bluuebunny/crossref_metadata_2025 huggingface dataset:
Cigarette Smoke Extract, but Not Electronic Cigarette Aerosol Extract, Inhibits Monoamine Oxidase in vitro and Produces Greater Acute Aversive/Anhedonic Effects Than Nicotine Alone on Intracranial Self-Stimulation in Rats
Authors: Harris Andrew C. , Muelken Peter , Alcheva Aleksandra , Stepanov Irina , LeSage Mark G.
Published: June 2022

Conventional tobacco cigarettes appear to have greater abuse liability than non-combusted products such as electronic cigarettes (ECs) and nicotine replacement therapy (NRT). This may be due to the higher levels of behaviorally active non-nicotine constituents [e.g., monoamine oxidase (MAO) inhibitors such as β-carbolines] in cigarette smoke (CS) compared to non-combusted products. To evaluate this hypothesis, the current studies compared the relative abuse liability of CS and EC aerosol extracts containing nicotine and a range of non-nicotine constituents to that of nicotine alone (NRT analog) using intracranial self-stimulation (ICSS) in rats. Effects of formulations on brain MAO activity in vitro and ex vivo were also studied to evaluate the potential role of MAO inhibition in the ICSS study. CS extract contained higher levels of several behaviorally active non-nicotine constituents (e.g., the β-carbolines norharmane and harmane) than EC extract. Nicotine alone reduced ICSS thresholds at a moderate nicotine dose, suggesting a reinforcement-enhancing effect that may promote abuse liability, and elevated ICSS thresholds at a high nicotine dose, suggesting an aversive/anhedonic effect that may limit abuse liability. CS extract elevated ICSS thresholds to a greater degree than nicotine alone at high nicotine doses. Effects of EC extract on ICSS did not differ from those of nicotine alone. Finally, CS extract significantly inhibited MAO-A and MAO-B activity in vitro, whereas EC extract and nicotine alone did not. None of the formulations inhibited MAO measured ex vivo. These findings indicate greater acute aversive/anhedonic effects for CS extract compared to nicotine alone, suggesting lower abuse liability. Although confirmation of our findings using other dosing regimens, preclinical addiction models, and tobacco product extracts is needed, these findings suggest that the centrally-mediated effects of MAO inhibitors and other non-nicotine constituents may not account for the greater abuse liability of cigarettes compared to non-combusted products. Nonetheless, identifying the specific constituent(s) mediating the effects of CS extracts in this study could help clarify mechanisms mediating tobacco addiction and inform FDA product standards.
Upper Limbs Muscle Co-contraction Changes Correlated With the Impairment of the Corticospinal Tract in Stroke Survivors: Preliminary Evidence From Electromyography and Motor-Evoked Potential
Authors: Sheng Wenfei , Li Shijue , Zhao Jiangli , Wang Yujia , Luo Zichong , Lo Wai Leung Ambrose , Ding Minghui , Wang Chuhuai , Li Le
Published: June 2022

Objective

Increased muscle co-contraction of the agonist and antagonist muscles during voluntary movement is commonly observed in the upper limbs of stroke survivors. Much remain to be understood about the underlying mechanism. The aim of the study is to investigate the correlation between increased muscle co-contraction and the function of the corticospinal tract (CST).

Methods

Nine stroke survivors and nine age-matched healthy individuals were recruited. All the participants were instructed to perform isometric maximal voluntary contraction (MVC) and horizontal task which consist of sponge grasp, horizontal transportation, and sponge release. We recorded electromyography (EMG) activities from four muscle groups during the MVC test and horizontal task in the upper limbs of stroke survivors. The muscle groups consist of extensor digitorum (ED), flexor digitorum (FD), triceps brachii (TRI), and biceps brachii (BIC). The root mean square (RMS) of EMG was applied to assess the muscle activation during horizontal task. We adopted a co-contraction index (CI) to evaluate the degree of muscle co-contraction. CST function was evaluated by the motor-evoked potential (MEP) parameters, including resting motor threshold, amplitude, latency, and central motor conduction time. We employed correlation analysis to probe the association between CI and MEP parameters.

Results

The RMS, CI, and MEP parameters on the affected side showed significant difference compared with the unaffected side of stroke survivors and the healthy group. The result of correlation analysis showed that CI was significantly correlated with MEP parameters in stroke survivors.

Conclusion

There existed increased muscle co-contraction and impairment in CST functionality on the affected side of stroke survivors. The increased muscle co-contraction was correlated with the impairment of the CST. Intervention that could improve the excitability of the CST may contribute to the recovery of muscle discoordination in the upper limbs of stroke survivors.
Mapping the Spatial Distribution of Fibrillar Polymorphs in Human Brain Tissue
Authors: Bashit Abdullah Al , Nepal Prakash , Connors Theresa , Oakley Derek H. , Hyman Bradley T. , Yang Lin , Makowski Lee
Published: June 2022

Alzheimer’s disease (AD) is a neurodegenerative disorder defined by the progressive formation and spread of fibrillar aggregates of Aβ peptide and tau protein. Polymorphic forms of these aggregates may contribute to disease in varying ways since different neuropathologies appear to be associated with different sets of fibrillar structures and follow distinct pathological trajectories that elicit characteristic clinical phenotypes. The molecular mechanisms underlying the spread of these aggregates in disease may include nucleation, replication, and migration all of which could vary with polymorphic form, stage of disease, and region of brain. Given the linkage between mechanisms of progression and distribution of polymorphs, mapping the distribution of fibrillar structuresin situhas the potential to discriminate between mechanisms of progression. However, the means of carrying out this mapping are limited. Optical microscopy lacks the resolution to discriminate between polymorphsin situ, and higher resolution tools such as ssNMR and cryoEM require the isolation of fibrils from tissue, destroying relevant spatial information. Here, we demonstrate the use of scanning x-ray microdiffraction (XMD) to map the locations of fibrillar polymorphs of Aβ peptides and tau protein in histological thin sections of human brain tissue. Coordinated examination of serial sections by immunohistochemistry was used to aid in the interpretation of scattering patterns and to put the observations in a broader anatomical context. Scattering from lesions in tissue shown to be rich in Aβ fibrils by immunohistochemistry exhibited scattering patterns with a prototypical 4.7 Å cross-β peak, and overall intensity distribution that compared well with that predicted from high resolution structures. Scattering from lesions in tissue with extensive tau pathology also exhibited a 4.7 Å cross-β peak but with intensity distributions that were distinct from those seen in Aβ-rich regions. In summary, these observations demonstrate that XMD is a rich source of information on the distribution of fibrillar polymorphs in diseased human brain tissue. When used in coordination with neuropathological examination it has the potential to provide novel insights into the molecular mechanisms underlying disease.
scSE-NL V-Net: A Brain Tumor Automatic Segmentation Method Based on Spatial and Channel “Squeeze-and-Excitation” Network With Non-local Block
Authors: Zhou Juhua , Ye Jianming , Liang Yu , Zhao Jialu , Wu Yan , Luo Siyuan , Lai Xiaobo , Wang Jianqing
Published: June 2022

Intracranial tumors are commonly known as brain tumors, which can be life-threatening in severe cases. Magnetic resonance imaging (MRI) is widely used in diagnosing brain tumors because of its harmless to the human body and high image resolution. Due to the heterogeneity of brain tumor height, MRI imaging is exceptionally irregular. How to accurately and quickly segment brain tumor MRI images is still one of the hottest topics in the medical image analysis community. However, according to the brain tumor segmentation algorithms, we could find now, most segmentation algorithms still stay in two-dimensional (2D) image segmentation, which could not obtain the spatial dependence between features effectively. In this study, we propose a brain tumor automatic segmentation method called scSE-NL V-Net. We try to use three-dimensional (3D) data as the model input and process the data by 3D convolution to get some relevance between dimensions. Meanwhile, we adopt non-local block as the self-attention block, which can reduce inherent image noise interference and make up for the lack of spatial dependence due to convolution. To improve the accuracy of convolutional neural network (CNN) image recognition, we add the “Spatial and Channel Squeeze-and-Excitation” Network (scSE-Net) to V-Net. The dataset used in this paper is from the brain tumor segmentation challenge 2020 database. In the test of the official BraTS2020 verification set, the Dice similarity coefficient is 0.65, 0.82, and 0.76 for the enhanced tumor (ET), whole tumor (WT), and tumor core (TC), respectively. Thereby, our model can make an auxiliary effect on the diagnosis of brain tumors established.
Anticipation of Scheduled Feeding in BTBR Mice Reveals Independence and Interactions Between the Light- and Food-Entrainable Circadian Clocks
Authors: Vijaya Shankara Jhenkruthi , Mistlberger Ralph E. , Antle Michael C.
Published: June 2022

Many animal species exhibit food-anticipatory activity (FAA) when fed at a fixed time of the day. FAA exhibits properties of a daily rhythm controlled by food-entrainable circadian oscillators (FEOs). Lesion studies indicate that FEOs are separate from the light-entrainable circadian pacemaker (LEP) located in the suprachiasmatic nucleus. While anatomically distinct, food- and light-entrainable clocks do appear to interact, and the output of these clocks may be modulated by their phase relation. We report here an analysis of FAA in the BTBR T+ Itpr3tf/J (BTBR) mouse strain that provides new insights into the nature of interactions between food- and light-entrained clocks and rhythms. BTBR mice fed ad libitum exhibit an unusually short active phase and free-running circadian periodicity (~22.5 h). In a light-dark cycle, BTBR mice limited to a 4 h daily meal in the light period show robust FAA compared to the C57BL/6J mice. In constant darkness, BTBR mice exhibit clear and distinct free-running and food-anticipatory rhythms that interact in a phase-dependent fashion. The free-running rhythm exhibits phase advances when FAA occurs in the mid-to-late rest phase of the free run, and phase delays when FAA occurs in the late active phase. A phase-response curve (PRC) inferred from these shifts is similar to the PRC for activity-induced phase shifts in nocturnal rodents, suggesting that the effects of feeding schedules on the LEP in constant darkness are mediated by FAA. A phase-dependent effect of the free-running rhythm on FAA was evident in both its magnitude and duration; FAA counts were greatest when FAA occurred during the active phase of the free-running rhythm. The LEP inhibited FAA when FAA occurred at the end of the subjective day. These findings provide evidence for interactions between food- and light-entrainable circadian clocks and rhythms and demonstrate the utility of the BTBR mouse model in probing these interactions.
Neurotrophic Factor-α1/Carboxypeptidase E Functions in Neuroprotection and Alleviates Depression
Authors: Xiao Lan , Loh Yoke Peng
Published: June 2022

Depression is a major psychiatric disease affecting all ages and is often co-morbid with neurodegeneration in the elderly. Depression and neurodegeneration are associated with decreased neurotrophic factors. In this mini-review the functions and potential therapeutic use of a newly discovered trophic factor, Neurotrophic factor-α1 (NF-α1), also known as Carboxypeptidase E (CPE), in depression and neuroprotection are discussed. NF-α1/CPE expression is enriched in CA3 neurons of the hippocampus. Families carrying null and homozygous non-sense mutations of the NF-α1/CPE gene share common clinical features including childhood onset obesity, type 2 diabetes, impaired intellectual abilities and hypogonadotrophic hypogonadism. Studies in animal models such as CPE knockout (KO) mice and CPEfat/fat mutant mice exhibit similar phenotypes. Analysis of CPE-KO mouse brain revealed that hippocampal CA3 was completely degenerated after weaning stress, along with deficits in hippocampal long-term potentiation. Carbamazepine effectively blocked weaning stress-induced hippocampal CA3 degeneration, suggesting the stress induced epileptic-like neuronal firing led to the degeneration. Analysis of possible mechanisms underlying NF-α1/CPE -mediated neuroprotection revealed that it interacts with the serotonin receptor, 5-HTR1E, and via β arrestin activation, subsequently upregulates ERK1/2 signaling and pro-survival protein, BCL2, levels. Furthermore, the NF-α1/CPE promoter contains a peroxisome proliferator-activated receptor (PPARγ) binding site which can be activated by rosiglitazone, a PPARγ agonist, to up-regulate expression of NF-α1/CPE and neurogenesis, resulting in anti-depression in animal models. Rosiglitazone, an anti-diabetic drug administered to diabetic patients resulted in decline of depression. Thus, NF-α1/CPE is a potential therapeutic agent or drug target for treating depression and neurodegenerative disorders.
10-Hydroxydec-2-Enoic Acid Reduces Hydroxyl Free Radical-Induced Damage to Vascular Smooth Muscle Cells by Rescuing Protein and Energy Metabolism
Authors: Fan Pei , Sha Fangfang , Ma Chuan , Wei Qiaohong , Zhou Yaqi , Shi Jing , Fu Jiaojiao , Zhang Lu , Han Bin , Li Jianke
Published: June 2022

10-Hydroxydec-2-enoic acid (10-HDA), an unsaturated hydroxyl fatty acid from the natural food royal jelly, can protect against cell and tissue damage, yet the underlying mechanisms are still unexplored. We hypothesized that the neutralization of the hydroxyl free radical (•OH), the most reactive oxygen species, is an important factor underlying the cytoprotective effect of 10-HDA. In this study, we found that the •OH scavenging rate by 10-HDA (2%, g/ml) was more than 20%, which was achieved through multiple-step oxidization of the –OH group and C=C bond of 10-HDA. Moreover, 10-HDA significantly enhanced the viability of vascular smooth muscle cells (VSMCs) damaged by •OH (P < 0.01), significantly attenuated •OH-derived malondialdehyde production that represents cellular lipid peroxidation (P < 0.05), and significantly increased the glutathione levels in •OH-stressed VSMCs (P < 0.05), indicating the role of 10-HDA in reducing •OH-induced cytotoxicity. Further proteomic analyses of VSMCs identified 195 proteins with decreased expression by •OH challenge that were upregulated by 10-HDA rescue and were primarily involved in protein synthesis (such as translation, protein transport, ribosome, and RNA binding) and energy metabolism (such as fatty acid degradation and glycolysis/gluconeogenesis). Taken together, these findings indicate that 10-HDA can effectively promote cell survival by antagonizing •OH-induced injury in VSMCs. To the best of our knowledge, our results provide the first concrete evidence that 10-HDA-scavenged •OH could be a potential pharmacological application for maintaining vascular health.
Concomitant Medication Effects on Immune Checkpoint Inhibitor Efficacy and Toxicity
Authors: Sieber Brendan , Strauss Julius , Li Zihai , Gatti-Mays Margaret E.
Published: June 2022

There are multiple approved indications for immune checkpoint inhibitors (ICI) in patients with advanced solid tumors. Polypharmacy, defined as the use of ≥ 5 medications, is common among cancer patients. The impact of these non-oncologic medications on ICI efficacy or the development of side effects, specifically immune related adverse events (irAEs), is unclear. Recent clinical studies investigating the connection between concomitant medications and ICI efficacy have produced conflicting results. A systematic literature search was performed on PubMed to identify published clinical studies evaluating the impact of metformin, angiotensin-converting-enzyme inhibitor (ACEi), angiotensin receptor blockers (ARBs) and aspirin on ICI outcomes and toxicity in patients with advanced solid tumors. Clinical outcomes assessed included overall response rate, progression free survival, overall patient survival and the development of adverse events, specifically irAEs. A total of 10 retrospective studies were identified. Most studies reported a small percentage (range 8% to 42%) of their study population taking the concomitant medications of interest. Collectively, the studies did not identify a significant impact on ICI efficacy with concomitant medication use. In addition, the impact on irAEs was rarely reported in these studies but no significant group effect on reported toxicities or irAEs was found. This review provides a comprehensive analysis of current clinical studies and illustrates potential alterations in the tumor microenvironment induced by the medications. Given the high occurrence of polypharmacy among patients with advanced cancer, gaining a better understanding of the impact of non-oncologic medications on immunotherapy is necessary to improve ICI efficacy and reduce toxicity.
Transitional Pain Care in Quebec: Did We Forget Our Youths? A Brief Research Report
Authors: Kudrina Irina , Bartlett Gillian , Pagé M. Gabrielle , Shir Yoram , Tourian Leon , Choinière Manon , Vedel Isabelle
Published: June 2022

Adolescents and young adults (AYAs) represent a unique population with distinct psycho-social risks and care needs. About 10% of AYAs live with chronic pain (CP) and transition to adult pain care between 16 and 25 years of age. These transitions in care happen simultaneously with other bio-psycho-social changes and require flexible multi-disciplinary support models. As it stands, transitional pain care appears suboptimal, fragmented, and opportunistic in Quebec (Canada). The objective of this Brief Report is, therefore, to present our study findings and propose a multi-disciplinary transitional framework vision applicable to AYAs living with CP. Data were collected using a sequential-consensual qualitative design with a longitudinal participatory component. The consecutive stages of this work included an exploratory stage, semi-structured interviews with primary care providers, and inter-disciplinary deliberative stakeholder consultation groups. The deductive inductive thematic approach and the three-level Health Care Transition Research Consortium's theoretical framework were used to analyze the data. A representative group of stakeholders discussed findings from the first two steps, made fifteen actionable recommendations and formulated their vision of a transitional pain care model that can be further adapted in other settings. The study results present important insights into various psycho-social factors associated with transitional pain care for AYAs.
Appraising Neonatal Morbidity and Mortality in a Developing Country Categorized by Gestational Age Grouping and Implications for Targeted Interventions
Authors: Mokuolu Olugbenga Ayodeji , Adesiyun Omotayo Oluwakemi , Ibrahim Olayinka Rasheed , Suberu Habibat Dirisu , Ibrahim Selimat , Bello Surajudeen Oyeleke , Mokikan Moboni , Obasa Temitope Olorunshola , Abdulkadir Mohammed Baba
Published: June 2022

Introduction

Despite the relatively higher neonatal morbidity and mortality in developing countries, there are limited data on the detailed analysis of the burden in Nigeria. With a database of over 14,000 admissions, this study presents a compelling picture of the current trends disaggregated by their gestational age groups. It provides unique opportunities for better-targeted interventions for further reducing newborn mortality in line with SDG 3, Target 3.2.

Methods

This prospective observational study involved newborn babies admitted to the Neonatal Intensive Care Unit of the University of Ilorin Teaching Hospital, Kwara State, Nigeria, between January 2007 and December 2018. The outcome was the neonatal mortality rates. The exposure variables included birth weight, gestational age (preterm versus term), and clinical diagnosis. Frequencies were generated on tables and charts, and the trends or associations were determined.

Results

Of the 14,760 neonates admitted, 9,030 (61.2%) were term babies, 4,847 (32.8%) were preterm babies, and in 792 (5%) of the admissions, the gestational ages could not be determined. Males constituted a higher proportion with 55.9%, and the total number of deaths in the study period was 14.7%. The mortality ratio was highest among babies with a birth weight of less than 1,000 g (38.0%) and gestational age of less than 28 weeks (65.5%). The trend analysis showed that the mortality rate decreased from 17.8 to 13% over the 12 years, p-value < 0.0001. For term babies, mortality decreased by 45%, from 15.7% in 2007 to 8.7% in 2018, while the decline in mortality for preterm babies was 28.4%, from 25.7% in 2007 to 18.4% in 2018. For both categories, p-values were < 0.001. Regarding morbidity in term babies, asphyxia occurred in (1:3), jaundice (1:5), sepsis (1:6), and respiratory disorders (1:6) of admissions. For mortality, asphyxia occurred in (1:2), sepsis (1:5), jaundice (1:8), and respiratory disorders (1:10) of deaths. The leading causes of morbidity among preterm babies were asphyxia (1:4), sepsis (1:5), respiratory disorders (1:9), and jaundice (1.10). For mortality, their contributions were asphyxia (≈1:2); sepsis (1:5); respiratory disorders (1:9), and jaundice (1:10).

Conclusion

There was a marked improvement in neonatal mortality trends. However, severe perinatal asphyxia, sepsis, hyperbilirubinemia, and respiratory disorders were the leading conditions contributing to 75% of the morbidities and mortalities. Measures to further accelerate the reduction in neonatal morbidity and mortality are discussed.
Case Report: Coexistence of Anti-Glomerular Basement Membrane Disease, Membranous Nephropathy, and IgA Nephropathy in a Female PatientWith Preserved Renal Function
Authors: Qu Wei , Liu Nan , Xu Tianhua , Tian Binyao , Wang Meng , Li Yanqiu , Ma Jianfei , Yao Li
Published: June 2022

The coexistence of anti-glomerular basement membrane (GBM) disease, idiopathic membranous nephropathy (IMN), and IgA nephropathy in one patient is a very rare case, which has not yet been reported. Whether the three diseases are correlated and the underlying mechanism remain unknown. Herein, we report a 48-year-old female patient that was admitted because of proteinuria and abnormal renal function, which was diagnosed as anti-GBM disease, idiopathic membranous nephropathy, and IgA nephropathy by renal biopsy. The patient received treatment including high-dose methylprednisolone pulse therapy, plasma exchange, and intravenous infusion of both cyclophosphamide (CTX) and rituximab. In the follow-up, the titer of the anti-GBM antibody gradually decreased, renal function was restored, and urinary protein was reduced, without significant adverse effects.
Cocktail of Astragalus Membranaceus and Radix Trichosanthis Suppresses Melanoma Tumor Growth and Cell Migration Through Regulation of Akt-Related Signaling Pathway
Authors: Zhang Qiuyan , Gao Lei , Huang Songli , Liang Yuxi , Hu Jingyan , Zhang Yuan , Wei Shengli , Hu Xiuhua
Published: June 2022

Background: Malignant melanoma has high morbidity and mortality and limited treatment options. Traditional Chinese medicine has great potential in the clinical therapy of cancer, and the theory of compatibility is one core content of Chinese medical theory. Astragalus Membranaceus and Radix Trichosanthis are clinically effective for the treatment of various cancers.

Methods: We verified the effects of AMD, RTD, and their “cocktail” on melanoma model in vitro and in vivo and the mechanism of its effect on the Akt-related signaling pathway by network pharmacology, MTT, flow cytometry, LDH, SOD, MDA assay, and Western blot.

Results: The network pharmacology analysis indicated that the PI3K-Akt pathway plays a crucial role in the treatment of malignant melanoma with these two herbs. In addition, AMD, RTD, and their “cocktail” could inhibit the proliferation of A375 cells by reducing the survival rate in a concentration-dependent manner and by regulating the cell cycle, and the compatibility of two herbs also could inhibit melanoma growth. They could, respectively, induce apoptosis and inhibit migration by affecting the expression of Bcl-2, Bax, p53, snail, E-cadherin, and N-cadherin. Furthermore, LDH activity was decreased, while SOD increased and MDA reduced. The factors of the Akt-related signaling pathway, Akt and p-Akt, were decreased.

Conclusion: This study showed that AMD, RTD, and their “cocktail” could regulate cell proliferation, apoptosis, and metastasis in A375 cells through the suppression of the Akt-related signaling pathway, and the “cocktail” groups had detoxification and additive effects. The best compatibility of the two herbs also can inhibit tumor growth and metastasis in vivo.
Prediction of Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors With a Panel of Autoantibodies: Protocol of a Multicenter, Prospective, Observational Cohort Study
Authors: Les Iñigo , Pérez-Francisco Inés , Cabero María , Sánchez Cristina , Hidalgo María , Teijeira Lucía , Arrazubi Virginia , Domínguez Severina , Anaut Pilar , Eguiluz Saioa , Elejalde Iñaki , Herrera Alberto , Martínez Mireia
Published: June 2022

Introduction: Immune checkpoint inhibitor (ICI) therapy is markedly improving the prognosis of patients with several types of cancer. On the other hand, the growth in the use of these drugs in oncology is associated with an increase in multiple immune-related adverse events (irAEs), whose optimal prevention and management remain unclear. In this context, there is a need for reliable and validated biomarkers to predict the occurrence of irAEs in patients treated with ICIs. Thus, the main objective of this study is to evaluate the diagnostic performance of a sensitive routinely available panel of autoantibodies consisting of antinuclear antibodies, rheumatoid factor, and antineutrophil cytoplasmic antibodies to identify patients at risk of developing irAEs.

Methods and Analysis: A multicenter, prospective, observational, cohort study has been designed to be conducted in patients diagnosed with cancer amenable to ICI therapy. Considering the percentage of ICI-induced irAEs to be 25% and a loss to follow-up of 5%, it has been estimated that a sample size of 294 patients is required to detect an expected sensitivity of the autoantibody panel under study of 0.90 with a confidence interval (95%) of no less than 0.75. For 48 weeks, patients will be monitored through the oncology outpatient clinics of five hospitals in Spain. Immune-related adverse events will be defined and categorized according to CTCAE v. 5.0. All the patients will undergo ordinary blood tests at specific moments predefined per protocol and extraordinary blood tests at the time of any irAE being detected. Ordinary and extraordinary samples will be frozen and stored in the biobank until analysis in the same autoimmunity laboratory when the whole cohort reaches week 48. A predictive model of irAEs will be constructed with potential risk factors of immune-related toxicity including the autoantibody panel under study.

Ethics and Dissemination: This protocol was reviewed and approved by the Ethical Committee of the Basque Country and the Spanish Agency of Medicines and Medical Devices. Informed consent will be obtained from all participants before their enrollment. The authors declare that the results will be submitted to an international peer-reviewed journal for their prompt dissemination.
Constructions of Unextendible Special Entangled Bases
Authors: Wang Yan-Ling
Published: June 2022

Unextendible product basis (UPB), a set of incomplete orthonormal product states whose complementary space has no product state, is very useful for constructing bound entangled states. Naturally, instead of considering the set of product states, Bravyi and Smolin considered the set of maximally entangled states. They introduced the concept of unextendible maximally entangled basis (UMEB), a set of incomplete orthonormal maximally entangled states whose complementary space contains no maximally entangled state [Phys. Rev. A 84, 042,306 (2011)]. An entangled state whose nonzero Schmidt coefficients are all equal to 1/k is called a special entangled state of “type k”. In this paper, we introduce a concept named special unextendible entangled basis of “type k” which generalizes both UPB and UMEB. A special unextendible entangled basis of “type k” (SUEBk) is a set of incomplete orthonormal special entangled states of “type k” whose complementary space has no special entangled state of “type k”. We present an efficient method to construct sets of SUEBk. The main strategy here is to decompose the whole space into two subspaces such that the rank of each element in one subspace can be easily upper bounded by k while the other one can be generated by two kinds of the special entangled states of “type k”. This method is very effective when k = pm ≥ 3 where p is a prime number. For these cases, we can obtain sets of SUEBk with continuous integer cardinality when the local dimensions are large.
Comparing Quasi-Parallel and Quasi-Perpendicular Configuration in the Terrestrial Magnetosheath: Multifractal Analysis
Authors: Gurchumelia Alexandre , Sorriso-Valvo Luca , Burgess David , Yordanova Emiliya , Elbakidze Khatuna , Kharshiladze Oleg , Kvaratskhelia Diana
Published: June 2022

The terrestrial magnetosheath is characterized by large-amplitude magnetic field fluctuations. In some regions, and depending on the bow-shock geometry, these can be observed on several scales, and show the typical signatures of magnetohydrodynamic turbulence. Using Cluster data, magnetic field spectra and flatness are observed in two intervals separated by a sharp transition from quasi-parallel to quasi-perpendicular magnetic field with respect to the bow-shock normal. The multifractal generalized dimensions Dq and the corresponding multifractal spectrum f(α) were estimated using a coarse-graining method. A p-model fit was used to obtain a single parameter to describe quantitatively the strength of multifractality and intermittency. Results show a clear transition and sharp differences in the intermittency properties for the two regions, with the quasi-parallel turbulence being more intermittent.
Vitamin D Receptor-Dependent Protective Effect of Moderate Hypoxia in a Mouse Colitis Model
Authors: Wang Zheng , Yang Hong , Lv Hong , Huang Changzhi , Qian Jiaming
Published: June 2022

Although hypoxia is important for maintaining the intestinal barrier, its effect on the barrier during acute colitis and the underlying mechanisms are not fully understood. To explore the influence of hypoxia in dextran sulfate sodium (DSS)-induced colitis mice and the role of hypoxia-inducible factor (HIF) and vitamin D receptor (VDR) in the process. Colitis mice were subjected to hypoxia to detect intestinal barrier function changes. And the mechanisms were explored in vitro. First, compared with colitis mice without hypoxia stimulation, those with hypoxia stimulation showed significantly decreased pathological damage and improved permeability of the intestinal barrier. The expression of tight junction proteins (occludin, ZO-1), HIF-1α as well as VDR was up-regulated in colitis mice with hypoxia stimulation. However, in VDR gene knockout (KO)colitis mice, hypoxia treatment showed no protective effect, suggesting the VDR dependency of this effect. Similarly although hypoxia stimulation could enhance the single-layer epithelial transmembrane electrical resistance in DLD-1 and NCM460 cells, these effects disappeared in VDR-knockdown cells. Furthermore, over-expression of HIF-1α in DLD-1 and NCM460 increased the expression of VDR, whereas HIF-1α-knockdown reduced the VDR expression directly. Chromatin immunoprecipitation and luciferase assays confirmed that HIF-1α can bind to the promoter region of the VDR gene under hypoxia. Finally, compared with their wild-type siblings, VDR-KO mice showed reduced abundance of anaerobic bacteria and SCFA-producing bacteria. Hypoxia was protective against DSS-induced colitis, and VDR is instrumental in it. Furthermore, HIF-1α-VDR mediates the effect of hypoxia on the barrier function. Moreover, intestinal flora may be an important link between hypoxia and VDR.
Time Series Transcriptomic Analysis by RNA Sequencing Reveals a Key Role of PI3K in Sepsis-Induced Myocardial Injury in Mice
Authors: Yan Xiao , Zhang Yun-Long , Han Xiao , Li Pang-Bo , Guo Shu-Bin , Li Hui-Hua
Published: June 2022

Septic cardiomyopathy is the main complication and cause of death of severe sepsis with limited therapeutic strategy. However, the molecular mechanism of sepsis-induced cardiac injury remains unclear. The present study was designed to investigate differentially expressed genes (DEGs) involved in the pathogenesis of septic cardiomyopathy induced by cecal ligation and puncture (CLP) in mice. Male C57BL/6J mice (8–10 weeks old) were subjected to CLP with 21-gauge needles for 24, 48, and 72 h. Myocardial function was assessed by echocardiography. The pathological changes of the heart were evaluated by hematoxylin and eosin as well as immunohistochemical staining. Time series RNA sequencing was utilized to investigate the gene expression profiles. CLP surgery resulted in a significant decrease of animal survival rate and left ventricle contractile function, and an increase in cardiac dilation and infiltration of proinflammatory cells including Mac-2+ macrophages in a time-dependent manner. RNA sequencing identified 5,607 DEGs in septic myocardium at 24, 48, and 72 h after CLP operation. Moreover, gene ontology analysis revealed that these DEGs were mainly associated with the biological processes, including cell adhesion, immune system process, inflammatory response, and positive regulation of cell migration. KEGG pathway enrichment analysis indicated that Staphylococcus aureus infection, osteoclast differentiation, leishmaniasis, and ECM-receptor interaction were significantly altered in septic hearts. Notably, Pik3r1 and Pik3r5 were localized in the center of the gene co-expression network, and were markedly upregulated in CLP-induced septic myocardium. Further, blocking PI3Kγ by the specific inhibitor CZC24832 significantly protected against sepsis-induced cardiac impairment. The present study uncovers the gene expression signatures of CLP-induced myocardial injury and sheds light on the role of Pik3r5 in septic cardiomyopathy.
A Diaporthe Fungal Endophyte From a Wild Grass Improves Growth and Salinity Tolerance of Tritordeum and Perennial Ryegrass
Authors: Toghueo Rufin M. K. , Zabalgogeazcoa Iñigo , Pereira Eric C. , Vazquez de Aldana Beatriz R.
Published: June 2022

Some microbiome components can provide functions that extend the capabilities of plants, increasing the environmental adaptability and performance of holobionts. Festuca rubra subsp. pruinosa is a perennial grass adapted to rocky sea cliffs, where soil and nutrients are very limited, and exposure to salinity is continuous. This study aimed to investigate if a Diaporthe fungal endophyte belonging to the core microbiome of Festuca rubra roots could improve the performance of two agricultural grasses. In a greenhouse experiment, plants of tritordeum (Triticum durum x Hordeum chilense) and perennial ryegrass (Lolium perenne) were inoculated with Diaporthe strain EB4 and subjected to two salinity conditions (0 and 200 mM NaCl). Biomass production, mineral elements, proline, hormone profiles, antioxidant capacity, and total phenolic compounds were examined in plants, and fungal functions potentially related to the promotion of plant growth were determined. The inoculation with Diaporthe promoted plant growth of both grasses, increasing leaf biomass (84% in tritordeum and 29% in perennial ryegrass), root biomass, nutrient content (N, Ca, Mg, and Fe), and the production of indole 3-acetic acid, regardless of the salinity treatment. Improved growth and nutrient uptake might occur because Diaporthe produces several extracellular enzymes capable of recycling organic nutrient pools. In addition, the fungus produced indole 3-acetic acid in vitro and modulated the production of this phytohormone in the plant. Under salinity, the activity of Diaporthe ameliorated the stress, increasing proline, nutrient uptake in roots, gibberellins, and indole 3-acetic acid, which in turn results into improved growth. Thus, this fungus can transfer to alternative hosts some advantages useful at its original habitat.
Application of the Recognition Algorithm of News Sentiment Dissemination Tendency Based on Multi-Mode Information Fusion
Authors: Chiba Makiko
Published: June 2022

Since the popularity of the Internet, it is now customary for people to browse the news on the Internet. In the process of browsing news, there are often comments to express and spread personal emotions. This has become a very popular way of spreading news sentiment. This research is based on information fusion technology to realize the research on the identification algorithm of news sentiment communication tendency. Based on the research results of many scholars, this article first elaborates the definition, method, and framework of information fusion technology. In this paper, the corresponding technology is selected, and then in the research of the tendency recognition algorithm, an emotion tendency recognition algorithm based on the integrated probabilistic reasoning model is proposed. The algorithm proved its effectiveness and robustness through experiments. Finally, the experimental results show that in all the parameter combination conditions, the algorithm can not only reduce the feature dimension but also ensure the accuracy of recognition under the probability of 89%.
Predictors of Persistent Participation in Youth Sport: A Systematic Review and Meta-Analysis
Authors: Zhang Meng , Wang Xiao-Chun , Shao Bin
Published: June 2022

There are many factors affecting decisions to persistent participation in sports and various approaches have been used to frame these antecedents. The aim of this paper was to systematically review and quantify the primary factors of persistent participation and to assess their respective strengths of association with persistent participation in youth sport. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines, a comprehensive search was implemented on 31st December 2021 in five databases and meta-analytic procedures were applied to data from studies meeting inclusion criteria. The results revealed that sports enjoyment (meta r = 0.45, 95%CI [0.42, 0.49]) was highly correlated with persistent intention, while persistent intention (SMD = 1.13, 95%CI [0.70, 1.56]) was highly correlated with persistent behavior. In addition, parental support, coach support, peer support, basic psychological needs and sports competence were the primary factors associated with persistent intention and persistent behavior, respectively. This study identified the key factors related to persistent participation and provide a complete understanding of children and adolescents' decisions to continue their participation in organized sports. Referring to the key factors, it can provide information for sports clubs and policy makers to develop strategies to increase youth participation in organized sport.

Systematic Review Registration

PROSPERO, identifier: CRD42021229397.
Animal-Assisted Interventions With Dogs in Special Education—A Systematic Review
Authors: Meixner Jana , Kotrschal Kurt
Published: June 2022

Dogs are becoming increasingly popular in pedagogical settings. Particularly children with special educational needs are believed to benefit from dog-assisted interventions. However, reliable evidence for supporting such claims is still scarce and reports on the effectiveness of this approach are often anecdotal. With our review we aim at evaluating the literature to answer the question, whether dog-assisted interventions in an educational setting can help children with special educational needs to improve and to develop their emotional, social and cognitive skills. Following the PRISMA Guidelines, the literature was systematically searched for experimental studies until February 2021. Eighteen studies were finally included, which varied greatly in type of intervention, outcomes measured, sample sizes, and scientific quality, which precluded a formal meta-analysis. Hence, we resorted to a narrative synthesis. Overall, the studies report mixed results in the different functional domains of stress reduction, motivation, social skills, cognitive abilities, reading abilities, social conduct, and mental wellbeing. No study reported any negative effects of the intervention. The most unequivocal evidence comes from studies on dogs’ effects on physiological stress response in challenging situations and on motivation and adherence to instructions, reporting significantly lower levels of cortisol in both children and pedagogues in the presence of dogs, as well as increased motivation to learn and participate. Findings for other outcomes, academic or social, however, remain inconclusive. Data on long-term effects are lacking altogether. Still, this review indicates the potentials of dog-assisted interventions in special pedagogy, particularly towards supporting a calm and trustful social atmosphere.
Toward the Impact of English as a Foreign Language Teachers’ Grit and Self-Efficacy on Their Burnout
Authors: Zhou Jinghan
Published: June 2022

Due to the adverse effects of teachers’ burnout on their professional performance, remarkable attention has been devoted to this mental state and its negative predictors. In this regard, multiple empirical research has been carried out to assess the effects of grit and self-efficacy as negative predictors of teacher burnout. Yet, no empirical or review study has delved into the impact of these variables at the same time. The current study attempts to fill this gap by delineating the impact of English as a Foreign Language (EFL) teachers’ grit and self-efficacy on their burnout. The significant role of grit and self-efficacy in curbing EFL teachers’ burnout was illustrated using theoretical and empirical evidence. The pedagogical implications are also offered.
The Effects of Physiological Demands on Visual Search Behaviours During 2 vs. 1 + GK Game Situations in Football: An in-situ Approach
Authors: Casanova Filipe , Esteves Pedro T. , Padilha Maickel Bach , Ribeiro João , Williams Andrew Mark , Garganta Júlio
Published: June 2022

We examined the effect of physiological workload on gaze behaviour during defensive performance in 2 vs. 1 +goalkeeper game situations in football. Twenty-two players were assigned to either a high- or low-performing group based on a validated measure of tactical performance. A total of 12 game sequences (trials) were presented under high- and low-workload conditions. At the end of each sequence, participants were asked to indicate their perceived exertion using the Rating Scale of Mental Effort and the Borg Scale. The low- and high-workload conditions were defined when the players achieved 60 and 90% of their maximal heart rate, respectively, as per their performance in the Yo-Yo Intermittent Recovery Test. Visual search behaviours were recorded using Tobii Pro eye-movement registration glasses. Players reported higher rates of perceived exertion on the high- compared to low-workload condition. Participants in the low-performing group increased their average fixation duration and decreased the number of fixations and number of fixation locations from the low- to high-workload conditions. The low- and high-performing groups displayed different visual search strategies with regards the areas of interest fixated upon. Participants in the high-performing group focused on the SpaceFrontPlayer, followed by Ball, and AnotherOpponent. The low-performing group spent more time focusing on the SpaceFrontPlayer and SpacePlayer than Ball and AnotherOpponent. It appears that physiological workload and tactical expertise interact in constraining visual search behaviours in football players. Coaches and practitioners should consider ways to manipulate individual and task constraints while attending to the close interplay between physiological workload, visual behaviour, and tactical performance during practise.
Statistical Assumptions and Reproducibility in Psychology: Data Mining Based on Open Science
Authors: Zhang Wenqing , Yan Shu , Tian Bo , Fei Dingzhou
Published: June 2022

The failures of reproducibility in psychology (or other social sciences) can be investigated by tracing their logical chains, from statistical hypothesis to their conclusion. This research starts with the normality hypothesis, the homoscedasticity hypothesis, and the robust hypothesis and uses the R language to simulate and analyze the original data of 100 studies in Estimating the Reproducibility of Psychological Science to explore the influence of the premise hypothesis on statistical methods on the reproducibility of psychological research. The results indicated the following: (1) the answer to the question about psychological studies being repeatable or not relates to the fields to which the subjects belonged, (2) not all the psychological variables meet the normal distribution hypothesis, (3) the t-test is a more robust tool for psychological research than the Analysis of Variance (ANOVA), and (4) the robustness of ANOVA is independent of the normality and variance congruence of the analyzed data. This study made us realize that the repeatable study factors in psychology are more complex than we expected them to be.
Assessment of Effect of Perceived Social Support on School Readiness, Mental Wellbeing, and Self-Esteem: Mediating Role of Psychological Resilience
Authors: Shi Yefei
Published: June 2022

Objective of this study is to investigate the impact of perceived social support on the self-esteem, mental wellbeing, and school readiness of left-behind (LB) children. It further aims at understanding the mediating role of psychological resilience between the relationships of perceived social support and self-esteem, mental wellbeing, and school readiness. For this purpose, population frame of the LB children between the ages of 8–12 years in Mainland China was taken. The sample size of 335 was taken to reach the findings through partial least square (PLS) structural equation modeling. The SmartPLS has been used to analyze the data. The results obtained in this study have shown that the perceived social support plays a very significant role in enhancing the mental wellbeing, self-esteem, and school readiness of the LB children. It has also been found that the perceived social support plays a positive role in the psychological resilience. Furthermore, it has also been found that the psychological resilience is an important predictor of self-esteem and school readiness. Further, the psychological resilience has proved to be significant mediator between the relationship of the perceived social support and self-esteem; and also between the relationship of the perceived social support and school readiness.