhibitory effect of atractylenolide I on the activation of NLRP3 inflammasomes. Overexpressing the Drp1 expression counteracted the restraint of atractylenolide I on the release of IL-1β of LPS/DSS-stimulated BMDMs. Atractylenolide I inhibited NLRP3 and caspase-1 expression in mice BMDMs, with no influence in the Drp1-overexpressed BMDMs. These results demonstrated that atractylenolide I inhibits NLRP3 inflammasome activation in colitis-associated colorectal cancer via suppressing Drp1-mediated mitochondrial fission.
Bibliometric and Visual Analysis of Vascular Calcification Research
Authors: Dong Qian , Liang Qingchun , Chen Ying , Li Jinhe , Lu Lihe , Huang Xiongqing , Zhou Qin
Published: July 2021

Background: Extensive studies related to vascular calcification (VC) were conducted in recent years. However, no bibliometric analysis has systematically investigated this topic. Our study aimed to determine the hotspots and frontiers of VC research in the past decade and provide a reference for future scientific research directions and decision-making in the VC field.

Methods: VC studies were acquired from the Web of Science Core Collection. Bibliometric and visual analyses were performed using CiteSpace, VOSviewer, and Microsoft Excel software.

Results: A total of 8,238 English articles on VC research published in 2011–2020 were obtained. In the past decade, annual publications and citations showed a significant growth trend, especially in 2018–2020. The most productive country, institution, journal and author are the United States, the University of California System, PLOS ONE, and Budoff MJ, respectively. The most frequently cited country, journal, and author are the United States, Journal of the American College of Cardiology, and Floege J, respectively. “Vascular calcification,” “atherosclerosis,” “chronic kidney disease,” and “cardiovascular disease” are the primary keywords. The burst keywords “revascularization,” “calciprotein particle,” “microRNA,” and “microcalcification” are speculated to be the research frontiers.

Conclusion: The main research hotspots in the VC field are the molecular mechanisms and prognosis of VC in patients with chronic kidney disease or cardiovascular disease. In addition, endovascular therapy and the development of new drugs targeting signal pathways for VC will become the focus of future research. Moreover, non-coding RNAs related to the diagnosis and treatment of VC are great research prospects.
Discovery of a New CDK4/6 and PI3K/AKT Multiple Kinase Inhibitor Aminoquinol for the Treatment of Hepatocellular Carcinoma
Authors: Xia Zhong-Kun , Wang Wei , Qiu Jian-Ge , Shi Xi-Nan , Li Hong-Jian , Chen Rong , Ke Kun-Bin , Dong Chao , Zhu Ying , Wu Shi-Guo , Zhang Rong-Ping , Meng Zhuo-Ran , Zhao Hui , Gu Peng , Leung Kwong-Sak , Wong Man-Hon , Liu Xiao-Dong , Zhou Feng-Mei , Zhang Jian-Ying , Yao Ya-Ting , Wang Si-Jia , Zhang Chun-Yang , Qin Yan-Ru , Lin Marie Chia-mi , Jiang Bing-Hua
Published: July 2021

Background:Hepatocellular carcinoma (HCC) is a lethal malignancy lacking effective treatment. The Cyclin-dependent kinases 4/6 (CDK4/6) and PI3K/AKT signal pathways play pivotal roles in carcinogenesis and are promising therapeutic targets for HCC. Here we identified a new CDK4/6 and PI3K/AKT multi-kinase inhibitor for the treatment of HCC.

Methods:Using a repurposing and ensemble docking methodology, we screened a library of worldwide approved drugs to identify candidate CDK4/6 inhibitors. By MTT, apoptosis, and flow cytometry analysis, we investigated the effects of candidate drug in reducing cell-viability,inducing apoptosis, and causing cell-cycle arrest. The drug combination and thermal proteomic profiling (TPP) method were used to investigate whether the candidate drug produced antagonistic effect. Thein vivoanti-cancer effect was performed in BALB/C nude mice subcutaneously xenografted with Huh7 cells.

Results:We demonstrated for the first time that the anti-plasmodium drug aminoquinol is a new CDK4/6 and PI3K/AKT inhibitor. Aminoquinol significantly decreased cell viability, induced apoptosis, increased the percentage of cells in G1 phase. Drug combination screening indicated that aminoquinol could produce antagonistic effect with the PI3K inhibitor LY294002. TPP analysis confirmed that aminoquinol significantly stabilized CDK4, CDK6, PI3K and AKT proteins. Finally,in vivostudy in Huh7 cells xenografted nude mice demonstrated that aminoquinol exhibited strong anti-tumor activity, comparable to that of the leading cancer drug 5-fluorouracil with the combination treatment showed the highest therapeutic effect.

Conclusion:The present study indicates for the first time the discovery of a new CDK4/6 and PI3K/AKT multi-kinase inhibitor aminoquinol. It could be used alone or as a combination therapeutic strategy for the treatment of HCC.
A Metabolic Pattern in Healthy Subjects Given a Single Dose of Metformin: A Metabolomics Approach
Authors: Dahabiyeh Lina A. , Mujammami Muhammad , Arafat Tawfiq , Benabdelkamel Hicham , Alfadda Assim A. , Abdel Rahman Anas M.
Published: July 2021

Metformin is a widely prescribed medication for the treatment of type 2 diabetes mellitus (T2DM). It possesses effective roles in various disorders, including cancer, dyslipidemia, and obesity. However, the underlying mechanisms of metformin's multiple benefits are not fully understood. Herein, a mass spectrometry-based untargeted metabolomics approach was used to investigate the metabolic changes associated with the administration of a single dose of metformin in the plasma of 26 healthy subjects at five-time points; pre-dose, before the maximum concentration of metformin (Cmax), Cmax, after Cmax, and 36 h post-dose. A total of 111 metabolites involved in various biochemical processes were perturbed, with branched-chain amino acid (BCAA) being the most significantly altered pathway. Additionally, the Pearson similarity test revealed that 63 metabolites showed a change in their levels dependent on metformin level. Out of these 63, the level of 36 metabolites was significantly altered by metformin. Significantly altered metformin-dependent metabolites, including hydroxymethyl uracil, propionic acid, glycerophospholipids, and eicosanoids, pointed to fundamental biochemical processes such as lipid network signaling, energy homeostasis, DNA lesion repair mechanisms, and gut microbiota functions that could be linked to the multiple beneficial roles of metformin. Thus, the distinctive metabolic pattern linked to metformin administration can be used as a metabolic signature to predict the potential effect and mechanism of actions of new chemical entities during drug development.
Gold Nanoparticles Modified With Polyethyleneimine Disturbed the Activity of Drug-Metabolic Enzymes and Induced Inflammation-Mediated Liver Injury in Mice
Authors: Chen Hanqing , Zhou Shuang , Zhu Meilin , Wang Bing , Chen Wei , Zheng Lingna , Wang Meng , Feng Weiyue
Published: July 2021

Gold nanoparticles (GNPs) have been used as a potential bioactive platform for drug delivery due to their unique optical and thermal characteristics. Liver is the main organ in orchestrating physiological homeostasis through metabolization of drugs and detoxification of exogenous substances. Therefore, it is crucial to deeply understand the mechanism of nanoparticle–liver interaction and the potential hepatic effects of GNPs in vivo. In this study, we studied the hepatic impacts of the intravenously injected polyethyleneimine (PEI)-modified GNPs (PEI-GNPs) on the expression of hepatic drug-metabolic enzymes and sterol responsive element binding protein 1c (SREBP-1c)-mediated de novo lipogenesis in mice for 24 h and 1 week. PEI-GNP accumulation in the liver is associated with increased liver inflammation, as evidenced by the gene expression of pro-inflammatory cytokines. Moreover, the GNP-induced hepatotoxicity in mice is partly due to liver inflammation–triggered disruption in the function of drug-metabolic enzymes, including hepatic uptake and efflux transporters, cytochrome P450 (CYP450), and UDP-glucuronosyltransferases (UGTs). The study provides evidence that it is necessary to consider the nanomaterial–liver interaction and manipulate the surface chemistry of GNPs prior to biomedical application of nanoparticles.
Piezo2 Knockdown Inhibits Noxious Mechanical Stimulation and NGF-Induced Sensitization in A-Delta Bone Afferent Neurons
Authors: Nencini Sara , Morgan Michael , Thai Jenny , Jobling Andrew I. , Mazzone Stuart B. , Ivanusic Jason J.
Published: July 2021

Piezo2 is a mechanically gated ion-channel that has a well-defined role in innocuous mechanical sensitivity, but recently has also been suggested to play a role in mechanically induced pain. Here we have explored a role for Piezo2 in mechanically evoked bone nociception in Sprague Dawley rats. We have used anin vivoelectrophysiological bone-nerve preparation to record the activity of single Aδ bone afferent neurons in response to noxious mechanical stimulation, after Piezo2 knockdown in the dorsal root ganglia with intrathecal injections of Piezo2 antisense oligodeoxynucleotides, or in control animals that received mismatch oligodeoxynucleotides. There were no differences in the number of Aδ bone afferent neurons responding to the mechanical stimulus, or their threshold for mechanical activation, in Piezo2 knockdown animals compared to mismatch control animals. However, bone afferent neurons in Piezo2 knockdown animals had reduced discharge frequencies and took longer to recover from stimulus-evoked fatigue than those in mismatch control animals. Piezo2 knockdown also prevented nerve growth factor (NGF)-induced sensitization of bone afferent neurons, and retrograde labeled bone afferent neurons that expressed Piezo2 co-expressed TrkA, the high affinity receptor for NGF. Our findings demonstrate that Piezo2 contributes to the response of bone afferent neurons to noxious mechanical stimulation, and plays a role in processes that sensitize them to mechanical stimulation.
Transcriptome Response to Cadmium Exposure in Barley (Hordeum vulgare L.)
Authors: Kintlová Martina , Vrána Jan , Hobza Roman , Blavet Nicolas , Hudzieczek Vojtěch
Published: July 2021

Cadmium is an environmental pollutant with high toxicity that negatively affects plant growth and development. To understand the molecular mechanisms of plant response to cadmium stress, we have performed a genome-wide transcriptome analysis on barley plants treated with an increased concentration of cadmium. Differential gene expression analysis revealed 10,282 deregulated transcripts present in the roots and 7,104 in the shoots. Among them, we identified genes related to reactive oxygen species metabolism, cell wall formation and maintenance, ion membrane transport and stress response. One of the most upregulated genes was PLANT CADMIUM RESISTACE 2 (HvPCR2) known to be responsible for heavy metal detoxification in plants. Surprisingly, in the transcriptomic data we identified four different copies of the HvPCR2 gene with a specific pattern of upregulation in individual tissues. Heterologous expression of all five barley copies in a Cd-sensitive yeast mutant restored cadmium resistance. In addition, four HvPCR2 were located in tandem arrangement in a single genomic region of the barley 5H chromosome. To our knowledge, this is the first example showing multiplication of the PCR2 gene in plants.