bluuebunny/crossref_metadata_2025 huggingface dataset:
A Minireview of the Promising Drugs and Vaccines in Pipeline for the Treatment of COVID-19 and Current Update on Clinical Trials
Authors: Venkadapathi Jeyanthi , Govindarajan Venkat Kumar , Sekaran Saravanan , Venkatapathy Santhi
Published: June 2021

The COVID-19 is affecting thousands of peoples day by day and continues to spread across the world. The present review has focused on promising repurposing drugs, including remdesivir, lopinvar/retinovar, favipiravir, hydroxychloroquine, monoclonal antibodies and vaccines against the SARS-CoV-2 infection. Besides, our review has also focused on many organizations that are in the race to develop vaccines using various approaches including DNA, RNA, viral vectors and subunit proteins against this highly contagious respiratory disease. The spike protein is being studied by scientists all over the world to develop potential vaccines. The antiviral drugs, antibodies and vaccines developed by various researchers around the world have entered clinical trials in humans. The current clinical trials for antiviral agents and vaccines with promising outcomes are being discussed. So far, four vaccines developed by the Pfizer-BioNTech vaccine, the Johnson and Johnson vaccine and two AstraZeneca vaccines (produced by SKBio in the Republic of Korea and Serum Institute of India) are approved by the World Health Organization for public use.
The Roles of the Cortical Motor Areas in Sequential Movements
Authors: Ohbayashi Machiko
Published: June 2021

The ability to learn and perform a sequence of movements is a key component of voluntary motor behavior. During the learning of sequential movements, individuals go through distinct stages of performance improvement. For instance, sequential movements are initially learned relatively fast and later learned more slowly. Over multiple sessions of repetitive practice, performance of the sequential movements can be further improved to the expert level and maintained as a motor skill. How the brain binds elementary movements together into a meaningful action has been a topic of much interest. Studies in human and non-human primates have shown that a brain-wide distributed network is active during the learning and performance of skilled sequential movements. The current challenge is to identify a unique contribution of each area to the complex process of learning and maintenance of skilled sequential movements. Here, I bring together the recent progress in the field to discuss the distinct roles of cortical motor areas in this process.
Learning Set Formation and Reversal Learning in Mice During High-Throughput Home-Cage-Based Olfactory Discrimination
Authors: Caglayan Alican , Stumpenhorst Katharina , Winter York
Published: June 2021

Rodent behavioral tasks are crucial to understanding the nature and underlying biology of cognition and cognitive deficits observed in psychiatric and neurological pathologies. Olfaction, as the primary sensory modality in rodents, is widely used to investigate cognition in rodents. In recent years, automation of olfactory tasks has made it possible to conduct olfactory experiments in a time- and labor-efficient manner while also minimizing experimenter-induced variability. In this study, we bring automation to the next level in two ways: First, by incorporating a radio frequency identification-based sorter that automatically isolates individuals for the experimental session. Thus, we can not only test animals during defined experimental sessions throughout the day but also prevent cagemate interference during task performance. Second, by implementing software that advances individuals to the next test stage as soon as performance criteria are reached. Thus, we can prevent overtraining, a known confounder especially in cognitive flexibility tasks. With this system in hand, we trained mice on a series of four odor pair discrimination tasks as well as their respective reversals. Due to performance-based advancement, mice normally advanced to the next stage in less than a day. Over the series of subsequent odor pair discriminations, the number of errors to criterion decreased significantly, thus indicating the formation of a learning set. As expected, errors to criterion were higher during reversals. Our results confirm that the system allows investigating higher-order cognitive functions such as learning set formation (which is understudied in mice) and reversal learning (which is a measure of cognitive flexibility and impaired in many clinical populations). Therefore, our system will facilitate investigations into the nature of cognition and cognitive deficits in pathological conditions by providing a high-throughput and labor-efficient experimental approach without the risks of overtraining or cagemate interference.
Theta-Range Oscillations in Stress-Induced Mental Disorders as an Oscillotherapeutic Target
Authors: Okonogi Toya , Sasaki Takuya
Published: June 2021

Emotional behavior and psychological disorders are expressed through coordinated interactions across multiple brain regions. Brain electrophysiological signals are composed of diverse neuronal oscillations, representing cell-level to region-level neuronal activity patterns, and serve as a biomarker of mental disorders. Here, we review recent observations from rodents demonstrating how neuronal oscillations in the hippocampus, amygdala, and prefrontal cortex are engaged in emotional behavior and altered by psychiatric changes such as anxiety and depression. In particular, we focus mainly on theta-range (4–12 Hz) oscillations, including several distinct oscillations in this frequency range. We then discuss therapeutic possibilities related to controlling such mental disease-related neuronal oscillations to ameliorate psychiatric symptoms and disorders in rodents and humans.
Oxytocin Regulates Synaptic Transmission in the Sensory Cortices in a Developmentally Dynamic Manner
Authors: Zhang Jing , Li Shu-Jing , Miao Wanying , Zhang Xiaodi , Zheng Jing-Jing , Wang Chen , Yu Xiang
Published: June 2021

The development and stabilization of neuronal circuits are critical to proper brain function. Synapses are the building blocks of neural circuits. Here we examine the effects of the neuropeptide oxytocin on synaptic transmission in L2/3 pyramidal neurons of the barrel field of the primary somatosensory cortex (S1BF). We find that perfusion of oxytocin onto acute brain slices significantly increases the frequency of miniature excitatory postsynaptic currents (mEPSC) of S1BF L2/3 pyramidal neurons at P10 and P14, but reduces it at the later ages of P22 and P28; the transition occurs at around P18. Since oxytocin expression is itself regulated by sensory experience, we also examine whether the effects of oxytocin on excitatory synaptic transmission correlate with that of sensory experience. We find that, indeed, the effects of sensory experience and oxytocin on excitatory synaptic transmission of L2/3 pyramidal neurons both peak at around P14 and plateau around P18, suggesting that they regulate a specific form of synaptic plasticity in L2/3 pyramidal neurons, with a sensitive/critical period ending around P18. Consistently, oxytocin receptor (Oxtr) expression in glutamatergic neurons of the upper layers of the cerebral cortex peaks around P14. By P28, however, Oxtr expression becomes more prominent in GABAergic neurons, especially somatostatin (SST) neurons. At P28, oxytocin perfusion increases inhibitory synaptic transmission and reduces excitatory synaptic transmission, effects that result in a net reduction of neuronal excitation, in contrast to increased excitation at P14. Using oxytocin knockout mice and Oxtr conditional knockout mice, we show that loss-of-function of oxytocin affects baseline excitatory synaptic transmission, while Oxtr is required for oxytocin-induced changes in excitatory synaptic transmission, at both P14 and P28. Together, these results demonstrate that oxytocin has complex and dynamic functions in regulating synaptic transmission in cortical L2/3 pyramidal neurons. These findings add to existing knowledge of the function of oxytocin in regulating neural circuit development and plasticity.
Circulating Growth Differentiation Factor 15 Levels Are Associated With Risk of Both Intracerebral and Subarachnoid Hemorrhage
Authors: Song Lu , Söderholm Martin , Svensson Edith H. , Borné Yan , Engström Gunnar
Published: June 2021

Background: Growth differentiation factor 15 (GDF-15) has been associated with the risk of developing major bleedings, including but not restricted to intracranial hemorrhages, in patients on oral anticoagulants or dual antiplatelet therapy. We hypothesized that there may be an association of GDF-15 with incidence of hemorrhagic strokes in the general population, which has not been investigated before.

Methods: Two different case-control studies, one for intracerebral hemorrhage (ICH) and one for subarachnoid hemorrhage (SAH), nested within the population-based Malmö Diet and Cancer cohort, were defined using the incidence density sampling method. GDF-15 was analyzed in frozen blood samples taken at the baseline examination in 1991–1996. The associations between GDF-15 and incident ICH (220 cases, 244 controls) and incident SAH (79 cases, 261 controls), respectively, were explored using conditional logistic regression adjusting for risk factors.

Results: GDF-15 levels at baseline were higher in both incident ICH and SAH cases, compared with their respective control subjects. After adjustment for risk factors, significant relationships with high GDF-15 concentrations were observed both for incident ICH (odds ratio (OR) per 1 log2 unit: 2.27, 95% confidence interval (CI): 1.52–3.41; P = 7.1 × 10−5) and incident SAH (OR: 2.16, 95% CI: 1.29–3.59; P = 0.0032).

Conclusions: High circulating GDF-15 levels were associated with incident ICH and incident SAH, independently of the main risk factors.
Stimulation-Induced Side Effects of Deep Brain Stimulation in the Ventralis Intermedius and Posterior Subthalamic Area for Essential Tremor
Authors: Kim Myung Ji , Chang Kyung Won , Park So Hee , Chang Won Seok , Jung Hyun Ho , Chang Jin Woo
Published: June 2021

Deep brain stimulation (DBS) targeting the ventralis intermedius (VIM) nucleus of the thalamus and the posterior subthalamic area (PSA) has been shown to be an effective treatment for essential tremor (ET). The aim of this study was to compare the stimulation-induced side effects of DBS targeting the VIM and PSA using a single electrode. Patients with medication-refractory ET who underwent DBS electrode implantation between July 2011 and October 2020 using a surgical technique that simultaneously targets the VIM and PSA with a single electrode were enrolled in this study. A total of 93 patients with ET who had 115 implanted DBS electrodes (71 unilateral and 22 bilateral) were enrolled. The Clinical Rating Scale for Tremor (CRST) subscores improved from 20.0 preoperatively to 4.3 (78.5% reduction) at 6 months, 6.3 (68.5% reduction) at 1 year, and 6.5 (67.5% reduction) at 2 years postoperation. The best clinical effect was achieved in the PSA at significantly lower stimulation amplitudes. Gait disturbance and clumsiness in the leg was found in 13 patients (14.0%) upon stimulation of the PSA and in significantly few patients upon stimulation of the VIM (p = 0.0002). Fourteen patients (15.1%) experienced dysarthria when the VIM was stimulated; this number was significantly more than that with PSA stimulation (p = 0.0233). Transient paresthesia occurred in 13 patients (14.0%) after PSA stimulation and in six patients (6.5%) after VIM stimulation. Gait disturbance and dysarthria were significantly more prevalent in patients undergoing bilateral DBS than in those undergoing unilateral DBS (p = 0.00112 and p = 0.0011, respectively). Paresthesia resolved either after reducing the amplitude or switching to bipolar stimulation. However, to control gait disturbance and dysarthria, some loss of optimal tremor control was necessary at that particular electrode contact. In the present study, the most common stimulation-induced side effect associated with VIM DBS was dysarthria, while that associated with PSA DBS was gait disturbance. Significantly, more side effects were associated with bilateral DBS than with unilateral DBS. Therefore, changing active DBS contacts to simultaneous targeting of the VIM and PSA may be especially helpful for ameliorating stimulation-induced side effects.
Metabolic Aspects of Migraine: Association With Obesity and Diabetes Mellitus
Authors: Rivera-Mancilla Eduardo , Al-Hassany Linda , Villalón Carlos M. , MaassenVanDenBrink Antoinette
Published: June 2021

Migraine is a disabling neurovascular disorder, characterized by moderate to severe unilateral headaches, nausea, photophobia, and/or phonophobia, with a higher prevalence in women than in men, which can drastically affect the quality of life of migraine patients. In addition, this chronic disorder is related with metabolic comorbidities associated with the patient's lifestyle, including obesity and diabetes mellitus (DM). Beyond the personal and socioeconomic impact caused by migraine, obesity and DM, it has been suggested that these metabolic disorders seem to be related to migraine since: (i) they are a risk factor for developing cardiovascular disorders or chronic diseases; (ii) they can be influenced by genetic and environmental risk factors; and (iii) while clinical and epidemiological studies suggest that obesity is a risk factor for migraine, DM (i.e., type 1 and type 2 DM) have been reported to be either a protective or a risk factor in migraine. On this basis, and given the high worldwide prevalence of migraine, obesity, and DM, this article provides a narrative review of the current literature related to the association between the etiology and pathophysiology of migraine and these metabolic disorders, considering lifestyle aspects, as well as the possible involvement of neurotransmitters, neuropeptides, and/or sex hormones. While a link between migraine and metabolic disorders has been suggested, many studies are contradictory and the mechanisms involved in this association are not yet sufficiently established. Therefore, further research should be focused on understanding the possible mechanisms involved.
ConvDip: A Convolutional Neural Network for Better EEG Source Imaging
Authors: Hecker Lukas , Rupprecht Rebekka , Tebartz Van Elst Ludger , Kornmeier Jürgen
Published: June 2021

The electroencephalography (EEG) is a well-established non-invasive method in neuroscientific research and clinical diagnostics. It provides a high temporal but low spatial resolution of brain activity. To gain insight about the spatial dynamics of the EEG, one has to solve the inverse problem, i.e., finding the neural sources that give rise to the recorded EEG activity. The inverse problem is ill-posed, which means that more than one configuration of neural sources can evoke one and the same distribution of EEG activity on the scalp. Artificial neural networks have been previously used successfully to find either one or two dipole sources. These approaches, however, have never solved the inverse problem in a distributed dipole model with more than two dipole sources. We present ConvDip, a novel convolutional neural network (CNN) architecture, that solves the EEG inverse problem in a distributed dipole model based on simulated EEG data. We show that (1) ConvDip learned to produce inverse solutions from a single time point of EEG data and (2) outperforms state-of-the-art methods on all focused performance measures. (3) It is more flexible when dealing with varying number of sources, produces less ghost sources and misses less real sources than the comparison methods. It produces plausible inverse solutions for real EEG recordings from human participants. (4) The trained network needs <40 ms for a single prediction. Our results qualify ConvDip as an efficient and easy-to-apply novel method for source localization in EEG data, with high relevance for clinical applications, e.g., in epileptology and real-time applications.
Disrupted Asymmetry of Inter- and Intra-Hemispheric Functional Connectivity at Rest in Medication-Free Obsessive-Compulsive Disorder
Authors: Jia Cuicui , Ou Yangpan , Chen Yunhui , Ma Jidong , Zhan Chuang , Lv Dan , Yang Ru , Shang Tinghuizi , Sun Lei , Wang Yuhua , Zhang Guangfeng , Sun Zhenghai , Wang Wei , Wang Xiaoping , Guo Wenbin , Li Ping
Published: June 2021

Disrupted functional asymmetry of cerebral hemispheres may be altered in patients with obsessive-compulsive disorder (OCD). However, little is known about whether anomalous brain asymmetries originate from inter- and/or intra-hemispheric functional connectivity (FC) at rest in OCD. In this study, resting-state functional magnetic resonance imaging was applied to 40 medication-free patients with OCD and 38 gender-, age-, and education-matched healthy controls (HCs). Data were analyzed using the parameter of asymmetry (PAS) and support vector machine methods. Patients with OCD showed significantly increased PAS in the left posterior cingulate cortex, left precentral gyrus/postcentral gyrus, and right inferior occipital gyrus and decreased PAS in the left dorsolateral prefrontal cortex (DLPFC), bilateral middle cingulate cortex (MCC), left inferior parietal lobule, and left cerebellum Crus I. A negative correlation was found between decreased PAS in the left DLPFC and Yale–Brown Obsessive-compulsive Scale compulsive behavior scores in the patients. Furthermore, decreased PAS in the bilateral MCC could be used to distinguish OCD from HCs with a sensitivity of 87.50%, an accuracy of 88.46%, and a specificity of 89.47%. These results highlighted the contribution of disrupted asymmetry of intra-hemispheric FC within and outside the cortico-striato-thalamocortical circuits at rest in the pathophysiology of OCD, and reduced intra-hemispheric FC in the bilateral MCC may serve as a potential biomarker to classify individuals with OCD from HCs.
Special Patterns of Dynamic Brain Networks Discriminate Between Face and Non-face Processing: A Single-Trial EEG Study
Authors: Yin Zhongliang , Wang Yue , Dong Minghao , Ren Shenghan , Hu Haihong , Yin Kuiying , Liang Jimin
Published: June 2021

Face processing is a spatiotemporal dynamic process involving widely distributed and closely connected brain regions. Although previous studies have examined the topological differences in brain networks between face and non-face processing, the time-varying patterns at different processing stages have not been fully characterized. In this study, dynamic brain networks were used to explore the mechanism of face processing in human brain. We constructed a set of brain networks based on consecutive short EEG segments recorded during face and non-face (ketch) processing respectively, and analyzed the topological characteristic of these brain networks by graph theory. We found that the topological differences of the backbone of original brain networks (the minimum spanning tree, MST) between face and ketch processing changed dynamically. Specifically, during face processing, the MST was more line-like over alpha band in 0–100 ms time window after stimuli onset, and more star-like over theta and alpha bands in 100–200 and 200–300 ms time windows. The results indicated that the brain network was more efficient for information transfer and exchange during face processing compared with non-face processing. In the MST, the nodes with significant differences of betweenness centrality and degree were mainly located in the left frontal area and ventral visual pathway, which were involved in the face-related regions. In addition, the special MST patterns can discriminate between face and ketch processing by an accuracy of 93.39%. Our results suggested that special MST structures of dynamic brain networks reflected the potential mechanism of face processing in human brain.
Right Inferior Parietal Lobule Activity Is Associated With Handwriting Spontaneous Tempo
Authors: Bonzano Laura , Bisio Ambra , Pedullà Ludovico , Brichetto Giampaolo , Bove Marco
Published: June 2021

Handwriting is a complex activity including motor planning and visuomotor integration and referring to some brain areas identified as “writing centers.” Although temporal features of handwriting are as important as spatial ones, to our knowledge, there is no evidence of the description of specific brain areas associated with handwriting tempo. People with multiple sclerosis (PwMS) show handwriting impairments that are mainly referred to as the temporal features of the task. The aim of this work was to assess differences in the brain activation pattern elicited by handwriting between PwMS and healthy controls (HC), with the final goal of identifying possible areas specific for handwriting tempo. Subjects were asked to write a sentence at their spontaneous speed. PwMS differed only in temporal handwriting features from HC and showed reduced activation with a subset of the clusters observed in HC. Spearman’s correlation analysis was performed between handwriting temporal parameters and the activity in the brain areas resulting from the contrast analysis, HC > PwMS. We found that the right inferior parietal lobule (IPL) negatively correlated with the duration of the sentence, indicating that the higher the right IPL activity, the faster the handwriting performance. We propose that the right IPL might be considered a “writing tempo center.”
Magnetic Resonance-Guided Stereotactic Body Radiotherapy of Liver Tumors: Initial Clinical Experience and Patient-Reported Outcomes
Authors: Weykamp Fabian , Hoegen Philipp , Klüter Sebastian , Spindeldreier C. Katharina , König Laila , Seidensaal Katharina , Regnery Sebastian , Liermann Jakob , Rippke Carolin , Koerber Stefan A. , Buchele Carolin , Debus Jürgen , Hörner-Rieber Juliane
Published: June 2021

Purpose/Objective

Stereotactic body radiation therapy (SBRT) has emerged as a valid treatment alternative for non-resectable liver metastases or hepatocellular carcinomas (HCC). Magnetic resonance (MR) guided SBRT has a high potential of further improving treatment quality, allowing for higher, tumoricidal irradiation doses whilst simultaneously sparing organs at risk. However, data on treatment outcome and patient acceptance is still limited.

Material/Methods

We performed a subgroup analysis of an ongoing prospective observational study comprising patients with liver metastases or HCC. Patients were treated with ablative MR-guided SBRT at the MRIdian Linac in the Department of Radiation Oncology at Heidelberg University Hospital between January 2019 and February 2020. Local control (LC) and overall survival (OS) analysis was performed using the Kaplan–Meier method. An in-house designed patient-reported outcome questionnaire was used to measure patients’ experience with the MR-Linac treatment. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE v. 5.0).

Results

Twenty patients (with n = 18 metastases; n = 2 HCC) received MR-guided SBRT for in total 26 malignant liver lesions. Median biologically effective dose (BED at α/β = 10) was 105.0 Gy (range: 67.2–112.5 Gy) and median planning target volume was 57.20 ml (range: 17.4–445.0 ml). Median treatment time was 39.0 min (range: 26.0–67.0 min). At 1-year, LC was 88.1% and OS was 84.0%. Grade I° gastrointestinal toxicity °occurred in 30.0% and grade II° in 5.0% of the patients with no grade III° or higher toxicity. Overall treatment experience was rated positively, with items scoring MR-Linac staff’s performance and items concerning the breath hold process being among the top positively rated elements. Worst scored items were treatment duration, positioning and low temperature.

Conclusion

MR-guided SBRT of liver tumors is a well-tolerated and well-accepted treatment modality. Initial results are promising with excellent local control and only mildest toxicity. However, prospective studies are warranted to truly assess the potential of MR-guided liver SBRT and to identify which patients profit most from this new versatile technology.
The lncRNA ADAMTS9-AS2 Regulates RPL22 to Modulate TNBC Progression via Controlling the TGF-β Signaling Pathway
Authors: Ni Kan , Huang Zhiqi , Zhu Yichun , Xue Dandan , Jin Qin , Zhang Chunhui , Gu Changjiang
Published: June 2021

Background

Long non-coding RNAs (lncRNAs) are key regulators of triple-negative breast cancer (TNBC) progression, but further work is needed to fully understand the functional relevance of these non-coding RNAs in this cancer type. Herein, we explored the functional role of the lncRNA ADAMTS9-AS2 in TNBC.

Methods

Next-generation sequencing was conducted to compare the expression of different lncRNAs in TNBC tumor and paracancerous tissues, after which ADAMTS9-AS2differential expression in these tumor tissues was evaluated via qPCR. The functional role of this lncRNA was assessed by overexpressing it in vitro and in vivo. FISH and PCR were used to assess the localization of ADAMTS9-AS2within cells. Downstream targets of ADAMTS9-AS2 signaling were identified via RNA pulldown assays and transcriptomic sequencing.

Results

The expression ofADAMTS9-AS2 was decreased in TNBC tumor samples (P < 0.05), with such downregulation being correlated with TNM stage, age, and tumor size. Overexpressing ADAMTS9-AS2 promoted the apoptotic death and cell cycle arrest of tumor cells in vitro and inhibited tumor growth in vivo. From a mechanistic perspective, ADAMTS9-AS2 was found to control the expression of RPL22 and to thereby modulate TGF-β signaling to control TNBC progression.

Conclusion

ADAMTS9-AS2 controls the expression of RPL22 and thereby regulates TNBC malignancy via the TGF-β signaling pathway.
m5C RNA Methylation Regulators Predict Prognosis and Regulate the Immune Microenvironment in Lung Squamous Cell Carcinoma
Authors: Pan Junfan , Huang Zhidong , Xu Yiquan
Published: June 2021

RNA methylation is a novel epigenetic modification that can be used to evaluate tumor prognosis. However, the underlying mechanisms are unclear. This study aimed to investigate the genetic characteristics of 5-methylcytosine (m5C) and N1-methyladenosine (m1A) regulators in lung squamous cell carcinoma (LUSC) and the prognostic value and immune-related effects of m5C regulators. To this end, we selected the public LUSC dataset from the Cancer Genome Atlas and Gene Expression Omnibus. The least absolute shrinkage and selection operator regression model was used to identify prognostic risk signatures. We used the UALCAN and Human Protein Atlas databases to study the expression of target gene mRNA/protein expression. Furthermore, the Tumor Immune Single Cell Hub and the Tumor Immune Estimation Resource were used to evaluate the degree of immune cell infiltration. Most of the m5C and m1A regulators showed significantly different expression between LUSC and normal samples. The m5C regulators were associated with poor prognosis. In addition, a prognostic risk signature was developed based on two m5C regulators, NOP2/Sun RNA methyltransferase 3 (NSUN3), and NOP2/Sun RNA methyltransferase 4 (NSUN4). Compared with normal lung tissues, the expression of NSUN3 and NSUN4 in the LUSC TCGA dataset was increased, which was related to clinicopathological characteristics and survival. NSUN3 and NSUN4 were related to the infiltration of six major immune cells; especially NSUN3, which was closely related to CD8+ T cells, while NSUN4 was closely related to neutrophils. Our findings suggest that m5C regulators can predict the clinical prognosis risk and regulate the tumor immune microenvironment in LUSC.
Perspectives on Immunotherapy of Metastatic Colorectal Cancer
Authors: Dai Yongjiu , Zhao Wenhu , Yue Lei , Dai Xinzheng , Rong Dawei , Wu Fan , Gu Jian , Qian Xiaofeng
Published: June 2021

Colorectal cancer, especially liver metastasis, is still a challenge worldwide. Traditional treatment such as surgery, chemotherapy and radiotherapy have been difficult to be further advanced. We need to develop new treatment methods to further improve the poor prognosis of these patients. The emergence of immunotherapy has brought light to mCRC patients, especially those with dMMR. Based on several large trials, some drugs (pembrolizumab, nivolumab) have been approved by US Food and Drug Administration to treat the patients diagnosed with dMMR tumors. However, immunotherapy has reached a bottleneck for other MSS tumors, with low response rate and poor PFS and OS. Therefore, more clinical trials are underway toward mCRC patients, especially those with MSS. This review is intended to summarize the existing clinical trials to illustrate the development of immunotherapy in mCRC patients, and to provide a new thinking for the direction and experimental design of immunotherapy in the future.
HLA-E Binding Peptide as a Potential Therapeutic Candidate for High-Risk Multiple Myeloma
Authors: Yang Ying , Liu Zhuogang , Wang Hongtao , Zhang Guojun
Published: June 2021

Human leukocyte antigen-E (HLA-E) has been putatively associated with the pathogenesis of multiple myeloma (MM). Our study first showed that HLA-E was differentially expressed on MM and normal plasma cells (39.27 ± 27.01 and 11.28 ± 0.79, respectively). Based on the median value of HLA-E expression, we further stratified MM patients into high and low-expression groups, and then found high expression of HLA-E was correlated with advanced ISS stage (p = 0.025) and high-risk cytogenetics risk stratification (p = 0.000) by the Pearson Chi-square test, suggesting that HLA-E could be considered as a biomarker for high-risk MM. Furthermore, peptide 3 (P3) from our previous study was confirmed to possess a high affinity to HLA-E positive MM cells. Taken together, HLA-E could be considered as a new marker and candidate treatment target for MM, while peptide P3 may act as a potential treatment choice for targeting MM cells.
Levobupivacaine Induces Ferroptosis by miR-489-3p/SLC7A11 Signaling in Gastric Cancer
Authors: Mao Shun-Hong , Zhu Chun-Hua , Nie Yu , Yu Jian , Wang Lei
Published: June 2021

Gastric cancer is one of the most the prevalent malignancies and the therapeutic strategies for patients with gastric cancer remains limited. Local anesthetic levobupivacaine has demonstrated potential anti-cancer property, but its correlation with gastric cancer and ferroptosis is poor understood. Here, we identified the novel function of levobupivacaine in regulating ferroptosis of gastric cancer cells. The treatment of levobupivacaine suppressed gastric cancer cell viabilities and Edu-positive cell proportions. The gastric cancer cell growth was reduced by levobupivacaine in vivo. Moreover, the treatment of levobupivacaine enhanced erastin-induced inhibitory impact on gastric cancer cell viabilities. The levels of Fe2+/iron and lipid ROS were induced by levobupivacaine in erastin and RSL3-stimulated gastric cancer cells. levobupivacaine-upregulated miR-489-3p enhanced ferroptosis of gastric cancer cells by targeting SLC7A11. MiR-489-3p was involved in levobupivacaine-induced ferroptosis of gastric cancer cells. Levobupivacaine/miR-489-3p/SLC7A11 axis attenuates gastric cancer cell proliferation in vitro. Therefore, we concluded that the local anesthetic levobupivacaine induced ferroptosis of gastric cancer cells to repress gastric cancer cell growth by miR-489-3p/SLC7A11 axis.
Mean First-Passage Time on Scale-Free Networks Based on Rectangle Operation
Authors: Wang Xiaomin , Su Jing , Ma Fei , Yao Bing
Published: June 2021

The mean first-passage time of random walks on a network has been extensively applied in the theory and practice of statistical physics, and its application effects depend on the behavior of first-passage time. Here, we firstly define a graphic operation, namely, rectangle operation, for generating a scale-free network. In this paper, we study the topological structures of our network obtained from the rectangle operation, including degree distribution, clustering coefficient, and diameter. And then, we also consider the characteristic quantities related to the network, including Kirchhoff index and mean first-passage time, where these characteristic quantities can not only be used to evaluate the properties of our network, but also have remarkable applications in science and engineering.
Magnetic Domain Structure in Ferromagnetic Kagome Metal DyMn6Sn6
Authors: Chen Zhaohui , Li Miao , Liu Caixing , Ma Zongwei , Han Yuyan , Gao Jianhua , Wei Wensen , Sheng Zhigao , Du Haifeng
Published: June 2021

Two types of magnetic domains, that is, type-I domain belt domain and type-II new stripe domain, are observed in a kagome metal DyMn6Sn6 by microscopic magneto-optic Kerr imaging technique. From 255 to 235 K, the spin reorientation is observed directly in DyMn6Sn6. We analyze the structure of two types of domains through brightness distribution of the images. The type-II domain exists from 235 to 160 K by zero-field cooling (ZFC). At the same time, type-I domain and type-II domain coexist and transform into each other with variation of temperature. Type-II domains can easily transform into type-I domains when the temperature and magnetic field changes, and this process is irreversible. These results demonstrate that the type-I domain is more stable than the type-II domain. The phase diagram of magnetic domains in DyMn6Sn6 is obtained.
Plant Proton Pumps and Cytosolic pH-Homeostasis
Authors: Cosse Maike , Seidel Thorsten
Published: June 2021

Proton pumps create a proton motif force and thus, energize secondary active transport at the plasma nmembrane and endomembranes of the secretory pathway. In the plant cell, the dominant proton pumps are the plasma membrane ATPase, the vacuolar pyrophosphatase (V-PPase), and the vacuolar-type ATPase (V-ATPase). All these pumps act on the cytosolic pH by pumping protons into the lumen of compartments or into the apoplast. To maintain the typical pH and thus, the functionality of the cytosol, the activity of the pumps needs to be coordinated and adjusted to the actual needs. The cellular toolbox for a coordinated regulation comprises 14-3-3 proteins, phosphorylation events, ion concentrations, and redox-conditions. This review combines the knowledge on regulation of the different proton pumps and highlights possible coordination mechanisms.
Estimating the Prevalence and Genetic Risk Mechanisms of ARFID in a Large Autism Cohort
Authors: Koomar Tanner , Thomas Taylor R. , Pottschmidt Natalie R. , Lutter Michael , Michaelson Jacob J.
Published: June 2021

This study is the first genetically-informed investigation of avoidant/restrictive food intake disorder (ARFID), an eating disorder that profoundly impacts quality of life for those affected. ARFID is highly comorbid with autism, and we provide the first estimate of its prevalence in a large and phenotypically diverse autism cohort (a subsample of the SPARK study,N= 5,157 probands). This estimate, 21% (at a balanced accuracy 80%), is at the upper end of previous estimates from studies based on clinical samples, suggesting under-diagnosis and potentially lack of awareness among caretakers and clinicians. Although some studies suggest a decrease of disordered eating symptoms by age 6, our estimates indicate that up to 17% (at a balanced accuracy 87%) of parents of autistic children are also at heightened risk for ARFID, suggesting a lifelong risk for disordered eating. We were also able to provide the first estimates of narrow-sense heritability (h2) for ARFID risk, at 0.45. Genome-wide association revealed a single hit nearZSWIM6, a gene previously implicated in neurodevelopmental conditions. While, the current sample was not well-powered for GWAS, effect size and heritability estimates allowed us to project the sample sizes necessary to more robustly discover ARFID-linked loci via common variants. Further genetic analysis using polygenic risk scores (PRS) affirmed genetic links to autism as well as neuroticism and metabolic syndrome.
Psychiatric Comorbidities in Children With ASD: Autism Centre Experience
Authors: Ivanović Iva
Published: June 2021

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with social communication deficits, restricted interests, and repetitive behaviours. In this lifelong condition the core features that cause impairment may also be expanded by behavioural and emotional problems. Individuals with ASD are likely to experience a higher prevalence of common mental disorders compared to the typically developed individuals. This high epidemiological burden of various psychiatric disorders among ASD population encourages further research and improvement in diagnostic practise in ASD and comorbid disorders. In this brief research report of a cross-sectional study, I aimed to estimate the psychiatric comorbidity prevalence and describe their general characteristics in children with ASD in the Autism Centre in Montenegro. The study population consisted of 152 patients who were diagnosed with ASD, 117 male and 35 female, and the mean age (SD) was 8.02 (4.26). In this brief research report prevalence of children with ASD with at least one psychiatric comorbidity was 36.84%. Only one psychiatric comorbidity disorder was reported in 17.16%, two in 9.87%, three in 8.55%, and in 0.66% patients four other psychiatric disorders. Psychiatric disorders present in this population sample were attention deficit hyperactivity disorder (17.76%), conduct disorder (13.10%), disruptive mood dysregulation disorder (9.87%), anxiety disorder and insomnia (7.89%), elimination disorder (3.29%), and depression (1.97%).
The Strasbourg Visual Scale: A Novel Method to Assess Visual Hallucinations
Authors: Giersch Anne , Huard Thomas , Park Sohee , Rosen Cherise
Published: June 2021

The experience of oneself in the world is based on sensory afferences, enabling us to reach a first-perspective perception of our environment and to differentiate oneself from the world. Visual hallucinations may arise from a difficulty in differentiating one's own mental imagery from externally-induced perceptions. To specify the relationship between hallucinations and the disorders of the self, we need to understand the mechanisms of hallucinations. However, visual hallucinations are often under reported in individuals with psychosis, who sometimes appear to experience difficulties describing them. We developed the “Strasbourg Visual Scale (SVS),” a novel computerized tool that allows us to explore and capture the subjective experience of visual hallucinations by circumventing the difficulties associated with verbal descriptions. This scale reconstructs the hallucinated image of the participants by presenting distinct physical properties of visual information, step-by-step to help them communicate their internal experience. The strategy that underlies the SVS is to present a sequence of images to the participants whose choice at each step provides a feedback toward re-creating the internal image held by them. The SVS displays simple images on a computer screen that provide choices for the participants. Each step focuses on one physical property of an image, and the successive choices made by the participants help them to progressively build an image close to his/her hallucination, similar to the tools commonly used to generate facial composites. The SVS was constructed based on our knowledge of the visual pathways leading to an integrated perception of our environment. We discuss the rationale for the successive steps of the scale, and to which extent it could complement existing scales.
Does High-Speed Rail Opening Affect the Health Care Environment?–Evidence From China
Authors: Song Cai-Xia , Qiao Cui-Xia , Luo Jing
Published: June 2021

Using the panel data of 280 prefecture-level cities in China from 2004 to 2014, this paper examines the effects of high-speed rail opening on health care environment based on Difference-in-Differences method (DID). Through an empirical analysis, the results proved that high-speed rail opening can significantly promote the health care environment and this effect is different in regions with different levels of economic development. Finally, we tested the mechanisms of how the high-speed rail opening affects the healthcare environment. High-speed rail opening improves the healthcare environment by increasing road accessibility and promoting economic development. Our results support the view that high-speed rail opening has an important contribution to the improvement of health care conditions.
NeuroSim Simulator for Compute-in-Memory Hardware Accelerator: Validation and Benchmark
Authors: Lu Anni , Peng Xiaochen , Li Wantong , Jiang Hongwu , Yu Shimeng
Published: June 2021

Compute-in-memory (CIM) is an attractive solution to process the extensive workloads of multiply-and-accumulate (MAC) operations in deep neural network (DNN) hardware accelerators. A simulator with options of various mainstream and emerging memory technologies, architectures, and networks can be a great convenience for fast early-stage design space exploration of CIM hardware accelerators. DNN+NeuroSim is an integrated benchmark framework supporting flexible and hierarchical CIM array design options from a device level, to a circuit level and up to an algorithm level. In this study, we validate and calibrate the prediction of NeuroSim against a 40-nm RRAM-based CIM macro post-layout simulations. First, the parameters of a memory device and CMOS transistor are extracted from the foundry’s process design kit (PDK) and employed in the NeuroSim settings; the peripheral modules and operating dataflow are also configured to be the same as the actual chip implementation. Next, the area, critical path, and energy consumption values from the SPICE simulations at the module level are compared with those from NeuroSim. Some adjustment factors are introduced to account for transistor sizing and wiring area in the layout, gate switching activity, post-layout performance drop, etc. We show that the prediction from NeuroSim is precise with chip-level error under 1% after the calibration. Finally, the system-level performance benchmark is conducted with various device technologies and compared with the results before the validation. The general conclusions stay the same after the validation, but the performance degrades slightly due to the post-layout calibration.
Maize Tassel Detection From UAV Imagery Using Deep Learning
Authors: Alzadjali Aziza , Alali Mohammed H. , Veeranampalayam Sivakumar Arun Narenthiran , Deogun Jitender S. , Scott Stephen , Schnable James C. , Shi Yeyin
Published: June 2021

The timing of flowering plays a critical role in determining the productivity of agricultural crops. If the crops flower too early, the crop would mature before the end of the growing season, losing the opportunity to capture and use large amounts of light energy. If the crops flower too late, the crop may be killed by the change of seasons before it is ready to harvest. Maize flowering is one of the most important periods where even small amounts of stress can significantly alter yield. In this work, we developed and compared two methods for automatic tassel detection based on the imagery collected from an unmanned aerial vehicle, using deep learning models. The first approach was a customized framework for tassel detection based on convolutional neural network (TD-CNN). The other method was a state-of-the-art object detection technique of the faster region-based CNN (Faster R-CNN), serving as baseline detection accuracy. The evaluation criteria for tassel detection were customized to correctly reflect the needs of tassel detection in an agricultural setting. Although detecting thin tassels in the aerial imagery is challenging, our results showed promising accuracy: the TD-CNN had an F1 score of 95.9% and the Faster R-CNN had 97.9% F1 score. More CNN-based model structures can be investigated in the future for improved accuracy, speed, and generalizability on aerial-based tassel detection.
A Computational Framework Towards the Tele-Rehabilitation of Balance Control Skills
Authors: Akbas Kubra , Mummolo Carlotta
Published: June 2021

Mobility has been one of the most impacted aspects of human life due to the spread of the COVID-19 pandemic. Home confinement, the lack of access to physical rehabilitation, and prolonged immobilization of COVID-19-positive patients within hospitals are three major factors that affected the mobility of the general population world-wide. Balance is one key indicator to monitor the possible movement disorders that may arise both during the COVID-19 pandemic and in the coming future post-COVID-19. A systematic quantification of the balance performance in the general population is essential for preventing the appearance and progression of certain diseases (e.g., cardiovascular, neurodegenerative, and musculoskeletal), as well as for assessing the therapeutic outcomes of prescribed physical exercises for elderly and pathological patients. Current research on clinical exercises and associated outcome measures of balance is still far from reaching a consensus on a “golden standard” practice. Moreover, patients are often reluctant or unable to follow prescribed exercises, because of overcrowded facilities, lack of reliable and safe transportation, or stay-at-home orders due to the current pandemic. A novel balance assessment methodology, in combination with a home-care technology, can overcome these limitations. This paper presents a computational framework for the in-home quantitative assessment of balance control skills. Novel outcome measures of balance performance are implemented in the design of rehabilitation exercises with customized and quantifiable training goals. Using this framework in conjunction with a portable technology, physicians can treat and diagnose patients remotely, with reduced time and costs and a highly customized approach. The methodology proposed in this research can support the development of innovative technologies for smart and connected home-care solutions for physical therapy rehabilitation.
Results of Adrenalectomy for Isolated, Metachronous Metastasis of Breast Cancer: A Retrospective Cohort Study
Authors: Illuminati Giulio , Pasqua Rocco , D'Ermo Giuseppe , Girolami Marco , Cerbelli Bruna , D'Amati Giulia , Carboni Fabio , Fiori Enrico
Published: June 2021

Background and Aim: Metachronous, isolated adrenal metastases from breast cancer are extremely rare. The aim of this study was to evaluate the results of adrenalectomy as a treatment of this uncommon condition.

Methods: Twelve female patients (median age: 68 years) underwent 13 adrenalectomies for isolated, metachronous metastases of breast cancer. Ten resections were performed thorugh open surgery and two were preformed through a laparoscopic approach. As main study endpoints, postoperative mortality, postoperative morbidity and disease-free survival were considered. Median length of follow-up was 40 months.

Results: Postoperative mortality was absent. Postoperative morbidity was 17%: one patient presented a postoperative pneumothorax requiring drainage and one patient required re-hospitalization 8 days after contralateral adrenalectomy for electrolyte imbalance. Two patients died of recurrent metastatic disease, 28 and 33 months respectively after adrenalectomy. One patient remained alive with hepatic metastases at 32 months from resection of adrenal recurrence. All in all, disease-free survival at 48 months was 75%.

Conclusions: Adrenalectomy for metachronous, isolated metastases of breast cancer can be performed with no postoperative mortality and minimal postoperative morbidity, enabling good long-term disease-free survival.